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Irinotecan (Liposomal)

Pronunciation

(eye rye no TEE kan lye po SO mal)

Index Terms

  • Irinotecan Liposome
  • Liposomal Irinotecan
  • Liposome-Encapsulated Irinotecan Hydrochloride PEP02
  • MM-398
  • Onivyde

Dosage Forms

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

Injectable, Intravenous:

Onivyde: 43 mg/10 mL (10 mL) [contains mpeg-2000-dspe (methoxy-terminated peg)]

Brand Names: U.S.

  • Onivyde

Pharmacologic Category

  • Antineoplastic Agent, Camptothecin
  • Antineoplastic Agent, Topoisomerase I Inhibitor

Pharmacology

Irinotecan (liposomal) is a topoisomerase 1 inhibitor encapsulated in a lipid bilayer (liposome). Irinotecan and its active metabolite (SN-38) bind reversibly to topoisomerase I-DNA complex preventing re-ligation 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.

Distribution

4.1 L; 95% of irinotecan remains liposome-encapsulated

Metabolism

Irinotecan hydrochloride: Primarily hepatic to SN-38 (active metabolite) by carboxylesterase enzymes; may also undergo CYP3A4-mediated metabolism to inactive metabolites (one of which may be hydrolyzed to release SN-38). SN-38 undergoes conjugation by UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. SN-38 is increased by UGT1A1*28 polymorphism (10% of North Americans are homozygous for UGT1A1*28 allele).

Excretion

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

Half-Life Elimination

Total irinotecan: ~26 hours; SN-38: ~68 hours

Protein Binding

<1%

Special Populations: Hepatic Function Impairment

Average steady-state concentrations for total SN-38 were increased by 37% in patients with baseline bilirubin concentrations of 1 to 2 mg/dL versus patients with baseline bilirubin levels <1 mg/dL.

Special Populations: Race

The average steady-state concentrations of total irinotecan and total SN-38 are 56% lower and 8% higher, respectively, in Asian patients versus white patients.

Use: Labeled Indications

Pancreatic adenocarcinoma, metastatic: Treatment of metastatic adenocarcinoma of the pancreas (in combination with fluorouracil and leucovorin) disease progression following gemcitabine-based therapy.

Limitations of use: Irinotecan (liposomal) is not indicated as a single agent for the treatment of metastatic adenocarcinoma of the pancreas.

Contraindications

Severe hypersensitivity to irinotecan (liposomal), irinotecan hydrochloride, or any component of the formulation

Dosing: Adult

Note: Premedicate with a corticosteroid and an antiemetic 30 minutes prior to infusion. Irinotecan (liposomal) and irinotecan (conventional) are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration.

Pancreatic adenocarcinoma, metastatic: IV: 70 mg/m2 once every 2 weeks (in combination with fluorouracil and leucovorin). Note: Reduce initial starting dose to 50 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele; the dose may be increased to 70 mg/m2 as tolerated in subsequent cycles.

Dosing: Geriatric

Refer to adult dosing

Dosing: Renal Impairment

CrCl 30 to 89 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, a population pharmacokinetic analysis showed no effect on total SN-38 exposure in patients with mild to moderate renal impairment.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (insufficient data).

Dosing: Hepatic Impairment

Bilirubin >ULN: There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for Toxicity

Note: Fluorouracil and leucovorin may also require dosage adjustment.

Hematologic toxicity: ANC <1,500/mm3 or neutropenic fever: Withhold treatment. Resume therapy when ANC ≥1,500/mm3 with a reduced dose for grade 3 or 4 neutropenia or neutropenic fever in subsequent cycles:

First occurrence: Reduce dose to 50 mg/m2 (in patients receiving 70 mg/m2); reduce dose to 43 mg/m2 in patients homozygous for UGT1A1*28 without previous increase to 70 mg/m2

Second occurrence: Reduce dose to 43 mg/m2 (in patients receiving 50 mg/m2); reduce dose to 35 mg/m2 in patients homozygous for UGT1A1*28 previously receiving 43 mg/m2

Third occurrence: Discontinue

Nonhematologic toxicity:

