Campto

Irinotecan hydrochloride trihydrate.

Active ingredient: irinotecan hydrochloride.
Each mL of sterile solution contains 20 mg of irinotecan hydrochloride (on the basis of trihydrate salt).
Vial of CAMPTO contains 100 mg of irinotecan hydrochloride trihydrate.
Irinotecan sterile solution is a pale yellow, clear, aqueous solution requiring dilution for intravenous administration.
Excipients/Inactive Ingredients: Sorbitol, lactic acid, sodium hydroxide, hydrochloric acid.

Therapeutic class: Irinotecan hydrochloride is an antineoplastic agent of the topoisomerase I inhibitor class, clinically investigated as CPT-11. Irinotecan is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata, or is chemically synthesized.
Pharmacology: Pharmacodynamics: Mechanism of action: Irinotecan and its active metabolite SN-38 bind to the topoisomerase I - DNA complex and prevent re-ligation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold. However, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan. The precise contribution of SN-38 to the activity of irinotecan is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form.
Pharmacokinetics: Absorption and distribution: After intravenous infusion in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.
Over the dose range of 50 to 350 mg/m², 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.
Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin.
Metabolism and excretion: Irinotecan (CPT-11) is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan (CPT-11) can also undergo CYP3A4-mediated oxidative metabolism to several pharmacologically inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as the UGT1A1*28 polymorphism (see Precautions). SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using two cell lines in vitro. The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).
Pharmacokinetics in special populations: Geriatric: The pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in a study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients <65 years of age compared with patients ≥65 years of age. In a study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients <65 years of age compared to patients ≥65 years of age were observed. Although dose-normalized AUC_0-24 for SN-38 in patients ≥65 years of age was 11% higher than in patients <65 years of age, this difference was not statistically significant.
Pediatric: see Precautions.
The pharmacokinetics of irinotecan and its major metabolites in the pediatric population was investigated in clinical trials conducted in the US and Europe. Overall, results and general conclusions regarding irinotecan pharmacokinetics were comparable in the US and European studies. Any differences in the findings between these studies are probably attributable to differences in the doses investigated (20 to 200 mg/m² and 200 to 720 mg/m² in the US and European studies, respectively) and the marked inter-patient variability in values determined for the pharmacokinetic parameters of irinotecan and SN-38.
US studies: Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m² (60-min infusion, n = 48) and 125 mg/m² (90-min infusion, n = 6). Irinotecan clearance (mean ± S.D.) was 17.3 ± 6.7 L/h/m² for the 50 mg/m² dose and 16.2 ± 4.6 L/h/m² for the 125 mg/m² dose, which is somewhat greater than in adults. 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]. A finding that dose-normalized SN-38 AUC values were comparable between adults and children was inconsistent with the increase in irinotecan clearance seen in the pediatric population and was probably reflective of the marked inter-patient variability (%CV values for SN-38 AUC were 84% to 120%). Indeed SN-38 exposure in pediatric patients was approximately 30% lower than in adults when comparison was made without regard to the variability of the data.
European studies: The pharmacokinetics of irinotecan and its major metabolites was investigated in pediatric patients with solid tumors in a phase I study at dose levels of 200 to 720 mg/m² (2-hour infusion, n = 77). Systemic exposure to irinotecan, SN-38, APC, and NPC was dose proportional. Pharmacokinetic parameters of irinotecan and its metabolites demonstrated marked inter-patient variability with values (mean ± S.D.) for irinotecan plasma clearance of 18 ± 8 L/h/m² and volume of distribution at steady state of 104 ± 84 L/m². Irinotecan clearance was 26% lower in adolescents than in children and dose normalized SN-38 and SN-38G exposures were 52% and 105% higher in adolescents than in children, respectively. Irinotecan clearance was higher and dose normalized values for SN-38, SN-38G and APC exposure were lower in the pediatric than in the adult population.
A population pharmacokinetic analysis of irinotecan was performed in 83 children and adolescents with relapsed or refractory rhabdomyosarcoma, primitive neuroectodermal tumor (PNET) including medulloblastoma or neuroblastoma receiving 600 mg/m² irinotecan as a 1-hour infusion once every 3 weeks as part of a phase II study. Mean values for irinotecan clearance and AUC demonstrated large inter- and intra-individual variability and were similar to those determined at the same dose in the European phase-I pediatric study.
Gender: The pharmacokinetics of irinotecan do not appear to be influenced by gender.
Race: The influence of race on the pharmacokinetics of irinotecan has not been evaluated.
Hepatic Insufficiency: (see Dosage & Administration) Irinotecan clearance is diminished in patients with hepatic dysfunction while relative exposure to the active metabolite SN-38 is increased. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in serum total bilirubin and transaminase concentrations.
Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of irinotecan has not been evaluated (see Dosage & Administration).
Pharmacogenomics: The active metabolite SN-38 is further metabolized via UGT1A1. Genetic variants of the UGT1A1 gene such as the UGT1A1*28 [(TA)7] and *6 alleles lead to reduced UGT1A1 enzyme expression or activity and decreased function to a similar extent.
Individuals who are homozygous or compound (double) heterozygous for these alleles (e.g., *28/*28, *6/*6,*6/*28) are UGT1A1 poor metabolizers and are at increased risk for severe or life-threatening neutropenia from Irinotecan Hydrochloride, USPI due to elevated systemic exposure to SN-38. The UGT1A1*6/*6 genotype should not be confused with 6/6 genotype, which is sometimes used to represent the genotype of individuals who are wild type for UGT1A1*28. Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia (see Dosage & Administration, Precautions and Pharmacokinetics as previously mentioned).
Published studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an increased risk of severe diarrhea. The risk evidence appears greater in UGT1A1*28 and *6 homozygous patients and in those taking irinotecan doses >125 mg/m² (see Precautions).
UGT1A1*28 and *6 alleles occur at various frequencies in different populations. Approximately 20% of Black or African American, 10% of White, and 2% of East Asian individuals are homozygous for the UGT1A1*28 allele. Approximately 2-6 % of East Asian individuals are homozygous for the UGT1A1*6 allele. The UGT1A1*6 allele is uncommon in Black or African American or in White individuals. Decreased function alleles other than UGT1A1*28 and *6 may be present in certain populations.
Toxicology: Preclinical safety data: The acute intravenous toxicity of irinotecan in animals is shown as follows. Lethality was observed after single intravenous irinotecan doses of approximately 111 mg/kg in mice and 73 mg/kg in rats (approximately 2.6 and 3.4 times the recommended human dose of 125 mg/m², respectively). Death was preceded by cyanosis, tremors, respiratory distress, and convulsions. Subacute toxicity studies show that irinotecan affects tissues with rapid cell proliferation (bone marrow, intestinal epithelia, thymus, spleen, lymph nodes, and testes). (See Table 1.)

