IRINOTECAN HYDROCHLORIDE 
■IRINOTECAN LIPOSOME INJECTION
Pronounciation
- (eye-rih-noh-TEE-kan hy-droh-KLOR-eyed) (eye-rih-noh-TEE-kan LIP-oh-sohm in-JEK-shun)
Trade Name(s)
- Camptosar, CPT-11
ONIVYDE
IRINOTECAN HYDROCHLORIDE ■IRINOTECAN LIPOSOME INJECTION
Pronounciation
Trade Name(s)
Both formulations (conventional and ONIVYDE):
Verify pregnancy status.
Dexamethasone 10 mg and a 5-HT3 blocker (e.g., ondansetron [Zofran] or granisetron [Kytril]) should be given on the day of treatment. Begin at least 30 minutes before giving irinotecan. Anticholinergic premedication: In addition, prophylactic or therapeutic atropine may be indicated in patients experiencing cholinergic symptoms. See Monitor.
First-line treatment of colorectal cancer:
Premedication as described above is recommended. Initiate regimen with the dose of irinotecan over 90 minutes. Follow immediately with the dose of leucovorin calcium (see leucovorin calcium monograph). Follow the leucovorin immediately with the dose of fluorouracil (see fluorouracil monograph). Doses and modified dosing recommendations are outlined in the chart Combination-Agent Dosage Regimens and Dose Modifications. Doses of irinotecan and fluorouracil may require modification based on toxicity.
See the following chart, Combination-Agent Dosage Regimens and> Dose Modifications, and see Dose Adjustments, combination therapy, and/or package insert.
aDose reductions beyond dose level –2 by decrements of ~20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Treatment of colorectal cancer after failure of treatment with fluorouracil: Irinotecan:
Administer as an infusion based on the following chart, Irinotecan Single-Agent Regimens and Dose Modifications. See Premedication. After adequate recovery, additional doses may be repeated in a similar cycle and continued indefinitely in patients who attain a response or in those whose disease remains stable.
aSubsequent 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. bSubsequent doses may be adjusted as low as 200 mg/M2 in 50 mg/M2 decrements depending upon individual patient tolerance. cProvided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. | ||||||||||||||||||||||||||||||
Onivyde (Liposomal Irinotecan)
Do not substitute ONIVYDE for other drugs containing irinotecan HCl.
Administer ONIVYDE before administering leucovorin and fluorouracil.
Administer a corticosteroid and an antiemetic 30 minutes before the ONIVYDE infusion.
Metastatic adenocarcinoma of the pancreas:
70 mg/M2 as an IV infusion over 90 minutes every 2 weeks. In patients known to be homozygous for the UGT1A1*28 allele, the recommended starting dose is 50 mg/M2 as an IV infusion over 90 minutes. Increase dose to 70 mg/M2 as tolerated in subsequent cycles. In clinical trials, a dose of 70 mg/M2 ONIVYDE was followed by leucovorin 400 mg/M2 IV over 30 minutes, followed by fluorouracil 2,400 mg/M2 IV over 46 hours every 2 weeks.
A reduction in the starting dose by one dose level may be required in patients with a performance status of 2, in patients who have previously received pelvic/abdominal irradiation, and in patients with increased bilirubin levels; see Elderly. Available information insufficient to recommend a dose for patients with bilirubin greater than 2 mg/dL. ■ Consider decreasing the starting dose by at least one level of irinotecan when administered in combination with other agents or as a single agent to a patient known to be homozygous for the UGT1A1*28 allele (an allele is an alternative form of a gene). The precise dose reduction for this patient population is not known. Subsequent dose modification should be based on individual patient tolerance as outlined in the following charts. Heterozygous patients (patients who carry one variant allele) appear to tolerate normal starting doses. ■ See Precautions.
Decrease dose based on toxicity as described in the following chart.
aNational Cancer Institute Common Terminology Criteria (Version 1.0). bRelative to the starting dose of the previous cycle. dExcludes alopecia, anorexia, asthenia. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reduce dose based on toxicity levels in the following chart, Guidelines for Irinotecan Dose Adjustments in Single-Agent Schedules. The most common reasons for dose reduction are late diarrhea, neutropenia, and leukopenia.
aAll dose modifications should be based on the worst preceding toxicity. bNational Cancer Institute Common Terminology Criteria (Version 1.0). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. ■ Withhold ONIVYDE for an absolute neutrophil count below 1,500/mm3 or neutropenic fever.■ Withhold ONIVYDE for diarrhea of Grade 2 to 4 severity.■ See the following chart for dose modifications recommended for adverse reactions.
aNCI CTCAE, v 4.0, National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0. | |||||||||||||||||||||||||||||
For recommended dose modifications for fluorouracil (5-FU) and/or leucovorin (LV), refer to their monographs and/or full prescribing information.
