Irinotecan (irinotecan HCl)

Because irinotecan often causes neutropenia, leukopenia, and anemia, which can be severe, the drug should not be used in patients with severe bone marrow failure. In addition, concurrent radiation therapy has not been adequately studied and is not recommended. Because conventional irinotecan hydrochloride for injection concentrate contains sorbitol, the drug should not be given to patients with hereditary fructose intolerance. Treatment with conventional or liposomal irinotecan should not be initiated until resolution of bowel obstruction.

Irinotecan is considered an antineoplastic agent of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%). Because nausea and/or vomiting occur frequently in patients receiving irinotecan therapy and may be severe, effective antiemetic therapy (e.g., dexamethasone 8 mg and a 5-HT3 serotonin receptor antagonist such as palonosetron) should be administered orally or IV at least 30 minutes prior to irinotecan therapy. Additional oral antiemetic therapy also should be considered for subsequent home use by the patient as needed. Unless clinically contraindicated, clinicians should consider prophylactic or therapeutic administration of antimuscarinic therapy (e.g., 0.25-1 mg of atropine sulfate by IV or subcutaneous injection) for patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, abdominal cramping, or early diarrhea (i.e., diarrhea with an onset during or shortly after (within 24 hours of) administration of irinotecan); such symptoms are expected to occur more frequently in patients receiving higher doses of irinotecan.

Dosage adjustment may be required according to the patient's status for activity of UGT1A1, a uridine diphosphate-glucuronosyltransferase (UGT) enzyme involved in the metabolism of SN-38, an active metabolite of irinotecan. In patients who are homozygous for the UGT1A1*28 allele, UGT1A1 activity is reduced, and the risk of irinotecan-induced neutropenia is increased; reduction in the initial dosage of conventional irinotecan by at least one dose level should be considered in such patients. The optimal dosage reduction for conventional irinotecan has not been established, and subsequent dosage adjustment may be necessary according to patient tolerance. The recommended initial dose of liposomal irinotecan in patients with metastatic adenocarcinoma of the pancreas who are homozygous for the UGT1A1*28 allele is 50 mg/m2; the dose may be increased to 70 mg/m2 as tolerated during subsequent cycles. In patients who are heterozygous for the UGT1A1*28 allele, UGT1A1 activity is intermediate, and the risk of irinotecan-induced neutropenia may be increased. Clinical results have been variable with conventional irinotecan.

Inadvertent overdosage of conventional irinotecan has occurred in several patients, including at least one fatal case, because the manufacturer's label on the vial was misread. Therefore, particular care should be taken to ensure that the correct dose of the drug is administered, including careful attention to the concentration of conventional irinotecan for injection concentrate present in the vial and the appropriate volume needed to provide the prescribed dose.

Patients should be instructed to contact their clinician if any of the following occur during irinotecan therapy: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration, such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth because of nausea or vomiting; inability to control diarrhea within 24 hours; new-onset cough or dyspnea; manifestations of severe hypersensitivity reactions; or fever or evidence of infection. Patients should be warned about the potential for dizziness or visual disturbances that may occur within 24 hours following the administration of conventional irinotecan and be advised not to drive or operate machinery if these symptoms occur. Patients also should be alerted to the possibility of alopecia during conventional or liposomal irinotecan therapy.

Irinotecan is commercially available in 2 types of formulations: conventional (nonencapsulated) and liposomal irinotecan hydrochloride. The properties of irinotecan may differ according to formulation, and the dosage and reconstitution instructions for irinotecan are specific to formulation. Liposomal irinotecan hydrochloride may not be substituted for other formulations of irinotecan hydrochloride.

Dosage of liposomal irinotecan hydrochloride is expressed in terms of anhydrous irinotecan, whereas dosage of conventional irinotecan hydrochloride is expressed in terms of the hydrated salt.