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Carcinogenicity/Mutagenicity: Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan C_max and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m²) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas.
Neither irinotecan nor SN-38 was mutagenic in the in vitro Ames assay. However, in the in vitro Chinese hamster cell chromosomal aberration assay, irinotecan produced a significant increase in the incidence of chromosomal aberrations in a concentration-dependent manner. Additionally, in the in vivo mouse micronucleus assay, a single intraperitoneal dose of irinotecan over the dosage range of 2.5 to 200 mg/kg caused a significant and dose-dependent increase in micronucleated polychromatic erythrocytes and a decrease in the reticulocyte/erythrocyte ratio in bone marrow cells.
Reproduction: No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats. However, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg (which in separate studies produced an irinotecan C_max and AUC about 5 and 1 times, respectively, the corresponding values in patients administered 125 mg/m²) and dogs at 0.4 mg/kg (which in separate studies produced an irinotecan C_max and AUC about one-half and 1/15^th, respectively, the corresponding values in patients administered 125 mg/m²).
Radioactivity related to ¹⁴C-irinotecan crosses the placenta of rats following intravenous administration of 10 mg/kg (which in separate studies produced an irinotecan C_max and AUC about 3 and 0.5 times, respectively, the corresponding values in patients administered 125 mg/m²). Irinotecan was teratogenic in rats at doses greater than 1.2 mg/kg/day (which in separate studies produced an irinotecan C_max and AUC about 2/3 and 1/40^th, respectively, of the corresponding values in patients administered 125 mg/m²) and in rabbits at 6 mg/kg/day (about one-half the recommended weekly human dose on a mg/m² basis). Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.

