Dosage Form: injection
Irinotecan Hydrochloride Injection
Package Insert
Rx only
For Intravenous Use Only
WARNINGS
Irinotecan hydrochloride injection 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 can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Both forms of diarrhea may be severe. Early diarrhea (occurring during or shortly after infusion of Irinotecan) may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by atropine (see PRECAUTIONS, General). Late diarrhea (generally occurring more than 24 hours after administration of Irinotecan) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly with loperamide. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia (see WARNINGS). Administration of Irinotecan should be interrupted and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND ADMINISTRATION).
Severe myelosuppression may occur (see WARNINGS).
Irinotecan Description
Irinotecan hydrochloride injection is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride was clinically investigated as CPT-11.
Irinotecan hydrochloride injection is supplied as a sterile, pale yellow, clear, aqueous solution. It is available in two single-dose sizes: 2 mL-fill vials containing 40 mg Irinotecan hydrochloride, and 5 mL-fill vials containing 100 mg Irinotecan hydrochloride. Each milliliter of solution contains 20 mg of Irinotecan hydrochloride (on the basis of the trihydrate salt), 45 mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan hydrochloride injection is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP.
Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Mappia foetida and Camptotheca acuminata. The chemical name is (S) - 4,11 - diethyl - 3,4,12,14 - tetrahydro - 4 - hydroxy - 3,14 - dioxo - 1H - pyrano[3',4':6,7] - indolizino[1,2 - b]quinolin - 9 - yl - [1,4'bipiperidine] - 1' - carboxylate, monohydrochloride, trihydrate. Its structural formula is as follows:
Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the molecular formula C33H38N4O6•HCl•3H2O and a molecular weight of 677.19. It is slightly soluble in water and organic solvents.
Irinotecan - Clinical Pharmacology
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation 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. Mammalian cells cannot efficiently repair these double-strand breaks.
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 (see Pharmacokinetics). 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.
Administration of Irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.
Pharmacokinetics
After intravenous infusion of Irinotecan in humans, Irinotecan plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 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 recommended 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. Pharmacokinetic parameters for Irinotecan and SN-38 following a 90-minute infusion of Irinotecan at dose levels of 125 and 340 mg/m2 determined in two clinical studies in patients with solid tumors are summarized in Table 1:
| Dose (mg/m2) | Irinotecan | SN-38 | ||||||
| Cmax (ng/mL) | AUC0-24 (ng•h/mL) | t1/2 (h) | Vz (L/m2) | CL (L/h/m2) | Cmax (ng/mL) | AUC0-24 (ng•h/mL) | t1/2 (h) | |
| Cmax -Maximum plasma concentration AUC0-24 -Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute infusion t1/2 - Terminal elimination half-life Vz - Volume of distribution of terminal elimination phase CL - Total systemic clearance | ||||||||
| ||||||||
| 125 | 1,660 | 10,200 | 5.8* | 110 | 13.3 | 26.3 | 229 | 10.4* |
| (N=64) | ±797 | ±3,270 | ±0.7 | ±48.5 | ±6.01 | ±11.9 | ±108 | ±3.1 |
| 340 | 3,392 | 20,604 | 11.7† | 234 | 13.9 | 56.0 | 474 | 21.0† |
| (N=6) | ±874 | ±6,027 | ±1.0 | ±69.6 | ±4.0 | ±28.2 | ±245 | ±4.3 |
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
The metabolic conversion of Irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. In vitro studies indicate that Irinotecan, SN-38 and another metabolite aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). In a prospective study, in which Irinotecan was administered as a single-agent (350 mg/m2) on a once-every-3-week schedule, patients with the UGT1A1 7/7 genotype had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele (UGT1A1 6/6 genotype) (see WARNINGS and DOSAGE AND ADMINISTRATION). 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 AUC0-24 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. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of Irinotecan (see DOSAGE AND ADMINISTRATION).
Pediatric
See Pediatric Use under PRECAUTIONS.
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
Irinotecan clearance is diminished in patients with hepatic dysfunction while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations. However, the tolerability of Irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Patients at Particular Risk Sections).
