TEKAMEN

Irinotecan is a topoisomerase inhibitor used for chemotherapy.

It is a water-soluble analogue of camptothecin, which is extracted from the Chinese tree Camptotheca acuminate.

The bis-piperidine side chain in the structure of irinotecan bestows enhanced water solubility.

As an anticancer drug, irinotecan was first commercially available in Japan in to treat various cancers such as lung, cervical and ovarian cancer.

Approved by the

FDA in 1996, 3 irinotecan is used to treat colorectal cancer and pancreatic adenocarcinoma. 7, 8, 10 Irinotecan liposome was approved by the FDA in February 2024.

The active metabolite

SN-38 is also a potent inhibitor of DNA topoisomerase I.

This leads to the arrest of the cell cycle in the S-G2 phase and cancer cell death.

Irinotecan is indicated for the treatment of: Metastatic carcinoma of the colon or rectum as first-line treatment in combination with fluorouracil and leucovorin. 7, 10.

• Metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy, as monotherapy 10 or in combination with fluorouracil and leucovorin.

Irinotecan liposome injection is used in adults for the treatment of: Metastatic pancreatic adenocarcinoma in combination with oxaliplatin, fluorouracil, and leucovorin as first-line treatment. 8, 11.

• Metastatic pancreatic adenocarcinoma in combination with fluorouracil and leucovorin after disease progression following gemcitabine-based therapy. 8,

Irinotecan is an antineoplastic agent.

The administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.

topoisomerase I, mitochondrial Inhibitor DNA topoisomerase 1 Inhibitor.

Over the recommended dose range of 50-350 mg/m 2, the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose.

Maximum concentrations of the active metabolite

SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan.

The plasma levels of

SN-38 are much lower than that of irinotecan. 2, 7 Following intravenous infusion in patients with solid tumours, the mean (± standard deviation) C max was 1,660 ± 797 ng/mL at a dose of 125 mg/m and 3,392 ± 874 ng/mL at a dose of 340 mg/m 2.

AUC 0–24 was 10,200 ± 3,270 ng x h/mL at a dose of 125 mg/m and 20,604 ± 6,027 ng x h/mL at a dose of 340 mg/m 2.

Following intravenous infusion in patients with solid tumours, the mean (± standard deviation) volume of distribution of terminal elimination phase was 110 ± 48.5 L/m at a dose of 125 mg/m and 234 ± 69.6 L/m at a dose of 340 mg/m 2.

Upon administration, irinotecan is converted primarily in the liver into its active metabolite, SN-38, by carboxylesterase.

SN-38 is formed by cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain.

While in vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies, SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I. 2, 7 SN-38 can further be glucuronidated by UGT1A1 to form SN-38 G. 1, 3, 7 Irinotecan can also undergo CYP3A4-mediated oxidation to form NPC and APC.

While some sources state that NPC and APC are weak inhibitors of topoisomerase I, 1, 2 they are unlikely to contribute to the pharmacological activity of irinotecan.

Hover over products below to view reaction partners Irinotecan SN-38 SN-38 G NPC SN-38 APC.

The disposition of irinotecan has not been fully elucidated in humans.

The urinary excretion of irinotecan, SN-38, and SN-38 glucuronide are 11% to 20%, <1%, and 3%, respectively.

The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours in two patients ranged from approximately 25% (100 mg/m 2 ) to 50% (300 mg/m 2 ).

After intravenous infusion of irinotecan in humans, the mean terminal elimination half-life of irinotecan is about 6-12 hours.

The mean terminal elimination half-life of the active metabolite SN-38 is about 10-20 hours.

The mean (± standard deviation) total systemic clearance of irinotecan in patients with solid tumours was 13.3 ± 6.01 L/h/m at a dose of 125 mg/m and 13.9 ± 4.0 L/h/m at a dose of 340 mg/m 2.

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The oral

LD is 1045 mg/kg in mice and 867 mg/kg in rats.

In clinical trials involving patients with various cancers, single doses of up to 750 mg/m of irinotecan were associated with similar adverse events reported with the recommended dosage and regimen.

There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal.

The most significant adverse reactions reported were severe neutropenia and severe diarrhea.

Because there is no known antidote for overdosage of irinotecan, maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

Hypersensitivity to

Irinotecan hydrochloride injection or its excipients Irinotecan hydrochloride injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.

Colorectal cancer single agent regimen 1: Irinotecan hydrochloride injection 125 mg/m 2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest.

Colorectal cancer single agent regimen 2: Irinotecan hydrochloride injection 350 mg/m 2 intravenous infusion over 90 minutes on day 1 every 3 weeks. 2.2 Colorectal Single Agent Regimens and 2 Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion.

The currently recommended regimens are shown in Table 3.

A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels.

Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

Table 3.

