irinotecan

ROUTE	ONSET	PEAK	DURATION
IV	unknown	21–29 days	27–34 days

Contraindicated in:

Hypersensitivity;
Hereditary fructose intolerance (contains sorbitol);
Concurrent use of ketoconazole or St. John's wort;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Previous pelvic or abdominal irradiation or age ≥65 yr (↑ risk of myelosuppression);
Presence of infection, underlying bone marrow depression, or concurrent chronic illness;
History of prior pelvic/abdominal irradiation and serum bilirubin >1–2 mg/dL (initial dose ↓ recommended);
Hepatic impairment;
Previous severe myelosuppression or diarrhea (reinstitute at lower dose following resolution);
Homozygous for UGT1A1*28 [*28/*28] or UGT1A1*6 [*6/*6] alleles or compound heterozygous for UGT1A1*28 or UGT1A1*6 [*6/*28] alleles (poor UGT1A1 metabolizers) or heterozygous for either the UGT1A1*28 or UGT1A1*6 alleles (*1/*28, *1/*6) (intermediate UGT1A1 metabolizers) (↑ risk of severe or life-threatening neutropenia);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children;
Geri: sensitivity to adverse effects (myelosuppression) in older adults; initiate at lower dose.

Adv. Reactions/Side Effects ⬆ ⬇

CV: edema, vasodilation

Derm: alopecia, rash, sweating

EENT: rhinitis

F and E: dehydration

GI: abdominal pain/cramping, anorexia, constipation, diarrhea, dyspepsia, flatulence, nausea, stomatitis, vomiting, ↑liver enzymes, abdominal enlargement, colonic ulceration

GU: ↓fertility, menstrual abnormalities

Hemat: anemia, leukopenia, neutropenia, thrombocytopenia

Local: injection site reactions

Metab: weight loss

MS: back pain

Neuro: dizziness, headache, insomnia, weakness.

Resp: coughing, dyspnea, INTERSTITIAL LUNG DISEASE

Misc: chills, fever, INFECTION

Interactions ⬆ ⬇

Drug-drug:

Combination withfluorouracilmay result in serious toxicity (dehydration, neutropenia, sepsis).
↑bone marrow depression may occur with other antineoplastics or radiation therapy.
Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, and voriconazole) and strong UGT1A1 inhibitors (atazanavir, and gemfibrozil) may ↑ levels of irinotecan and its active metabolite; should be discontinued ≥1 wk before initiating irinotecan.
Phenobarbital, phenytoin, carbamazepine, rifampin, or rifabutin may ↓ levels of irinotecan and its active metabolite; consider using an alternative anticonvulsant at least 2 wk before initiating irinotecan.
Laxatives should be avoided (diarrhea may be ↑).
Diuretics↑ risk of dehydration (may discontinue during therapy).
Dexamethasone may ↑ risk of hyperglycemia and lymphocytopenia.
Prochlorperazine given on the same day as irinotecan ↑ risk of akathisia.
May ↓ antibody response to and ↑ risk of adverse reactions from live virus vaccines.

Drug-Natural Products:

St. John's wort↓ levels of the active metabolite; concurrent use is contraindicated; should be discontinued at least 2 wk before initiating irinotecan.

Route/Dosage ⬆ ⬇

Other regimens are used; careful modification required for all levels of toxicity/tolerance

Single Agent

IV (Adults ): Weekly dosage schedule: 125 mg/m² once weekly for 4 wk, followed by a 2-wk rest period. Cycle may be repeated using doses which depend on patient tolerance and degree of toxicity encountered. Once-every-3-wk schedule: 350 mg/m² once every 3 wk. Cycle may be repeated using doses which depend on patient tolerance and degree of toxicity encountered.
IV Geriatric Patients >70 yr): Weekly dosage schedule: 125 mg/m² once weekly for 4 wk, followed by a 2-wk rest period. Cycle may be repeated using doses which depend on patient tolerance and degree of toxicity encountered. Once-every-3-wk schedule: 300 mg/m² once every 3 wk. Cycle may be repeated using doses which depend on patient tolerance and degree of toxicity encountered.
IV (Adults Homozygous for UGT1A1*28 [*28/*28] or UGT1A1*6 [*6/*6] Alleles or Compound Heterozygous for UGT1A1*28 or UGT1A1*6 [*6/*28] Alleles): Weekly dosage schedule: 100 mg/m² once weekly for 4 wk, followed by a 2-wk rest period. Cycle may be repeated using doses which depend on patient tolerance and degree of toxicity encountered. Once-every-3-wk schedule: 300 mg/m² once every 3 wk. Cycle may be repeated using doses which depend on patient tolerance and degree of toxicity encountered.