Specific techniques required; see Precautions.
Available in single-dose vials in 2-mL, 5-mL, and 15-mL sizes with a concentration of 20 mg/mL. Must be diluted for infusion with D5W (preferred) or NS to concentrations between 0.12 and 2.8 mg/mL. Usually diluted in 250 to 500 mL D5W.
Available in a single-dose vial containing 43 mg irinotecan free base at a concentration of 4.3 mg/mL. It is a slightly yellow, opaque, liposomal dispersion. Withdraw the calculated volume from the vial and dilute in 500 mL D5W or NS. Mix by gentle inversion. Protect diluted solution from light.
Conventional irinotecan: Specific information not available. ONIVYDE: Do not use in-line filters.
Conventional irinotecan: Packaged in a blister pack to protect against accidental breakage and leakage. Store in carton protected from light at CRT. When mixed with D5W, is chemically and physically stable for 48 hours if refrigerated and in ambient fluorescent lighting and for 24 hours at CRT. Do not refrigerate if mixed with NS; a precipitate may form. Stable for 24 hours at CRT when mixed in NS. Because of the risk of microbial contamination, the manufacturer recommends that solutions mixed in D5W or NS be used within 4 hours if kept at RT. However, if reconstitution and dilution are performed under strict aseptic conditions (e.g., on a laminar air flow bench), the solution should be used (i.e., infusion completed) within 12 hours at RT or 24 hours (D5W) if refrigerated. Avoid freezing.
Refrigerate in carton at 2° to 8° C (36° to 46° F) to protect from light. Do not freeze. Administer diluted solution within 4 hours of preparation when stored at RT or within 24 hours if refrigerated. Allow diluted solution to come to RT before administration. Do not freeze. Discard unused portion.
Manufacturer states, “Other drugs should not be added to the infusion solution.”
Other sources suggest a few compatibilities based on concentration and manufacturer; consult a pharmacist.
Compatibility information not available from manufacturer; consult a pharmacist.
A semi-synthetic derivative of camptothecin. An alkaloid extract from plants such as Camptotheca acuminata. A class of antineoplastic agent that inhibits the enzyme topoisomerase I required for DNA replication. Together with its active metabolite SN-38 it causes cell death by damaging DNA produced during the S-phase of the cell cycle. Maximum plasma SN-38 levels are reached within 1 hour of infusion end. Terminal half-life of irinotecan is about 6 to 12 hours; SN-38 is 10 to 20 hours. Irinotecan is moderately bound to plasma proteins (30% to 68%), but SN-38 is highly bound (95%). Metabolic conversion of irinotecan to SN-38 primarily occurs in the liver. SN-38 is conjugated to a glucuronide metabolite by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1). Approximately 25% to 50% excreted through bile and urine.
A topoisomerase 1 inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1 relieves torsional strain in DNA by inducing single-strand breaks. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase 1–DNA complex and prevent re-ligation of the single-strand breaks, leading to cell death. 95% of irinotecan remains liposome-encapsulated. Terminal elimination half-life is approximately 25.8 hours. Protein binding is less than 0.44% of the total irinotecan in ONIVYDE. Metabolism and excretion of irinotecan liposome have not been evaluated.
As a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum. ■ For patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
Treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Used in combination with fluorouracil and leucovorin.
Not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.
History of hypersensitivity to conventional or liposomal formulations of irinotecan or any of their components.
Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1308. ■ Administered by or under the direction of the physician specialist. ■ Adequate diagnostic and treatment facilities must be available. ■ Can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. ■ Patients who are homozygous for the UGT1A1*28 allele have decreased UGT1A1 enzyme activity. This leads to a higher exposure to SN-38 and an increased risk for neutropenia; see Dose Adjustments. A laboratory test is available to determine the UGT1A1 status of patients. ■ Can cause severe or life-threatening diarrhea that may be either early or late onset (see discussion under individual agents).■ Severe hypersensitivity reactions, including anaphylaxis, have been reported. ■ Interstitial pulmonary disease has been reported and can be fatal. Use caution in patients with pleural effusions and/or impaired pulmonary function. Risk factors may include pre-existing lung disease or use of pneumotoxic agents (e.g., amiodarone [Nexterone]), radiation therapy, or colony-stimulating factors; see Antidote.
