Irinotecan PhaRes20 mg/ml

Irinotecan PhaRes is a topoisomerase I inhibitor chemotherapy agent with the following evidence-based uses:

Established/FDA-approved uses

• Metastatic colorectal cancer, first-line combination therapy: Irinotecan PhaRes in combination with 5-fluorouracil and leucovorin (the FOLFIRI regimen) as first-line treatment.
• Metastatic colorectal cancer, second-line/monotherapy: Irinotecan PhaRes as a single agent for patients whose disease has recurred or progressed following fluorouracil-based chemotherapy.

Guideline-supported / combination-therapy uses

• Used within combination regimens (e.g. FOLFIRI, FOLFIRINOX) for advanced colorectal and pancreatic cancers, per oncology treatment guidelines; these uses require combination with other cytotoxic or biologic agents and physician-directed protocol selection.

Off-label uses (not FDA-approved, but reported in oncology literature/practice)

• Small-cell lung cancer, gastric cancer, and certain pediatric solid tumors, used in specialist oncology settings only.

Irinotecan PhaRes must only be prescribed and administered by, or under the supervision of, a physician experienced in the use of cancer chemotherapeutic agents.

Each mL of Irinotecan Hydrochloride injection/IV infusion concentrate typically contains Irinotecan Hydrochloride trihydrate equivalent to 20 mg irinotecan hydrochloride (or 17.3 mg irinotecan free base per mL), supplied in single-use vials (commonly 40 mg/2 mL, 100 mg/5 mL, and 300 mg/15 mL strengths) for dilution and intravenous infusion. Exact strength and pack size may vary by manufacturer/brand.

Irinotecan PhaRes is a semisynthetic derivative of camptothecin and belongs to the topoisomerase I inhibitor class of cytotoxic chemotherapy agents. It is converted in the body to an active metabolite, SN-38, which is substantially more potent than the parent compound in inhibiting topoisomerase I, an enzyme essential for DNA replication and repair in dividing cells.

Irinotecan PhaRes is administered only by intravenous infusion under close medical supervision, typically as part of combination chemotherapy protocols for colorectal cancer.

Irinotecan PhaRes belongs to the therapeutic class of antineoplastic agents, specifically the topoisomerase I inhibitors (camptothecin analogues), used in the treatment of certain solid tumor cancers.

Irinotecan Hydrochloride and its active metabolite SN-38 bind to and stabilize the topoisomerase I-DNA complex, preventing re-ligation of single-strand DNA breaks made by topoisomerase I during replication. This leads to accumulation of DNA damage and double-strand breaks during S-phase, ultimately triggering cell death in rapidly dividing tumor cells.

Pharmacokinetics

• Metabolism: Irinotecan Hydrochloride is hydrolyzed by carboxylesterase enzymes to the active metabolite SN-38, which is far more cytotoxic than the parent drug. SN-38 is subsequently glucuronidated by the hepatic enzyme UGT1A1 to an inactive metabolite (SN-38G) for elimination.
• Genetic factor: Patients homozygous for the UGT1A1*28 allele (reduced UGT1A1 activity) have significantly reduced glucuronidation capacity and are at increased risk of severe neutropenia; UGT1A1 genotyping may be considered before starting therapy in some clinical settings.
• Elimination: Primarily via biliary/fecal excretion, with a smaller renal component.

Irinotecan PhaRes is diluted in 5% dextrose injection or 0.9% sodium chloride injection and administered as an intravenous infusion over 90 minutes through a peripheral or central line, under supervision of personnel trained in chemotherapy administration. It must not be given by rapid IV push, intramuscular, subcutaneous, or intrathecal injection. Extravasation should be avoided; the infusion site should be monitored.

Irinotecan PhaRes has the following well-established, clinically significant interactions:

• Strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, ritonavir): increase active metabolite (SN-38) exposure, raising the risk of severe toxicity (myelosuppression, diarrhea). Concurrent use should be avoided; if unavoidable, alternative agents or dose adjustment should be considered.
• Strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, St. John's Wort): reduce SN-38 exposure and may decrease efficacy of Irinotecan PhaRes. Concurrent use should be avoided; allow adequate washout before starting therapy if a patient has been on an inducer.
• Other myelosuppressive or bone-marrow-suppressing drugs/radiation: additive hematologic toxicity; requires close monitoring.
• Laxatives and diuretics: may worsen dehydration/electrolyte loss in the setting of irinotecan-induced diarrhea and should be used cautiously.
• Live vaccines: should generally be avoided during chemotherapy with Irinotecan PhaRes due to immunosuppression risk.

Very common

• Nausea and vomiting
• Diarrhea (both early-onset cholinergic-type and late-onset — see Precautions and Warnings for management)
• Neutropenia, anemia, thrombocytopenia
• Abdominal pain, anorexia
• Alopecia (hair loss)
• Fatigue/asthenia

Serious/less common

• Febrile neutropenia and neutropenic sepsis
• Severe dehydration and electrolyte imbalance secondary to diarrhea
• Interstitial lung disease
• Thromboembolic events
• Renal impairment (usually secondary to dehydration/sepsis)
• Infusion-related reactions and acute cholinergic syndrome (sweating, salivation, abdominal cramping, early diarrhea, visual disturbance) during/shortly after infusion

Irinotecan PhaRes can cause fetal harm and is associated with embryo-fetal toxicity based on its mechanism of action and animal reproduction studies. Irinotecan PhaRes should be strictly avoided during pregnancy; if it must be considered, it should be used only if clearly needed and the potential benefit justifies the potential risk to the fetus, and only after full discussion with the treating physician. Women of reproductive potential should use effective contraception during treatment and for a defined period after the last dose (as advised by the oncologist), and men with female partners of reproductive potential should also use effective contraception.