CAMPTO (irinotecan hydrochloride) is indicated for the treatment of patients with advanced colorectal cancer: In combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease.
As a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

Strictly follow the recommended dosage unless directed otherwise by the physician. All doses of irinotecan should be administered as an intravenous infusion over 30 to 90 minutes.
Single-agent dosage schedules: Single-agent dosage schedules have been extensively studied for metastatic colorectal cancer.
Starting dose: Weekly Dosage Schedule: The recommended single-agent starting dose of irinotecan is 125 mg/m². A lower starting dose may be considered (e.g., 100 mg/m²) for patients with any of the following conditions: prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer. Treatment should be given in repeated 6-week cycles, comprising weekly treatment for 4 weeks, followed by a 2-week rest.
Once-Every-2-Week Dosage Schedule: The usual recommended starting dose of irinotecan is 250 mg/m² every 2 weeks by intravenous infusion. A lower starting dose may be considered (e.g., 200 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer.
Once-Every-3-Week Dosage Schedule: The usual recommended starting dose of irinotecan for the once-every-3-week dosage schedule is 350 mg/m². A lower starting dose may be considered (e.g., 300 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer.
Special populations: Elderly: The dose should be chosen carefully in this population due to their greater frequency of decreased biological functions. This population should require more intensive surveillance (see Pharmacology: Pharmacokinetics under Actions).
Patients with impaired hepatic function: In patients with hepatic dysfunction, the following starting doses are recommended: (See Tables 2 and 3.)

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Patients with impaired renal function: Studies in this population have not been conducted (See Pharmacology: Pharmacokinetics under Actions). Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis.
Combination-agent dosage schedules: Starting Dose: Irinotecan in Combination with 5-Fluorouracil (5-FU) and folinic acid (FA): Irinotecan in combination with 5-FU and folinic acid is recommended for use in patients with metastatic colorectal cancer. For all regimens, the dose of folinic acid should be administered immediately after irinotecan, with the administration of 5-FU to occur immediately after receipt of folinic acid. The currently recommended regimens are shown as follows: Regimen 1 (6-week cycle with bolus 5-FU/FA): The recommended starting dose is 125 mg/m² of irinotecan, 500 mg/m² bolus 5-FU, and 20 mg/m² bolus folinic acid.
Regimen 2 (6-week cycle with infusional 5-FU/FA): The recommended starting dose is 180 mg/m² of irinotecan, 400 mg/m² bolus 5-FU, 600 mg/m² 5-FU infusion, and 200 mg/m² folinic acid.
Lower starting doses may be considered for irinotecan (e.g., 100 mg/m²) and 5-FU (e.g., 400 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer. Treatment should be given in repeated 6-week cycles, comprising weekly treatment for 4 weeks, followed by a 2-week rest.
Duration of treatment: For both single-agent and combination-agent regimens, treatment with additional cycles of irinotecan may be continued indefinitely in patients who attain a tumor response or in patients whose cancer remains stable. Patients should be carefully monitored for toxicity and should be removed from therapy if unacceptable toxicity occurs that is not responsive to dose modification and routine supportive care.
Dose modification recommendations: The recommended dose modifications during a cycle of therapy and at the start of each subsequent cycle of therapy for single-agent dosage schedules are described in Table 4. These recommendations are based on toxicities commonly observed with the administration of irinotecan. For modifications at the start of a subsequent cycle of therapy, the dose of irinotecan should be decreased relative to the initial dose of the previous cycle.
The recommended dose modifications during a cycle of therapy and at the start of each subsequent cycle of therapy for irinotecan, 5-FU, and folinic acid are described in Table 5.
All dose modifications should be based on the worst preceding toxicity. A new cycle of therapy should not begin until the toxicity has recovered to Grade 2 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing irinotecan.
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 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. (See Table 4.)

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Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 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. (See Table 5.)

