irinotecan liposomal

eye-rye-no-TEE-kan lye-po-SO-mal

Therapeutic Classification: antineoplastics

Pharmacologic Classification: enzyme inhibitors

High Alert

First-line treatment of metastatic pancreatic adenocarcinoma (in combination with oxaliplatin, 5-fluorouracil, and leucovorin).
Metastatic pancreatic adenocarcinoma that has progressed following gemcitabine-based therapy (in combination with 5-fluorouracil and leucovorin).

Interferes with DNA synthesis by inhibiting the enzyme topoisomerase 1.

Therapeutic effects:

Death of rapidly replicating cells, particularly malignant ones.

Absorption: IV administration results in complete bioavailability.

Distribution: 95% of irinotecan remains liposome-encapsulated.

Metabolism/Excretion: Converted by the liver to SN-38, its active metabolite, which is metabolized by the liver by UDP-glucuronosyl 111 transferase 1A1 (UGT1A1) to an inactive metabolite; irinotecan also metabolized by CYP3A4 to inactive metabolites. Asian patients have higher concentration of SN-38 compared to White patients. 11–20% excreted by kidneys.

Half-Life: Irinotecan: 25.8 hr; SN-38: 67.8 hr.

ROUTE	ONSET	PEAK	DURATION
IV	unknown	unknown	unknown

Contraindicated in:

Hypersensitivity;
Bowel obstruction;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Asian patients (↑ risk of severe neutropenia);
Patients homozygous for the UGT1A1*28 allele (i.e., with genetically reduced UGT1A1 activity) (↑ risk of neutropenia);
Pre-existing lung disease, use of pneumotoxic medicinal products or colony stimulating factors, or previously received radiation therapy (↑ risk of interstitial lung disease);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: bradycardia

Derm: alopecia, diaphoresis, flushing

EENT: lacrimation, miosis, rhinitis

F and E: hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia

GI: ↑liver enzymes, anorexia, diarrhea, hypoalbuminemia, nausea, stomatitis, vomiting, ↑salivation, abdominal cramping

GU: ↓serum creatinine

Hemat: anemia, lymphopenia, neutropenia, thrombocytopenia

Metab: ↓weight

Neuro: fatigue

Resp: INTERSTITIAL LUNG DISEASE

Misc: fever, HYPERSENSITIVITY REACTIONS(INCLUDING ANAPHYLAXIS), INFUSION REACTIONS

Drug-drug:

Strong CYP3A4 inhibitors, including clarithromycin, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, ritonavir, and voriconazole, and strong UGT1A1 inhibitors, including atazanavir and gemfibrozil, may ↑ levels of irinotecan and SN-38; avoid concurrent use; discontinue use ≥1 wk before initiating irinotecan.
Strong CYP3A4 inducers, including phenobarbital, phenytoin, carbamazepine, rifampin, rifapentine, or rifabutin, may ↓ levels of irinotecan and SN-38; avoid concurrent use and use alternative medication ≥2 wk before initiating irinotecan.

Drug-Natural Products:

St. John's wort may ↓ levels of irinotecan and SN-38; avoid concurrent use; discontinue use ≥2 wk before initiating irinotecan.

Do not substitute for other medications containing irinotecan.

First-Line Treatment of Pancreatic Adenocarcinoma

IV (Adults ): 50 mg/m² every 2 wk.

Metastatic Pancreatic Adenocarcinoma with Disease Progression

IV (Adults ): 70 mg/m² every 2 wk. Administer prior to leucovorin and 5-fluorouracil.
IV (Adults Homozygous for homozygous for the UGT1A1*28 allele): 50 mg/m² every 2 wk; may ↑ dose to 70 mg/m² as tolerated in subsequent cycles. Administer prior to leucovorin and 5-fluorouracil.