It is not known whether Irinotecan PhaRes or its active metabolite passes into breast milk; because of the potential for serious adverse reactions in a nursing infant, breastfeeding should be discontinued during treatment with Irinotecan PhaRes and for a period after the last dose as advised by the physician.

Boxed warnings

• Severe diarrhea: Irinotecan PhaRes can cause both early-onset (cholinergic-type, occurring during or shortly after infusion, managed with atropine) and late-onset diarrhea (occurring more than 24 hours after infusion, which can be severe and life-threatening). Late-onset diarrhea should be treated promptly and aggressively with high-dose loperamide at the first sign of loose stool, and patients should be instructed to have loperamide available and to seek medical attention for diarrhea that does not respond, or is accompanied by fever or severe dehydration.
• Severe myelosuppression: Irinotecan PhaRes can cause severe and life-threatening neutropenia, which can lead to febrile neutropenia and sepsis. Blood counts should be monitored regularly, and doses withheld or reduced for significant myelosuppression. Irinotecan PhaRes must be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents, with ready access to facilities for managing complications.

Other precautions

• UGT1A1 polymorphism: patients homozygous for the UGT1A1*28 allele are at increased risk of severe neutropenia; genotyping may be considered before treatment, with dose reduction considered in identified patients.
• Hepatic impairment: increased risk of toxicity; dose adjustment or closer monitoring may be required based on bilirubin/liver function.
• Renal impairment: use with caution; limited data are available, and closer monitoring is advised.
• Interstitial lung disease: monitor for new or worsening dyspnea, cough, and fever; interrupt treatment if pulmonary infiltrates are identified pending diagnostic evaluation.
• Concurrent strong CYP3A4 inhibitors/inducers: see Interactions; avoid concurrent use where possible.
• Use only under the supervision of an oncologist in a facility equipped to manage chemotherapy-related complications.

There is no known specific antidote for Irinotecan PhaRes overdosage. Overdose may result in exacerbation of known adverse effects, principally severe neutropenia and severe diarrhea. If overdose of Irinotecan PhaRes is suspected, seek immediate medical attention or contact emergency services/poison control; the patient should be closely monitored in a hospital setting with supportive care, including maximal supportive measures to prevent dehydration and to treat infection, as directed by the treating physician. Do not attempt to manage a suspected overdose at home.

Store Irinotecan PhaRes vials at room temperature (below 30°C), protected from light, in the original outer carton. Do not freeze. Once diluted for infusion, the solution should be used within the time period specified by the manufacturer and stored under the specified conditions (typically refrigerated and protected from light if not used immediately). Keep out of reach of children. Discard any unused portion of opened vials appropriately as cytotoxic waste, following institutional protocols.

Pregnant women

See Pregnancy and Lactation — Irinotecan PhaRes should be avoided in pregnancy due to embryo-fetal toxicity risk.

Breastfeeding women

See Pregnancy and Lactation — breastfeeding should be discontinued during and for a period after treatment with Irinotecan PhaRes.

Elderly patients

Elderly patients (particularly those over 65 years) may be at increased risk of severe diarrhea and myelosuppression with Irinotecan PhaRes; closer monitoring is recommended, and dose modification may be needed.

Hepatic impairment

Patients with elevated bilirubin or hepatic impairment are at increased risk of toxicity and may require dose reduction and closer monitoring.

Renal impairment

Data are limited; use with caution and monitor closely.

UGT1A1*28 homozygous patients

Increased risk of severe neutropenia; dose reduction may be considered following genotyping.

The duration of treatment with Irinotecan PhaRes is individualized by the treating oncologist based on the specific chemotherapy protocol, tumor response, and tolerability, and is typically continued in cycles until disease progression, unacceptable toxicity, or as otherwise determined by the treatment plan.

Irinotecan PhaRes is supplied as a ready-to-dilute liquid concentrate (not a lyophilized powder) in most standard formulations; it requires dilution (not reconstitution) in 5% dextrose or 0.9% sodium chloride injection prior to intravenous infusion, per the specific product's prescribing information. (Note: certain liposomal irinotecan formulations may have separate specific preparation instructions not covered here.)

Irinotecan Hydrochloride belongs to the antineoplastic, topoisomerase I inhibitor (camptothecin analogue) drug class.

Irinotecan Hydrochloride and its active metabolite SN-38 inhibit topoisomerase I, an enzyme required to relieve torsional strain in DNA during replication. By stabilizing the topoisomerase I-DNA cleavable complex and preventing re-ligation of DNA strand breaks, Irinotecan Hydrochloride causes irreversible double-strand DNA damage during the S-phase of the cell cycle, leading to death of rapidly dividing cancer cells.

Category D (can cause fetal harm; use only if potential benefit justifies potential risk to the fetus)

The safety and efficacy of Irinotecan PhaRes for routine use in pediatric patients have not been fully established for most indications. Irinotecan PhaRes has been studied and used off-label in specialized pediatric oncology settings for certain relapsed/refractory solid tumors, but only under the direct supervision of a pediatric oncologist experienced in its use, with close monitoring for myelosuppression and diarrhea. It should not be used in children outside of a specialist oncology treatment protocol.