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Dosage in Patients with Reduced UGT1A1 Activity: When administered in combination with other agents, or as a single-agent, consider a reduction in the starting dose by at least one level of Irinotecan Hydrochloride Injection, USP for patients known to be homozygous for the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the UGT1A1*28 and *6 alleles (*6/*28) (see previously mentioned, Precautions, and Pharmacology under Actions). Subsequent dosage modifications may be required based on individual patient tolerance to treatment (see previously mentioned).

Single doses of up to 750 mg/m² irinotecan have been given to patients with various cancers. The adverse events in these patients were similar to those reported with the recommended dosages and regimens. 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. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications. There is no known antidote for overdosage of irinotecan.

Irinotecan is contraindicated in patients with a known hypersensitivity to the drug or its excipients (see Precautions).

Administration: Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Irinotecan will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks: in patients presenting a risk factor, particularly those with a WHO performance status = 2; in the few rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrheal treatment combined with high fluid intake at onset of delayed diarrhea). Strict hospital supervision is recommended for such patients.
Cholinergic symptoms: Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing (vasodilation), bradycardia, and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea (i.e., diarrhea generally occurring during or within 8 hours of administration of irinotecan). These symptoms may be observed during or shortly after infusion of irinotecan, are thought to be related to the anticholinesterase activity of the irinotecan parent compound, and are expected to occur more frequently with higher irinotecan doses. Therapeutic or prophylactic administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing cholinergic symptoms.
Extravasation: While irinotecan is not a known vesicant, care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site, and application of ice is recommended.
Hepatic: In clinical studies, National Cancer Institute (NCI) Common Toxicity Criteria Grade 3 or 4 liver enzyme abnormalities have been observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastases and are not clearly related to irinotecan.
Hematology: Irinotecan commonly causes neutropenia, leukopenia, and anemia, any of which may be severe and therefore, should not be used in patients with severe bone marrow failure. Serious thrombocytopenia is uncommon. In clinical studies, the frequency of NCI Grade 3 and 4 neutropenia has been significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also have had a significantly greater likelihood of experiencing first-cycle Grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL. There were no significant differences in the frequency of Grade 3 and 4 neutropenia by age or gender (see Dosage & Administration).
Neutropenic fever (concurrent NCI Grade 4 neutropenia and ≥Grade 2 fever) occurred in fewer than 10% of patients in clinical studies; however, deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan. Neutropenic complications should be managed promptly with antibiotic support. Therapy with irinotecan should be temporarily discontinued if neutropenic fever occurs or if the absolute neutrophil count drops below 1000/mm³. The dose of irinotecan should be reduced if clinically significant neutropenia occurs (see Dosage & Administration).
Patients with reduced UGT1A1 activity: Published studies have shown that individuals who are homozygous for either the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or who are compound or double heterozygous for the UGT1A1*28 and *6 alleles (*6/*28) are at increased risk for severe or life-threatening neutropenia during treatment with Irinotecan Hydrochloride, USP. These individuals are UGT1A1 poor metabolizers and experience increased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*28, *1/*6) are intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia (see Dosage & Administration and Pharmacology under Actions).
Consider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer status (see Pharmacology: Pharmacogenomics under Actions).
When administering Irinotecan Hydrochloride, USP, consider a reduction in the Irinotecan Hydrochloride, USP starting dose by at least one level for patients known to be homozygous or compound heterozygous for the UGT1A1*28 and/or *6 alleles (*28/*28, *6/*6, *6/*28). Closely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after treatment with Irinotecan Hydrochloride, USP. The precise dosage reduction in this patient population is not known. Subsequent dosage modifications may be required based on individual patient tolerance to treatment (see Dosage & Administration).
Hypersensitivity reactions: Hypersensitivity reactions, including severe anaphylactic/anaphylactoid reactions, have been reported.
Immunosuppressant effects/increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including irinotecan, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving irinotecan. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Late diarrhea: Late diarrhea (generally occurring more than 8 hours after administration of irinotecan) can be prolonged, may lead to dehydration, electrolyte imbalance, or sepsis and may be life-threatening. In the clinical studies testing the every 3-week-dosage schedule, the median time to the onset of late diarrhea was 5 days after irinotecan infusion. In the clinical studies evaluating the weekly dosage schedule, the median time to onset of late diarrhea was 11 days following administration of irinotecan. For patients starting treatment at the 125 mg/m² weekly dose, the median duration of any grade of late diarrhea was 3 days. Among those patients treated at the 125 mg/m² weekly dose who experienced Grade 3 or 4 late diarrhea, the median duration of the entire episode of diarrhea was 7 days. Results from a prospective study of the weekly dosage schedule did not demonstrate any difference in the rate of late onset diarrhea in patients ≥65 years of age than patients <65 years of age. However, patients ≥65 years of age should be closely monitored due to a greater risk of early diarrhea observed in this population. Colonic ulceration, sometimes with bleeding, has been observed in association with irinotecan-induced diarrhea.