In addition to GI and hematologic toxicity, other severe adverse effects have occurred in patients receiving conventional or liposomal irinotecan. Hypersensitivity reactions, including severe anaphylactic or anaphylactoid reactions, have been reported. Renal impairment and acute renal failure have occurred, usually in patients who became volume-depleted from severe vomiting and/or diarrhea. Cardiovascular and thromboembolic events also have been reported in patients receiving conventional irinotecan. (See Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)

The manufacturer of conventional irinotecan recommends close monitoring in patients older than 65 years of age because of increased risk of treatment-related toxicity, such as early and late diarrhea, during therapy with conventional irinotecan. Patients receiving conventional irinotecan/fluorouracil/leucovorin therapy should be monitored closely (e.g., weekly assessment), particularly during the first cycle of treatment, since most of the treatment-related toxicities leading to early death occurred within the first 3-4 weeks. Changes in serum electrolytes and/or acid-base balance, including hyponatremia or hypernatremia, hypokalemia, and/or metabolic acidosis, may be an early indication of treatment-related toxicity; patients with abnormalities in serum sodium, potassium, and/or bicarbonate concentrations, with or without concomitant elevations in BUN or serum creatinine concentrations, should be evaluated carefully for dehydration and receive aggressive medical management, including fluid and electrolyte replacement.

Liposomal irinotecan hydrochloride can only be obtained through select specialty distributors. Clinicians may consult the Onivyde(R) website for specific availability information (https://www.onivyde.com).

Dosage of conventional or liposomal irinotecan should be modified as necessary based on individual patient tolerance; the patient should be monitored carefully to obtain optimum therapeutic response with minimum adverse effects. Among those receiving conventional or liposomal irinotecan-based combination therapy, doses of fluorouracil also should be modified as necessary based on individual patient tolerance.

The manufacturer states that a new cycle of conventional irinotecan therapy should not be undertaken until the granulocyte count has recovered to at least 1500/mm3, the platelet count has recovered to at least 100,000/mm3, and treatment-related diarrhea has fully resolved. If the patient experiences multiple toxicities, adjustment of conventional irinotecan hydrochloride dose within a cycle of therapy and prior to starting a new cycle of therapy should be based on the preceding toxicity requiring the largest dose reduction. Treatment should be delayed for 1-2 weeks to allow for recovery from treatment-related toxicities. If the patient experiences an irinotecan-induced toxicity that does not resolve after delaying drug administration for 2 weeks, discontinuance of the drug should be considered.

Among patients receiving conventional irinotecan as a single agent, initial doses of conventional irinotecan hydrochloride are based on body surface area alone, but subsequent doses within a cycle of therapy or for a new cycle of therapy in patients receiving the drug on a weekly dosage schedule should be adjusted in increments of 25-50 mg/m2 to a dose within the range of 50-150 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan; subsequent doses for a new cycle of therapy in patients receiving the drug once every 3 weeks should be decreased in increments of 50 mg/m2 to a dose as low as 200 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan. If the patient experiences no toxicity within a cycle of therapy using the once-every-3-weeks dosage schedule, the current conventional irinotecan hydrochloride dose should be maintained for the subsequent cycle of therapy. If the patient experiences no toxicity during an entire 6-week cycle of therapy using the weekly dosage schedule, the dose of conventional irinotecan hydrochloride may be increased by 25 mg/m2 at the start of the next cycle; however, the dose should not exceed 150 mg/m2.

The Recommended Dosage Modifications tables (Tables 2-4) describe recommended modifications in conventional irinotecan hydrochloride dose based on commonly observed toxicities of the drug for patients receiving combination or single-agent therapy with the drug. The dose-limiting toxicities of conventional irinotecan are diarrhea and neutropenia.

Recommended dosage modifications for liposomal irinotecan based on observed toxicities of the drug are described in the following sections on specific types and severities of toxicity.

For a more complete discussion of dosage modifications, cautions, and precautions associated with conventional or liposomal irinotecan therapy, the respective manufacturer's labeling should be consulted.

Conventional or liposomal irinotecan hydrochloride is administered by IV infusion. Care should be taken to avoid extravasation of conventional irinotecan, and the infusion site should be monitored for signs of inflammation. Should manifestations of extravasation appear, the infusion should immediately be stopped and restarted in another vein. The manufacturer of conventional irinotecan recommends that extravasation of the drug be treated by flushing the infusion site promptly with sterile water and applying an ice pack.

Procedures for proper handling and disposal of antineoplastic drugs (e.g., use of protective clothing and gloves) should be used to avoid exposure to conventional or liposomal irinotecan during preparation of IV solutions. If conventional irinotecan hydrochloride for injection concentrate or a solution of the drug comes in contact with the skin or mucous membranes, the skin should be washed immediately and thoroughly with soap and water or the mucosa should be flushed with copious amounts of water.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.