Renal Insufficiency
The influence of renal insufficiency on the pharmacokinetics of Irinotecan has not been evaluated. Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis.
Drug-Drug Interactions
Anticonvulsants
Exposure to Irinotecan and its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carbamazepine. The appropriate starting dose for patients taking these anticonvulsants has not been formally defined. The following drugs are also CYP3A4 inducers: rifampin, rifabutin. For patients requiring anticonvulsant treatment, consideration should be given to substituting non-enzyme inducing anticonvulsants at least 2 weeks prior to initiation of Irinotecan therapy. Dexamethasone does not appear to alter the pharmacokinetics of Irinotecan.
St. John's Wort
St. John's Wort is an inducer of CYP3A4 enzymes. Exposure to the active metabolite SN-38 is reduced in patients receiving concomitant St. John's Wort. St. John's Wort should be discontinued at least 2 weeks prior to the first cycle of Irinotecan, and St. John's Wort is contraindicated during Irinotecan therapy.
Ketoconazole
Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients receiving concomitant ketoconazole have increased exposure to Irinotecan and its active metabolite SN-38. Patients should discontinue ketoconazole at least 1 week prior to starting Irinotecan therapy and ketoconazole is contraindicated during Irinotecan therapy.
Neuromuscular blocking agents
Interaction between Irinotecan and neuromuscular blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.
Atazanavir sulfate
Coadministration 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 coadministering these drugs.
Clinical Studies
Irinotecan has been studied in clinical trials as a single-agent (see DOSAGE AND ADMINISTRATION). Weekly and a once-every-3-week dosage schedules were used for the single-agent Irinotecan studies. Clinical studies of single-agent use are described below.
Second-Line Treatment for Recurrent or Progressive Metastatic Colorectal Cancer After 5-FU-Based Treatment
Weekly Dosage Schedule
Data from three open-label, single-agent, clinical studies, involving a total of 304 patients in 59 centers, support the use of Irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. These studies were designed to evaluate tumor response rate and do not provide information on actual clinical benefit, such as effects on survival and disease-related symptoms. In each study, Irinotecan was administered in repeated 6-week cycles consisting of a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest period. Starting doses of Irinotecan in these trials were 100, 125, or 150 mg/m2, but the 150-mg/m2 dose was poorly tolerated (due to unacceptably high rates of grade 4 late diarrhea and febrile neutropenia). Study 1 enrolled 48 patients and was conducted by a single investigator at several regional hospitals. Study 2 was a multicenter study conducted by the North Central Cancer Treatment Group. All 90 patients enrolled in Study 2 received a starting dose of 125 mg/m2. Study 3 was a multicenter study that enrolled 166 patients from 30 institutions. The initial dose in Study 3 was 125 mg/m2 but was reduced to 100 mg/m2 because the toxicity seen at the 125-mg/m2 dose was perceived to be greater than that seen in previous studies. All patients in these studies had metastatic colorectal cancer, and the majority had disease that recurred or progressed following a 5-FU-based regimen administered for metastatic disease. The results of the individual studies are shown in Table 2.