Late diarrhea should be treated promptly with loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally expected for the patient. The recommended dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night, the patient may take 4 mg of loperamide every 4 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours. Premedication with loperamide is not recommended. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated and should be given antibiotic support if they develop ileus, fever, or severe neutropenia. In addition to the antibiotic treatment, hospitalization is recommended for management of the diarrhea, in the following cases: Diarrhea associated with fever; Severe diarrhea (requiring intravenous hydration); Patients with vomiting associated with delayed (i.e., late) diarrhea; Diarrhea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.
After the first treatment, subsequent weekly chemotherapy treatments should be delayed in patients until return of pre-treatment bowel function for at least 24 hours without need for anti-diarrhea medication. If NCI Grade 2, 3, or 4 diarrhea occurs, subsequent doses of irinotecan should be reduced within the current cycle (see Dosage & Administration).
Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with irinotecan until resolution of the bowel obstruction.
Nausea & vomiting: Irinotecan is emetogenic. Nausea and vomiting can be severe and usually occurs during or shortly after infusion of irinotecan. It is recommended that patients receive premedication with antiemetic agents. Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan. Physicians should also consider providing patients with an antiemetic regimen for subsequent use as needed. Patients with vomiting associated with delayed (i.e., late) diarrhea should be hospitalized as soon as possible for treatment.
Neurologic: Dizziness has been observed and may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration.
Renal: Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of acute renal failure. These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting, or diarrhea. Rare instances of renal dysfunction due to tumor lysis syndrome have also been reported.
Respiratory: NCI Grade 3 or 4 dyspnea has been observed. The extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnea is unknown. A potentially life-threatening pulmonary syndrome, consisting of dyspnea, fever, and a reticulonodular pattern on chest x-ray, was observed in a small percentage of patients in early Japanese studies. The contribution of irinotecan to these preliminary events was difficult to assess because these patients also had lung tumors and some had pre-existing non-malignant pulmonary disease.
Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.
Others: Since this product contains sorbitol, it is unsuitable in hereditary fructose intolerance.
Performance status: Patients with poor performance status are at increased risk of irinotecan-related adverse events. Specific dosing recommendations for patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 may apply depending upon the regimen used (see Dosage & Administration). Patients with performance status of 3 or 4 should not receive irinotecan. In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in clinical trials comparing these agents, higher rates of hospitalisation, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.
Gastric cancer: Patients with gastric cancer appear to experience greater myelosuppression and other toxicities when given irinotecan. A lower starting dose should be considered in these patients (see Dosage & Administration).
Effects on ability to drive and use machines: The effect of irinotecan on the ability to drive or use machinery has not been evaluated. However, patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of irinotecan, and advised not to drive or operate machinery if these symptoms occur (see Precautions).
Special populations: Irradiation therapy: Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the administration of irinotecan. Physicians should use caution in treating patients with extensive prior irradiation. Specific dosing recommendations may apply to this population depending upon the regimen used (see Dosage & Administration).
Hepatic insufficiency: In patients with hyperbilirubinemia, the clearance of irinotecan is decreased (see Pharmacology: Pharmacokinetics under Actions) and therefore, the risk of hematotoxicity is increased. The use of irinotecan in patients with a serum total bilirubin concentration of >3.0 x institutional upper limit of normal (IULN) given as a single-agent on the once-every-3-weeks schedule has not been established (see Dosage & Administration). Liver function should be monitored before initiation of treatment and monthly, or as clinically indicated.
Use in Children: The effectiveness of irinotecan in pediatric patients has not been established (see Pharmacology: Pharmacokinetics under Actions). 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/m² 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/m² of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3, 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 hypokalaemia 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).
Use in the Elderly: Specific dosing recommendations may apply to this population depending upon the regimen used (see Dosage & Administration).