Single-Agent Regimens of irinotecan hydrochloride injection and Dose Modifications a Subsequent doses may be adjusted as high as 150 mg/m 2 or to as low as 50 mg/m in 25 to 50 mg/m 2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m in 50 mg/m 2 decrements depending upon individual patient tolerance. c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.

Regimen 1 (weekly) a 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest Starting Dose and Modified Dose Levels c (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 125 100 75 Regimen 2 (every 3 weeks) b 350 mg/m 2 intravenous infusion over 90 minutes, once every 3 weeks c Starting Dose and Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 350 300 250 Dose Modifications Based on recommended dose-levels described in Table 3, Single-Agent Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules.

All dose modifications should be based on the worst preceding toxicity.

Table 4: Recommended Dose Modifications For Single-Agent Schedules a a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3, and the platelet count has recovered to ≥100,000/mm 3, and treatment-related diarrhea is fully resolved.

Treatment should be delayed to 2 weeks to allow for recovery from treatment-related toxicities.

If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan hydrochloride injection.

Grade b (Value) During a Cycle of Therapy At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle a Weekly Weekly Once Every 3 Weeks No toxicity Maintain dose level ↑ 25 mg/m 2 up to a maximum dose of 150 mg/m 2 Maintain dose level Neutropenia 1 (1500 to 1999/mm 3 ) Maintain dose level Maintain dose level Maintain dose level 2 (1000 to 1499/mm 3 ) ↓ 25 mg/m 2 Maintain dose level Maintain dose level 3 (500 to 999/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 (<500/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m 2 when resolved ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other hematologic toxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.

Diarrhea 1 (2–3 stools/day > pretx c ) Maintain dose level Maintain dose level Maintain dose level 2 (4–6 stools/day > pretx) ↓ 25 mg/m 2 Maintain dose level Maintain dose level 3 (7–9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other nonhematologic d toxicities 1 Maintain dose level Maintain dose level Maintain dose level 2 ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 3 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 2.3 Dosage in Patients with Reduced UGT1A1 Activity When administered as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1 * 28 allele.

However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment. 2.4 Premedication It is recommended that patients receive premedication with antiemetic agents.

In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT 3 blocker (e.g., ondansetron or granisetron).

Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan hydrochloride injection.

Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.

Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. 2.5 Preparation of Infusion Solution Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.

Irinotecan hydrochloride injection 20 mg/mL is intended for single use only and any unused portion should be discarded.

Irinotecan hydrochloride injection must be diluted prior to infusion.

Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL.

Other drugs should not be added to the infusion solution.

The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting.

Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours.

Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates.

Freezing irinotecan hydrochloride injection and admixtures of irinotecan hydrochloride injection may result in precipitation of the drug and should be avoided.

The irinotecan hydrochloride injection solution should be used immediately after reconstitution as it contains no antibacterial preservative.

Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F).

In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hours if kept at room temperature.

If reconstitution and dilution are performed under strict aseptic conditions (e.g., on Laminar Air Flow bench), irinotecan hydrochloride injection solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F). 2.6 Safe Handling Care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection.

The use of gloves is recommended.

If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water.

If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water.

Several published guidelines for handling and disposal of anticancer agents are available. 2.7 Extravasation Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation.

Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.

Irinotecan hydrochloride injection, USP is available in single-dose amber glass vials in the following package sizes: 5mL NDC 72485-212-05 Store at 20°C to 25°C (68°F to 77°F). .

Protect from light.

Protect from freezing.

Keep the vial in the carton until the time of use.

Inspect the vial for damage and visible signs of leaks before removing from the carton.

If damaged, incinerate the unopened package.

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from irinotecan hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The effectiveness of irinotecan in pediatric patients has not been established.

Results from two open-label, single arm studies were evaluated.

One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/ m of irinotecan was infused for 5 consecutive days every 3 weeks.

Grade 3-4 neutropenia was experienced by 54 (31.8%) patients.Neutropenia was complicated by fever in 15 (8.8%) patients.

Grade 3-4 diarrhea was observed in 35 (20.6%) patients.

This adverse event profile was comparable to that observed in adults.

In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m of irinotecan was infused for 5 consecutive days on weeks and 4.

This single agent therapy was followed by multimodal therapy.

Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%).

The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship).

Pharmacokinetic parameters for irinotecan and

SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m 2 (60-min infusion, n=48) and 125 mg/m 2 (90-min infusion, n=6).

Irinotecan clearance (mean + S.D). was 17.3 + 6.7 L/h/m for the 50mg/m 2 dose and 16.2 + 4.6 L/h/m for the 125 mg/m 2 dose, which is comparable to that in adults.

SN-38 AUC values were comparable between adults and children.

Minimal accumulation of irinotecan and

SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks.

Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population.

The starting dose of irinotecan hydrochloride in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m 2.

The frequency of grade and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002).

In another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients > 65 years of age was 28.6% [26/91] and in patients <65 years of age was 23.9% [22/92.