Suspension for injection: 4.3 mg/mL

Observe patient for signs and symptoms of hypersensitivity reactions (rash, pruritus, laryngeal edema, wheezing). Discontinue therapy permanently if symptoms are severe.
Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, guaiac stools, urine, and emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension.
Monitor closely for the development of diarrhea. Do not administer to patients with bowel obstruction. If Grade 3 or 4 diarrhea occurs, withhold therapy. Two types may occur. The early type occurs within 24 hr of administration and may be preceded by cramps and sweating. Administer atropine 0.25–1 mg IV to ↓ symptoms of early-onset diarrhea. Potentially life-threatening diarrhea may occur >24 hr after a dose and may be accompanied by severe dehydration and electrolyte imbalance. Use loperamide 4 mg to treat late-occurring diarrhea. Monitor fluid and electrolyte replacement to prevent complications. For first episode of Grade 3 or 4 diarrhea, once recovered to ≤Grade 1, ↓ dose of irinotecan liposomal to 50 mg/m² for patients receiving 70 mg/m², 40 mg/m² for patients receiving 50 mg/m², or 43 mg/m²in patients homozygous for UGT1A1*28 without previous increase to 70 mg/m². Following second occurrence of recovery from Grade 3 or 4 diarrhea, ↓ irinotecan liposomal dose to 43 mg/m²for patients receiving 70 mg/m², 32.5 mg/m²for patients receiving 50 mg/m², or 35 mg/m²in patients homozygous for UGT1A1*28 without previous increase to 70 mg/m². Following third occurrence of recovery from Grade 3 or 4 diarrhea, ↓ irinotecan liposomal dose to 25 mg/m²for patients receiving 50 mg/m²; discontinue therapy in patients receiving 70 mg/m² or in patients homozygous for UGT1A1*28. Following fourth occurrence of recovery from Grade 3 or 4 diarrhea, discontinue therapy in patients receiving 50 mg/m².
If signs of pulmonary toxicity (progressive dyspnea, cough, fever) occur, interrupt therapy. If interstitial lung disease is determined, discontinue therapy.
Assess for cholinergic symptoms (rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping, diarrhea) during therapy. Atropine IV may be used to prevent or treat symptoms.
Monitor for signs and symptoms of infusion reactions (rash, urticaria, periorbital edema, pruritus). May occur day of infusion.

Lab Test Considerations:

Monitor CBC with differential and platelet count on Days 1 and 8 of every cycle and more frequently if indicated. Temporarily discontinue therapy if ANC <1500 cells/mm³ or if neutropenic fever occurs. Resume therapy when ANC ≥1500/mm³. If first episode of Grade 3 or 4 neutropenia, once recovered to ≤Grade 1, ↓ dose of irinotecan liposomal to 50 mg/m² for patients receiving 70 mg/m², 40 mg/m² for patients receiving 50 mg/m², or 43 mg/m²in patients homozygous for UGT1A1*28 without previous increase to 70 mg/m². Following second occurrence of recovery from Grade 3 or 4 neutropenia, ↓ irinotecan liposomal dose to 43 mg/m²for patients receiving 70 mg/m², 32.5 mg/m²for patients receiving 50 mg/m², or 35 mg/m²in patients homozygous for UGT1A1*28 without previous increase to 70 mg/m². Following third occurrence of recovery from Grade 3 or 4 neutropenia, ↓ irinotecan liposomal dose to 25 mg/m²for patients receiving 50 mg/m²; discontinue therapy in patients receiving 70 mg/m² or in patients homozygous for UGT1A1*28. Following fourth occurrence of recovery from Grade 3 or 4 neutropenia, discontinue therapy in patients receiving 50 mg/m².
- May cause ↑ serum alkaline phosphatase and AST concentrations and ↓ serum levels of calcium, potassium, magnesium, sodium, phosphate, and albumin.

Rate: Administer over 90 min; do not use in-line filters. Discard unused portion.

Nausea and vomiting are common. Administer a corticosteroid and antiemetic 30 min prior to infusion.
Intermittent Infusion: Diluent: Dilute dose in 500 mL or D5W or 0.9% NaCl. Mix by gentle inversion. Solution is a white to slightly yellow, opaque, liposomal dispersion. Administer within 4 hr of dilution if stored at room temperature or 24 hr if refrigerated; do not freeze. Protect solution from light.
Y-Site Incompatibility: Do not administer other drugs through same IV line.

Instruct patient to report occurrence of diarrhea to health care professional immediately, especially if it occurs >24 hr after dose. Diarrhea may be accompanied by severe dehydration and electrolyte imbalance. It may be life-threatening and should be treated promptly. Patient should have loperamide for treatment.
Instruct patient to notify health care professional promptly if fever; chills; sore throat; signs of infection; bleeding gums; bruising; petechiae; or blood in urine, stool, or emesis occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor. Caution patient not to drink alcoholic beverages or take products containing aspirin or other NSAIDs.
Instruct patient to notify health care professional immediately if signs and symptoms of hypersensitivity reaction (chest tightness; shortness of breath; wheezing; dizziness or faintness; or swelling of face, eyelids, or lips) or if cough or shortness of breath occurs.
Advise parents to notify health care professional of all Rx or OTC medications, vitamins, or herbal products, especially St. John's wort, being taken and to consult with health care professional before taking other medications.
Discuss with patient possibility of hair loss. Explore methods of coping.
Rep: May cause fetal harm. Advise females of reproductive potential of the need for effective contraception during therapy and for 7 mo after last dose and to avoid breastfeeding during therapy and for 1 mo following final dose. Advise male patients with female partners of reproductive potential to use effective contraception during therapy and for ≥4 mo after last dose. Advise patient to notify health care professional if pregnancy is planned or suspected.
Emphasize the need for periodic lab tests to monitor for side effects.

Decrease in size and spread of malignancy.

Onivyde

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