Can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Both forms may be severe. Interrupt therapy and reduce subsequent doses if severe diarrhea occurs; seeDose Adjustments. Late diarrhea may be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients must not be treated with irinotecan until resolution of any bowel obstruction. ■ May cause severe myelosuppression. Bacterial, viral, and fungal infections have occurred. Deaths due to sepsis following severe neutropenia have been reported. Patients who have previously received pelvic/abdominal irradiation, patients with a baseline serum total bilirubin level of 1 mg/dL or more, or patients with deficient glucuronidation of bilirubin (e.g., patients with Gilbert syndrome) may be at a greater risk of myelosuppression. ■ Hepatic dysfunction may impair the metabolism of both irinotecan and SN-38. Patients with a bilirubin of 1 to 2 mg/dL are at increased risk for developing Grade 3 or 4 neutropenia. The manufacturer does not recommend a dose for patients with a bilirubin greater than 2 mg/dL and states that insufficient information is available to recommend dosing. ■ Use with caution in patients with renal impairment. Has not been studied. Not recommended for use in patients on dialysis. ■ Renal impairment and acute renal failure have been reported; see Monitor. ■ Use caution in elderly patients (may have an increased incidence and severity of diarrhea). ■ Use caution in patients with poor performance status. Patients with a baseline performance status of 2 had higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths than patients with a performance status of 0 or 1. ■ Contains sorbitol. Do not use in patients with hereditary fructose intolerance. ■ The regimen of 5-FU/LV (administered for 4 to 5 days every 28 days) should not be used in combination with irinotecan outside a carefully controlled, well-designed clinical study. Regimen has caused increased toxicity and death. ■ See Monitor.
Severe or life-threatening neutropenia, neutropenic fever or sepsis, and fatal neutropenic sepsis have occurred. The incidence of Grade 3 or 4 neutropenia was higher among Asian patients compared with White patients in clinical trials. Withhold ONIVYDE for absolute neutrophil count below 1,500/mm3 or neutropenic fever; see Monitor. ■ Severe diarrhea has occurred in patients receiving liposomal irinotecan in combination with fluorouracil and leucovorin. Withhold ONIVYDE for diarrhea of Grade 2 to 4 severity. An individual patient may experience both early- and late-onset diarrhea; see Monitor. ■ Do not administer ONIVYDE to patients with bowel obstruction.■ Not studied in patients with hepatic impairment. ■ No pharmacokinetic effects noted in patients with mild to moderate renal impairment. Data for severe renal impairment are insufficient.
Prophylactic antiemetics are recommended; see Usual Dose. To reduce nausea and vomiting and increase patient comfort after initial dosing, additional antiemetics should be available (e.g., prochlorperazine, ondansetron, granisetron). ■ Monitor vital signs. ■ Obtain an accurate bowel history to evaluate changes in bowel habits after administration of irinotecan. ■ Monitor for “early” diarrhea. Occurs during or within 24 hours of irinotecan administration and is cholinergic in nature. Usually transient and only infrequently is severe. May be accompanied by other cholinergic symptoms (e.g., abdominal cramping, bradycardia, diaphoresis, flushing, increased salivation, lacrimation, miosis, rhinitis). Patients who have a cholinergic reaction to irinotecan will probably have similar reactions to subsequent doses. Atropine 0.25 to 1 mg IV or SC may be considered for treatment or for prophylactic use unless clinically contraindicated.■ Monitor for “late” diarrhea (more than 24 hours after irinotecan administration), which probably results from cytotoxic effects on GI epithelium. May be prolonged; may cause dehydration, electrolyte imbalances, or sepsis; and can be life threatening. At first onset, give loperamide 4 mg; give 2 mg every 2 hours (4 mg every 4 hours during the night) until diarrhea-free for a minimum of 12 hours. Monitor carefully; replace fluids and electrolytes as needed; see Patient Education. ■ Maintain adequate hydration. Orthostatic hypotension or dizziness may indicate dehydration. ■ Initiate antibiotic therapy in patients who develop ileus, fever, or severe neutropenia.■ Be alert for signs of bone marrow suppression or infection. Prophylactic antibiotics may be indicated pending results of C/S in a febrile neutropenic patient. ■ Monitor for thrombocytopenia (platelet count less than 50,000/mm3). Initiate precautions to prevent excessive bleeding (e.g., inspect IV sites, skin, and mucous membranes; use extreme care during invasive procedures; test urine, emesis, stool, and secretions for occult blood). ■ Monitor for S/S of a hypersensitivity reaction (e.g., chest pain, chills, dizziness, dyspnea, fever, flushing, hypotension, nausea, pruritus, rash, urticaria) or an infusion reaction (e.g., asthenia, chills, fatigue, fever, vomiting). ■ Monitor for S/S of interstitial lung disease. Withhold therapy in patients with new or progressive cough, dyspnea, and fever pending diagnostic evaluation; see Precautions and Antidote. ■ See Dose Adjustments.