Hepatic Impairment

IV (Adults ): Bilirubin 1–2 mg/dL and history of prior pelvic/abdominal irradiation:Weekly dosage schedule: Initiate therapy at lower dose (100 mg/m²); once weekly for 4 wk, followed by a 2-wk rest period. Cycle may be repeated with dose adjusted as tolerated. Once-every-3-wk schedule: 300 mg/m² once every 3 wk. Cycle may be repeated with dose adjusted as tolerated.

As Part of Combination Therapy With Leucovorin and 5-Fluorouracil

IV (Adults ): Regimen 1 (Bolus regimen): 125 mg/m² once weekly for 4 wk, followed by a 2-wk rest period. Cycle may be repeated using doses that depend on patient tolerance and degree of toxicity encountered; Regimen 2 (Infusional regimen): 180 mg/m² every 2 wk for 3 doses, followed by a 3-wk rest period. Cycle may be repeated using doses that depend on patient tolerance and degree of toxicity encountered.
IV (Adults Homozygous for UGT1A1*28 [*28/*28] or UGT1A1*6 [*6/*6] Alleles or Compound Heterozygous for UGT1A1*28 or UGT1A1*6 [*6/*28] Alleles): Regimen 1 (Bolus regimen): 100 mg/m² once weekly for 4 wk, followed by a 2-wk rest period. Cycle may be repeated using doses that depend on patient tolerance and degree of toxicity encountered; Regimen 2 (Infusional regimen): 150 mg/m² every 2 wk for 3 doses, followed by a 3-wk rest period. Cycle may be repeated using doses that depend on patient tolerance and degree of toxicity encountered.

Availability ⬆ ⬇

(Generic available)

Solution for injection: 20 mg/mL

Assessment ⬆ ⬇

Monitor vital signs frequently during administration.
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. Two types may occur. The early type occurs within 24 hr of administration and may be preceded by cramps and sweating. Atropine 0.25–1 mg IV or SUBQ may be given to decrease symptoms. Potentially life-threatening diarrhea may occur >24 hr after a dose; may be accompanied by severe dehydration and electrolyte imbalance. Loperamide 4 mg initially, followed by 2 mg every 2 hr until diarrhea ceases for at least 12 hr (or 4 mg every 4 hr if given during sleeping hours) should be administered promptly to treat late-occurring diarrhea. Do not administer loperamide at these doses for >48 hr. Careful fluid and electrolyte replacement should be instituted to prevent complications. If diarrhea of 2–3 stools/day pretreatment occurs, maintain dose. If diarrhea of 4–6 stools/day pretreatment occurs during a cycle,↓ by 25 mg/m². If diarrhea of 4–6 stools/day pretreatment occurs at the beginning of a weekly cycle or at the beginning of a once every 3-wk cycle, maintain dose. If diarrhea of 7–9 stools/day pretreatment occurs during a cycle, hold dose until resolved to ≤Grade 2, then ↓ by 25 mg/m². If diarrhea of 7–9 stools/day pretreatment occurs at the beginning of a weekly cycle,↓ by 25 mg/m². If diarrhea of 7–9 stools/day pretreatment occurs at the beginning of a once every 3-wk cycle,↓ by 50 mg/m². If diarrhea ≥10 stools/day pretreatment occurs during a cycle, hold dose until resolved to ≤Grade 2, then ↓ by 50 mg/m². If diarrhea ≥10 stools/day pretreatment occurs at the beginning of a weekly cycle or at the beginning of a once every 3-wk cycle,↓ by 50 mg/m².
Assess IV site frequently for inflammation. Avoid extravasation. If extravasation occurs, infusion must be stopped and restarted in another vein to avoid damage to SUBQ tissue. Flushing site with sterile water and application of ice over the extravasated site are recommended.
If signs of pulmonary toxicity (dyspnea, cough, fever) occur, interrupt therapy. If interstitial pulmonary disease is determined, discontinue irinotecan.
Assess for cholinergic symptoms (rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping, diarrhea) during therapy. Atropine 0.25–1 mg SUBQ or IV may be used to prevent or treat symptoms.