| Study | ||||
| 1 | 2 | 3 | ||
| ||||
| Number of Patients | 48 | 90 | 64 | 102 |
| Starting Dose (mg/m2/wk × 4) | 125* | 125 | 125 | 100 |
| Demographics and Treatment Administration | ||||
| Female/Male (%) | 46/54 | 36/64 | 50/50 | 51/49 |
| Median Age in years (range) | 63 (29-78) | 63 (32-81) | 61 (42-84) | 64 (25-84) |
| Ethnic Origin (%) | ||||
| White | 79 | 96 | 81 | 91 |
| African American | 12 | 4 | 11 | 5 |
| Hispanic | 8 | 0 | 8 | 2 |
| Oriental/Asian | 0 | 0 | 0 | 2 |
| Performance Status (%) | ||||
| 0 | 60 | 38 | 59 | 44 |
| 1 | 38 | 48 | 33 | 51 |
| 2 | 2 | 14 | 8 | 5 |
| Primary Tumor (%) | ||||
| Colon | 100 | 71 | 89 | 87 |
| Rectum | 0 | 29 | 11 | 8 |
| Unknown | 0 | 0 | 0 | 5 |
| Prior 5-FU Therapy (%) | ||||
| For Metastatic Disease | 81 | 66 | 73 | 68 |
| ≤ 6 months after Adjuvant | 15 | 7 | 27 | 28 |
| > 6 months after Adjuvant | 2 | 16 | 0 | 2 |
| Classification Unknown | 2 | 12 | 0 | 3 |
| Prior Pelvic/Abdominal Irradiation (%) | ||||
| Yes | 3 | 29 | 0 | 0 |
| Other | 0 | 9 | 2 | 4 |
| None | 97 | 62 | 98 | 96 |
| Duration of Treatment with Irinotecan (median, months) | 5 | 4 | 4 | 3 |
| Relative Dose Intensity† (median %) | 74 | 67 | 73 | 81 |
| Efficacy | ||||
| Confirmed Objective Response Rate (%)‡ (95% CI) | 21 (9.3 - 32.3) | 13 (6.3 - 20.4) | 14 (5.5 - 22.6) | 9 (3.3 - 14.3) |
| Time to Response (median, months) | 2.6 | 1.5 | 2.8 | 2.8 |
| Response Duration (median, months) | 6.4 | 5.9 | 5.6 | 6.4 |
| Survival (median, months) | 10.4 | 8.1 | 10.7 | 9.3 |
| 1-Year Survival (%) | 46 | 31 | 45 | 43 |
In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m2. Among these 193 patients, 2 complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting dose of 100 mg/m2. The majority of responses were observed within the first two cycles of therapy, but responses did occur in later cycles of treatment (one response was observed after the eighth cycle). The median response duration for patients beginning therapy at 125 mg/m2 was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to Irinotecan were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. The response rate was 18.5% in patients with a performance status of 0 and 8.2% in patients with a performance status of 1 or 2. Patients with a performance status of 3 or 4 have not been studied. Over half of the patients responding to Irinotecan had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to Irinotecan at approximately the same rate as those who had not previously received irradiation.
Once-Every-3-Week Dosage Schedule
Single-Arm Studies: Data from an open-label, single-agent, single-arm, multicenter, clinical study involving a total of 132 patients support a once every-3-week dosage schedule of Irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that recurred or progressed following treatment with 5-FU. Patients received a starting dose of 350 mg/m2 given by 30-minute intravenous infusion once every 3 weeks. Among the 132 previously treated patients in this trial, the intent-to-treat response rate was 12.1% (95% CI, 7.0% to 18.1%).
Randomized Trials: Two multicenter, randomized, clinical studies further support the use of Irinotecan given by the once-every-3-week dosage schedule in patients with metastatic colorectal cancer whose disease has recurred or progressed following prior 5-FU therapy. In the first study, second-line Irinotecan therapy plus best supportive care was compared with best supportive care alone. In the second study, second-line Irinotecan therapy was compared with infusional 5-FU-based therapy. In both studies, Irinotecan was administered intravenously at a starting dose of 350 mg/m2 over 90 minutes once every 3 weeks. The starting dose was 300 mg/m2 for patients who were 70 years and older or who had a performance status of 2. The highest total dose permitted was 700 mg. Dose reductions and/or administration delays were permitted in the event of severe hematologic and/or nonhematologic toxicities while on treatment. Best supportive care was provided to patients in both arms of Study 1 and included antibiotics, analgesics, corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. If late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was given. Patients in the control arm of the second study received one of the following 5-FU regimens: (1) LV, 200 mg/m2 IV over 2 hours; followed by 5-FU, 400 mg/m2 IV bolus; followed by 5-FU, 600 mg/m2 continuous IV infusion over 22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to 300 mg/m2/day protracted continuous IV infusion until toxicity; (3) 5-FU, 2.6 to 3 g/m2 IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m2/day every week IV for 6 weeks with 2-week rest between cycles. Patients were to be followed every 3 to 6 weeks for 1 year.