Anaphylactic reaction: Discontinue permanently

Diarrhea: Withhold therapy for grade 2 to 4 diarrhea. Administer IV or SubQ atropine 0.25 to 1 mg (unless clinically contraindicated) for early-onset diarrhea of any severity. Administer loperamide for late-onset diarrhea of any severity. Following recovery to ≤ grade 1 diarrhea, resume treatment at a reduced dose:

First occurrence: Reduce dose to 50 mg/m2 (in patients receiving 70 mg/m2); reduce dose to 43 mg/m2 in patients homozygous for UGT1A1*28 without previous increase to 70 mg/m2

Second occurrence: Reduce dose to 43 mg/m2 (in patients receiving 50 mg/m2); reduce dose to 35 mg/m2 in patients homozygous for UGT1A1*28 previously receiving 43 mg/m2

Third occurrence: Discontinue

Interstitial lung disease (ILD): Discontinue

Other grade 3 or 4 adverse reactions: Withhold therapy. Upon recovery to ≤ grade 1 toxicity, resume treatment at a reduced dose:

First occurrence: Reduce dose to 50 mg/m2 (in patients receiving 70 mg/m2); reduce dose to 43 mg/m2 in patients homozygous for UGT1A1*28 without previous increase to 70 mg/m2

Second occurrence: Reduce dose to 43 mg/m2 (in patients receiving 50 mg/m2); reduce dose to 35 mg/m2 in patients homozygous for UGT1A1*28 previously receiving 43 mg/m2

Third occurrence: Discontinue

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Withdraw appropriate dose from the vial and dilute in 500 mL D5W or NS. Mix by gentle inversion; protect diluted solution from light.

Administration

Administer by IV infusion over 90 minutes. Premedicate with a corticosteroid and an antiemetic 30 minutes prior to infusion. Administer irinotecan (liposomal) prior to fluorouracil and leucovorin. Do not use in-line filters for administration.

Administer IV or SubQ atropine 0.25 to 1 mg (unless clinically contraindicated) for early onset diarrhea of any severity; initiate loperamide for late-onset diarrhea of any severity.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5W, NS

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Solution diluted for administration in D5W or NS is stable for up to 4 hours when stored at room temperature, or up to 24 hours when refrigerated (administration should be completed within these time frames). Allow diluted solution to come to room temperature prior to administration.

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

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

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Avoid combination

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

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

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

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

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

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

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

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.). 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.). Monitor therapy

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

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

SORAfenib: May increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. SORAfenib may increase the serum concentration of Irinotecan Products. Monitor therapy

St John's Wort: May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be reduced. St John's Wort may decrease the serum concentration of Irinotecan Products. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

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

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

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

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

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

UGT1A1 Inhibitors: May increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 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. Avoid combination

Adverse Reactions

Frequency not always defined. Percentages reported as part of combination chemotherapy regimens.

Cardiovascular: Septic shock (≥2%)

Central nervous system: Fatigue (≤56%)

Dermatologic: Alopecia (14%)

Endocrine & metabolic: Increased serum alanine aminotransferase (51%), hypoalbuminemia (43%), hypomagnesemia (35%), hypocalcemia (32%), hypokalemia (32%), hypophosphatemia (29%), hyponatremia (27%), weight loss (17%), dehydration (8%)

Gastrointestinal: Diarrhea (59%, grade 3/4: 13%; early onset 30%, grade 3/4: 3%; late onset 43%, grade 3/4: 9%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), gastroenteritis (3%)

Hematologic & oncologic: Anemia (97%, grades 3/4: 6%), lymphopenia (81%, grades 3/4: 27%), neutropenia (52%, grades 3/4: 20%; incidence of neutropenia was higher among Asian patients), thrombocytopenia (41%, grades 3/4: 2%), neutropenic fever (≤3%, grades 3/4: ≤3%)

Hypersensitivity: Severe hypersensitivity

Infection: Sepsis (4%, grades 3/4: 3%), neutropenic sepsis (≤3%, grades 3/4: ≤3%)

Local: Catheter infection (3%)

Neuromuscular & skeletal: Weakness (≤56%)

Renal: Increased creatinine clearance (18%)

Respiratory: Pneumonia (≥2%), interstitial pulmonary disease

Renal: Acute renal failure (≥2%)

Miscellaneous: Fever (23%)

ALERT: U.S. Boxed Warning

Bone marrow suppression:

Fatal neutropenic sepsis occurred in 0.8% of patients receiving irinotecan (liposomal). Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving irinotecan (liposomal) in combination with fluorouracil and leucovorin. Withhold irinotecan (liposomal) for absolute neutrophil count below 1,500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.