Obtain a WBC with differential, hemoglobin, and platelet count before each dose. ■ Obtain baseline electrolytes and liver function tests. Repeat as indicated. ■ Not a vesicant, but monitor injection site for inflammation and/or extravasation. ■ If late-onset diarrhea develops, subsequent weekly chemotherapy treatments should be delayed until pretreatment bowel function has returned for at least 24 hours without the need for antidiarrheal medication. If Grade 2, 3, or 4 late diarrhea recurs, subsequent doses of irinotecan should be decreased; see Dose Adjustments. ■ Avoid use of diuretics and laxatives in patients with diarrhea. ■ Monitor renal function and hydration status. Rare cases of renal impairment or acute renal failure have been reported, usually in patients who became dehydrated from vomiting and/or diarrhea.
ONIVYDE (Liposomal Irinotecan):
Prophylactic antiemetics and corticosteroids are recommended 30 minutes before ONIVYDE infusion. ■ Monitor CBC on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1,500/mm3 or if neutropenic fever occurs. Resume when the ANC is 1,500 mm3 or above; see Dose Adjustments. ■ Monitor for infusion reactions occurring on the day of administration. S/S have included periorbital edema, pruritus, rash, and urticaria.
Both formulations: Review patient counseling information. ■ Report any unusual or unexpected symptoms or side effects as soon as possible. ■ Report black or bloody stools, diarrhea not under control within 24 hours, dry mouth, fever or chills, inability to retain oral fluids due to nausea and vomiting, infections, symptoms of dehydration (e.g., light-headedness, dizziness, fainting), urine changes, or vomiting immediately; each must be treated promptly. Have loperamide available. Dose of loperamide prescribed for late diarrhea is higher than the usual dose recommendation. Limit use at this dose to 48 hours to avoid risk of paralytic ileus. ■ May cause dizziness or visual disturbances (usually within 24 hours of administration); use caution in tasks that require alertness. ■ Compliance with regimen imperative (e.g., taking temperature, obtaining lab work, adequate rest, nourishment, and fluids). ■ Both formulations: Effective birth control required. ONIVYDE: Advise females of reproductive potential to use effective contraception during treatment and for 1 month after the final dose. Advise males with female partners of reproductive potential to use condoms during treatment and for 4 months after the final dose. ■ Inform health care professionals of any problems with previous treatments. ■ See Appendix D.
Avoid pregnancy. May cause fetal harm. ■ Discontinue breast-feeding during treatment and for 1 month after the final dose. ■ Safety and effectiveness for use in pediatric patients not established.
Half-life slightly extended. ■ Reduce starting dose by one dose level to 300 mg/M2 in patients 70 years and older in the single-agent, once-every-3-weeks regimen. No change in the starting dose is recommended for elderly patients receiving the weekly dose schedule of irinotecan. See Usual Dose and Dose Adjustments. ■ Risk of early and late diarrhea increased in the elderly. ■ Monitor carefully; may dehydrate more quickly from diarrhea. Begin loperamide therapy promptly. Avoid laxatives.
No overall differences in safety and effectiveness observed between the elderly and younger patients.
Interaction of conventional irinotecan and/or ONIVYDE with other drugs has not been adequately studied.