Pregnancy: There are no adequate and well-controlled studies of irinotecan in pregnant women. Irinotecan is teratogenic in rats and rabbits (see Pharmacology: Toxicology: Preclinical safety data under Actions). Irinotecan may cause fetal harm when administered to a pregnant woman.
Women of childbearing potential should not be started on irinotecan until pregnancy is excluded. Pregnancy should be avoided if either partner is receiving irinotecan.
Due to the potential for genotoxicity, advise female patients of reproductive potential to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan.
Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of irinotecan.
Lactation: The available data are limited to one patient only. Irinotecan and its active metabolite SN-38 were measured in the milk of one lactating patient. The effect on newborn/infants is unknown. Because of the potential for serious adverse reactions in nursing infants, it is recommended not to breastfeed when receiving therapy with irinotecan.
In rats, radioactivity appeared in the 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.

Clinical studies: Adverse reactions data has been extensively collected and analyzed for the clinical studies program in metastatic colorectal cancer that recurred or progressed following 5-FU-based therapy (second-line) and are presented as follows (patient population described as follows). The adverse reactions for other indications are expected to be similar to those for second-line colorectal cancer.
Clinical studies of the 100- to 125-mg/m² single-agent weekly dosage schedule: The weekly dosage schedule of irinotecan was evaluated in three clinical studies of 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy. Five (1.6%) deaths were potentially drug-related. These five patients experienced a constellation of medical events (myelosuppression, neutropenic sepsis without fever, small bowel obstruction, fluid accumulation, stomatitis, nausea, vomiting, diarrhea, and dehydration) that are known effects of irinotecan.
Neutropenic fever, defined as NCI Grade 4 neutropenia and Grade 2 or greater fever, occurred in nine other patients; these patients recovered with supportive care.
Eighty-one (26.6%) patients were hospitalized for events judged to be related to administration of irinotecan. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting; neutropenia/leukopenia, with or without diarrhea and/or fever; and nausea and/or vomiting.
Adjustments in the dose of irinotecan were made during the cycle of treatment and for subsequent cycles based on individual patient tolerance. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with irinotecan because of adverse events.
Clinical studies of the 300- to 350-mg/m² once-every-3-week single-agent dosage schedule: A total of 316 patients with metastatic colorectal cancer whose disease had progressed following prior 5-FU therapy received irinotecan in two studies involving once-every-3-week administration. Three (1%) deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, Grade 4 diarrhea, and asthenia, respectively. Hospitalizations due to serious adverse events, whether or not related to irinotecan administration, occurred at least once in 60% of patients who received irinotecan and, 8% of patients treated with irinotecan discontinued treatment due to adverse events.
Listing of adverse events: The drug-related adverse events (NCI Grades 1-4) as judged by the investigator that were reported in greater than 10% of the 304 patients enrolled in the three studies of the weekly dosage schedule are listed by body system in descending order of frequency in Table 6. (See Table 6.)

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NCI Grade 3 or 4 adverse events reported in the clinical studies of the weekly and once-every-3-week-dosage schedules (N = 620) are listed in Table 7, Table 8 and Table 9. (See Tables 7, 8 and 9.)