Lab Test Considerations:

Consider laboratory test to determine the UGT1A1 status. Testing can detect the UGT1A1 *6 and *28, genotypes.Verify negative pregnancy test before starting therapy.Monitor CBC with differential and platelet count prior to each dose. If neutropenia, ANC 1500–1999/mm³ occurs, maintain dose. If ANC 1000–1499/mm³ occurs during a cycle,↓ dose by 25 mg/m². If ANC 1000–1499/mm³ occurs at beginning of cycle, maintain dose. If ANC 500–999/mm³ occurs during a cycle, hold dose until resolved to ≤Grade 2, then ↓ by 25 mg/m². If ANC 500–999/mm³ occurs at the beginning of a weekly cycle,↓ dose by 25 mg/m². If ANC 500–999/mm³ occurs at the beginning of a once every 3-wk cycle,↓ dose by 50 mg/m². If ANC <500/mm³ occurs during a cycle, hold dose until resolved to ≤Grade 2, then ↓ by 50 mg/m². If ANC 500–999/mm³ occurs at the beginning of a weekly cycle or at the beginning of a once every 3-wk cycle,↓ dose by 50 mg/m². If neutropenic fever occurs during a cycle, hold dose until resolved, then ↓ by 50 mg/m² when resolved. If neutropenic fever occurs at the beginning of a weekly cycle or at the beginning of a once every 3-wk cycle,↓ by 50 mg/m². Administration of a colony-stimulating factor may be considered if clinically significant decreases in WBC (<2000/mm³), neutrophil count (<1000/mm³), hemoglobin (<9 g/dL), or platelet count (<100,000 cells/mm³) occur.
- May cause ↑ serum alkaline phosphatase and AST concentrations.

Implementation ⬆ ⬇

IV Administration:

Prepare solution in a biologic cabinet. Wear gloves, gown, and mask while handling IV medication. Discard IV equipment in specially designated containers.
Nausea and vomiting are common. Pretreatment with dexamethasone 10 mg along with agents such as ondansetron or granisetron should be started on the same day as irinotecan at least 30 min before administration. Prochlorperazine may be used on subsequent days but may increase risk of akathisia if given on the same day as irinotecan.
Intermittent Infusion: Diluent: Dilute before infusion with D5W or 0.9% NaCl. Usual diluent is 500 mL of D5W.Concentration: 0.12–2.8 mg/mL. Solution is pale yellow. Do not administer solutions that are cloudy, discolored, or contain particulate matter. Solution is stable for 24 hr if refrigerated. To prevent microbial contamination, solutions should be prepared immediately prior to use and begin infusion as soon as possible after preparation.
Rate: Administer dose over 90 min.

Patient/Family Teaching ⬆ ⬇

Explain purpose of irinotecan to patient.
Instruct patient to report occurrence of diarrhea to health care professional immediately if diarrhea occurs for first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hr. Diarrhea may be accompanied by severe dehydration and electrolyte imbalance. It may be life-threatening; treat promptly. Loperamide may be used for treatment up to 48 hr.
Instruct patient to monitor their temperature and to notify health care professional promptly if fever; chills; sore throat; signs of infection; bleeding gums; bruising; petechiae; blood in urine, stool, or emesis occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to monitor temperature frequently, 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 nurse of pain at injection site immediately.
Instruct patient to notify health care professional if vomiting, fainting, or dizziness occurs.
Discuss with patient possibility of hair loss. Explore methods of coping.
Instruct patient not to receive any vaccinations without consulting health care professional.
Rep: May cause fetal harm. Advise females of reproductive potential to use highly effective contraception during and for 6 mo after last dose of therapy and to avoid breastfeeding during and for 7 days after final dose. Advise males with female partners of reproductive potential to use condoms during and for 3 mo after last dose. May impair female and male infertility.
Emphasize the need for periodic lab tests to monitor for side effects.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