A total of 535 patients were randomized in the two studies at 94 centers. The primary endpoint in both studies was survival. The studies demonstrated a significant overall survival advantage for Irinotecan compared with best supportive care (p=0.0001) and infusional 5-FU-based therapy (p=0.035) as shown in Figures 3 and 4. In Study 1, median survival for patients treated with Irinotecan was 9.2 months compared with 6.5 months for patients receiving best supportive care. In Study 2, median survival for patients treated with Irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional 5-FU-based therapy. Multiple regression analyses determined that patients' baseline characteristics also had a significant effect on survival. When adjusted for performance status and other baseline prognostic factors, survival among patients treated with Irinotecan remained significantly longer than in the control populations (p=0.001 for Study 1 and p=0.017 for Study 2). Measurements of pain, performance status, and weight loss were collected prospectively in the two studies; however, the plan for the analysis of these data was defined retrospectively. When comparing Irinotecan with best supportive care in Study 1, this analysis showed a statistically significant advantage for Irinotecan, with longer time to development of pain (6.9 months versus 2.0 months), time to performance status deterioration (5.7 months versus 3.3 months), and time to > 5% weight loss (6.4 months versus 4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance status of 1 or 2 showed an improvement in performance status when treated with Irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002). Because of the inclusion of patients with non-measurable disease, intent-to-treat response rates could not be assessed.
In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. At the start of each cycle of therapy, patients completed a questionnaire consisting of 30 questions, such as "Did pain interfere with daily activities?" (1 = Not at All, to 4 = Very Much) and "Do you have any trouble taking a long walk?" (Yes or No). The answers from the 30 questions were converted into 15 subscales, that were scored from 0 to 100, and the global health status subscale that was derived from two questions about the patient's sense of general well being in the past week. In addition to the global health status subscale, there were five functional (i.e., cognitive, emotional, social, physical, role) and nine symptom (i.e., fatigue, appetite loss, pain assessment, insomnia, constipation, dyspnea, nausea/vomiting, financial impact, diarrhea) subscales. The results as summarized in Table 4 are based on patients' worst post-baseline scores. In Study 1, a multivariate analysis and univariate analyses of the individual subscales were performed and corrected for multivariate testing. Patients receiving Irinotecan reported significantly better results for the global health status, on two of five functional subscales, and on four of nine symptom subscales. As expected, patients receiving Irinotecan noted significantly more diarrhea than those receiving best supportive care. In Study 2, the multivariate analysis on all 15 subscales did not indicate a statistically significant difference between Irinotecan and infusional 5-FU.
| Study 1 | Study 2 | |||
| Irinotecan | BSC* | Irinotecan | 5-FU | |
| ||||
| Number of Patients | 189 | 90 | 127 | 129 |
| Demographics and Treatment Administration | ||||
| Female/Male (%) | 32/68 | 42/58 | 43/57 | 35/65 |
| Median Age in years (range) | 59 (22-75) | 62 (34-75) | 58 (30-75) | 58 (25-75) |
| Performance Status (%) | ||||
| 0 | 47 | 31 | 58 | 54 |
| 1 | 39 | 46 | 35 | 43 |
| 2 | 14 | 23 | 8 | 3 |
| Primary Tumor (%) | ||||
| Colon | 55 | 52 | 57 | 62 |
| Rectum | 45 | 48 | 43 | 38 |
| Prior 5-FU Therapy (%) | ||||
| For Metastatic Disease | 70 | 63 | 58 | 68 |
| As Adjuvant Treatment | 30 | 37 | 42 | 32 |
| Prior Irradiation (%) | 26 | 27 | 18 | 20 |
| Duration of Study Treatment (median, months) (Log-rank test) | 4.1 | — | 4.2 (p=0.02) | 2.8 |
| Relative Dose Intensity (median %)† | 94 | — | 95 | 81-99 |
| Survival | ||||
| Survival (median, months) (Log-rank test) | 9.2 (p=0.0001) | 6.5 | 10.8 (p=0.035) | 8.5 |
| QLQ-C30 Subscale | Study 1 | |||||
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