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The following additional drug-related events have been reported in clinical studies with irinotecan, but do not meet the criteria as defined previously as either >10% drug-related NCI Grades 1-4 or as a NCI Grade 3 or 4 drug-related event: rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, dizziness, extravasation, tumor lysis syndrome, and colonic ulceration.
Post-marketing surveillance: Cardiac disorders: Myocardial ischemic events have been observed following irinotecan therapy predominantly in patients with underlying cardiac disease, other known risk factors for cardiac disease or previous cytotoxic chemotherapy (see also Table 6, thromboembolic events).
Gastrointestinal disorders: Infrequent cases of intestinal obstruction, ileus, megacolon, or gastrointestinal hemorrhage, and rare cases of colitis, including typhlitis, ischemic and ulcerative colitis were reported. In some cases, colitis was complicated by ulceration, bleeding, ileus, or infection. Cases of ileus without preceding colitis have also been reported. Rare cases of intestinal perforation were reported.
Rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed.
Hypovolemia: There have been rare cases of renal impairment and acute renal failure, generally in patients who became infected and/or volume depleted from severe gastrointestinal toxicities.
Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis.
Infections and infestations: Bacterial, fungal and viral infections have been reported.
Immune system disorders: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been reported (see Precautions).
Musculoskeletal and connective tissue disorders: Early effects, such as muscular contraction or cramps and paresthesia have been reported.
Nervous system disorders: Speech disorders, generally transient in nature, have been reported in patients treated with irinotecan; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.
Respiratory, thoracic and mediastinal disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects, such as dyspnea have been reported (see Precautions). Hiccups have also been reported.
Investigations: Rare cases of hyponatremia mostly related with diarrhea and vomiting have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis have been very rarely reported.

CYP3A4 and/or UGT1A1 inhibitors: Irinotecan and active metabolite SN-38 are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) (see Pharmacology: Pharmacokinetics under Actions). Co-administration of irinotecan with inhibitors of CYP3A4 and/or UGT1A1 may result in increased systemic exposure to irinotecan and the active metabolite SN-38. Physicians should take this into consideration when administering irinotecan with these drugs.
Ketoconazole: Irinotecan clearance is greatly reduced in patients receiving concomitant ketoconazole, leading to increased exposure to SN-38. Ketoconazole should be discontinued at least 1 week prior to starting irinotecan therapy and should not be administered during irinotecan therapy.
Atazanavir sulfate: Co-administration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs.
CYP3A4 inducers: Anticonvulsants: Concomitant administration of CYP3A-inducing anticonvulsant drugs (e.g., carbamazepine, phenobarbital or phenytoin) leads to reduced exposure to the active metabolite SN-38. Consideration should be given to starting or substituting non-enzyme-inducing anticonvulsants at least one week prior to initiation of irinotecan therapy in patients requiring anticonvulsant treatment.
St. John's Wort (Hypericum perforatum): Exposure to the active metabolite SN-38 is reduced in patients taking concomitant St. John's Wort. St. John's Wort should be discontinued at least 1 week prior to the first cycle of irinotecan, and should not be administered during irinotecan therapy.
Other interactions: Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out, since irinotecan has anticholinesterase activity. Drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.
Antineoplastic agents: The adverse effects of irinotecan, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having a similar adverse effect profile.
Dexamethasone: Lymphocytopenia has been reported in patients receiving irinotecan, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of lymphocytopenia. However, serious opportunistic infections have not been observed and no complications have specifically been attributed to lymphocytopenia.
Hyperglycemia has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of irinotecan. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients.
Laxatives: Laxative use during therapy with irinotecan is expected to worsen the incidence or severity of diarrhea.
Diuretics: Dehydration secondary to vomiting and/or diarrhea may be induced by irinotecan. The physician may wish to withhold diuretics during dosing with irinotecan and during periods of active vomiting or diarrhea.
Bevacizumab: Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38.

Incompatibilities: Other drugs should not be added to the infusion solution.
Special precautions for disposal and other handling: Preparation: Irinotecan must be diluted prior to infusion in 5% Dextrose Injection, (preferred) or 0.9% Sodium Chloride Injection to a final concentration range of 0.12 to 2.8 mg/mL.
Irinotecan is intended for single use only and any unused portion should be discarded. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe.
It is recommended that in order to reduce microbiological hazard, the infusion solutions should be prepared immediately prior to use and infusion commenced as soon as practicable after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
Handling: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan. The use of gloves is recommended. If irinotecan contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan contacts the mucous membranes, flush thoroughly with water.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe.

Store below 30°C. Store protected from light.

Cytotoxic Chemotherapy

L01CE02 - irinotecan ; Belongs to the class of Topoisomerase 1 (TOP1) inhibitors. Used in the treatment of cancer.

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