Gastrointestinal toxicity:

Severe diarrhea occurred in 13% of patients receiving irinotecan (liposomal) in combination with fluorouracil and leucovorin. Do not administer irinotecan (liposomal) to patients with bowel obstruction. Withhold irinotecan (liposomal) for diarrhea of grade 2 to 4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Fatal neutropenic sepsis occurred in nearly 1% of patients receiving irinotecan (liposomal). Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving irinotecan (liposomal) in combination with fluorouracil and leucovorin. Withhold irinotecan (liposomal) for absolute neutrophil count below 1,500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment (days 1 and 8 of each cycle and more frequently if clinically necessary). May require therapy interruption, dose reduction, and/or discontinuation. Anemia, lymphopenia, and thrombocytopenia also commonly occur. The incidence of neutropenia was higher in Asian patients (compared to white patients).

• Gastrointestinal toxicity: [US Boxed Warning]: Severe diarrhea (may be life-threatening) occurred in 13% of patients receiving irinotecan (liposomal) in combination with fluorouracil and leucovorin. Do not administer irinotecan (liposomal) to patients with bowel obstruction. Withhold irinotecan (liposomal) for diarrhea of grade 2 to 4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity. Early onset diarrhea occurs within 24 hours of chemotherapy, and may cause other symptoms of cholinergic reaction. Late onset diarrhea occurs more than 24 hours following chemotherapy. Diarrhea may require therapy interruption, dosage reduction, and/or discontinuation. Nausea, vomiting, and stomatitis commonly occur.

• Hypersensitivity reactions: Severe hypersensitivity reactions (including anaphylaxis) have occurred with irinotecan (conventional). Monitor closely; permanently discontinue irinotecan (liposomal) therapy if severe hypersensitivity occurs.

• Pulmonary toxicity: Irinotecan (conventional) may cause severe and fatal interstitial lung disease (ILD). Withhold irinotecan (liposomal) during diagnostic evaluation if new or progressive dyspnea, cough, or fever occurs during use. Discontinue therapy if ILD diagnosis is confirmed.

Disease-related concerns:

• Bowel obstruction: Do not administer in patients with bowel obstruction.

• Hepatic impairment: The pharmacokinetics of irinotecan (liposomal) have not been studied in patients with hepatic impairment. However, exposure to the active metabolite (SN-38) is increased in patients with hepatic impairment receiving irinotecan (conventional); toxicities may be increased.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. CYP3A4 enzyme inducers may decrease exposure to irinotecan and SN-38 (active metabolite); avoid concomitant use (substitute non-enzyme inducing therapies at least 2 weeks prior to irinotecan [liposomal] initiation). Enzyme inhibitors may increase exposure; avoid concomitant use (discontinue strong CYP3A4 inhibitors at least 1 week prior to irinotecan [liposomal] initiation).

Dosage form specific issues:

• Liposomal vs conventional formulation dosing: Irinotecan (liposomal) and irinotecan (conventional) are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration.

Other warnings/precautions:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

Complete blood counts on days 1 and 8 of each cycle and as clinically indicated; bilirubin, electrolytes (with severe diarrhea); bowel movements (diarrhea episodes) and hydration status; signs/symptoms of pulmonary toxicity or hypersensitivity reactions

Pregnancy Considerations

Animal reproduction studies have not been conducted with the liposomal formulation. Based on the mechanism of action as well as animal data using irinotecan (conventional), irinotecan (liposomal) may cause fetal harm if administered during pregnancy. Women of childbearing potential should use effective contraception while receiving treatment and avoid pregnancy for one month following the last dose. Males with female partners of reproductive potential should use condoms during therapy and for four months following the last dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience mouth sores, lack of appetite, alopecia, or weight loss. Have patient report immediately to prescriber diarrhea, signs of infection, signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, nausea, or vomiting), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), bruising, bleeding, loss of strength and energy, black, tarry, or bloody stools, severe nausea, or vomiting (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience,and judgment in diagnosing, treating, and advising patients.

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