Concomitant use with CYP3A4 enzyme–inducing anticonvulsants and strong CYP3A4 inducers may increase the metabolism of irinotecan, which decreases concentrations and effectiveness. Avoid use of strong CYP3A4 inducers (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort) if possible. Substitute non–enzyme inducing therapies at least 2 weeks before initiation of irinotecan therapy. ■ CYP3A4 inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) and UGT1A1 inhibitors (e.g., atazanavir, gemfibrozil, indinavir, ketoconazole) may decrease metabolism, which increases serum concentrations and the risk of toxicity. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors if possible. Discontinue at least 1 week before starting irinotecan therapy. ■ Do not administer live virus vaccines to patients receiving antineoplastic drugs.
Additive bone marrow suppression may occur with radiation therapy and/or other bone marrow–suppressing agents (e.g., azathioprine, chloramphenicol, melphalan). Dose reduction may be required. ■ Concurrent administration with irradiation is not recommended. ■ Use caution or withhold diuretics (e.g., furosemide) and laxatives during treatment; may increase risk of dehydration secondary to vomiting and/or diarrhea.
Myelosuppression (anemia, leukopenia, neutropenia) and diarrhea (“early” [e.g., abdominal cramping or pain, diaphoresis] or “late”) occur in patients and are the most common dose-limiting toxicities with irinotecan administration.
Common adverse reactions (greater than 30%) observed in combination therapy are abdominal pain, abnormal bilirubin, alopecia, anemia, anorexia, asthenia, constipation, diarrhea, fever, infection, leukopenia (including lymphocytopenia), mucositis, nausea, neutropenia, pain, thrombocytopenia, and vomiting.
Common adverse reactions (greater than 30%) observed in single-agent therapy are abdominal pain, alopecia, anemia, anorexia, asthenia, constipation, diarrhea, fever, leukopenia (including lymphocytopenia), nausea, neutropenia, weight loss, and vomiting.
Other reported side effects with irinotecan include abdominal bloating, back pain, chills, confusion, coughing, dehydration, dizziness, dyspepsia, dyspnea, edema, exfoliative dermatitis, flatulence, flushing, headache, hypersensitivity reactions (including anaphylaxis), hyponatremia, hypotension, increased alkaline phosphatase and AST, increased bilirubin, insomnia, interstitial pulmonary disease, muscular contractions or cramps, myocardial infarction, neutropenic fever, neutropenic infection, paresthesia, pneumonia, pulmonary embolism, rash, rhinitis, somnolence, stomatitis, thrombophlebitis, and weight loss may occur. In addition, ileus without preceding colitis has occurred. Renal impairment or failure has occurred, usually in patients who became volume depleted from severe vomiting and/or diarrhea.
Asthenia, decreased appetite, diarrhea, fatigue, fever, lymphopenia, nausea, neutropenia, stomatitis, and vomiting are most common. The most common serious side effects were acute renal failure, dehydration, diarrhea, fever, nausea, neutropenic fever or neutropenic sepsis, pneumonia, sepsis, septic shock, thrombocytopenia, and vomiting. Diarrhea, vomiting, and sepsis were the most common reasons for discontinuing therapy. Anemia, diarrhea, nausea, and neutropenia were the most common reasons for dose reduction.
Asymptomatic elevated pancreatic enzymes (e.g., amylase, lipase), dysarthria (transient), ischemic or ulcerative colitis, megacolon, myocardial ischemic events, pancreatitis.
Keep physician informed of all side effects and monitor carefully. Adjust or omit dose as indicated for toxicity; see Dose Adjustments. Treat diarrhea immediately; see Monitor. In the event of an acute onset of new or progressive, unexplained pulmonary symptoms (e.g., cough, dyspnea, fever), interrupt irinotecan and other coprescribed chemotherapeutic agents pending diagnostic evaluation. If interstitial pulmonary disease is diagnosed, discontinue irinotecan and other chemotherapy and initiate appropriate treatment as needed. Administration of whole blood products (e.g., packed RBCs, platelets, leukocytes) and/or blood modifiers (e.g., darbepoetin alfa, epoetin alfa, filgrastim, pegfilgrastim, sargramostim) may be indicated to treat bone marrow toxicity. Death may occur from the progression of many side effects. No known antidote for overdose. Maximum supportive care (e.g., to prevent dehydration due to diarrhea and to treat any infectious complications) will help sustain patient in toxicity. If extravasation occurs, flush site with SWFI, elevate the extremity, and apply ice.