Irinotel Injection(Pharmacia & Upjohn)
WARNINGS
IRINOTEL 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.
IRINOTEL 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 IRINOTEL) 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 IRINOTEL) 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 IRINOTEL should be interrupted and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND ADMINISTRATION ).
Severe myelosuppression may occur (see WARNINGS ).
DESCRIPTION
IRINOTEL Injection (irinotecan hydrochloride injection) is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride was clinically investigated as CPT-11.
IRINOTEL is supplied as a sterile, pale yellow, clear, aqueous solution. It is available in two single-dose sizes: 2 mL-fill vials contain 40 mg irinotecan hydrochloride and 5 mL-fill vials contain 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. IRINOTEL 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 Camptotheca acuminata . The chemical name is ( S ) -4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1 H -pyrano[3',4':6,7]- indolizino[1,2-b]quinolin-9-yl-[1,4'-bipiperidine]-1'-carboxylate, monohydrochloride, trihydrate.
Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the empirical formula C 33 H 38 N 4 O 6 •HCl•3H 2 O and a molecular weight of 677.19. It is slightly soluble in water and organic solvents.
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 IRINOTEL 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/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. Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m 2 determined in two clinical studies in patients with solid tumors are summarized in Table 1:
Table 1. Summary of Mean (± Standard Deviation) Irinotecan and SN-38 Pharmacokinetic
Parameters in Patients with Solid
Tumors Dose Irinotecan SN-38
(mg/m 2 ) C max AUC 0-24 t 1/2 V z CL C max AUC 0-24 t 1/2
(ng/mL) (ng•h/mL) (h) (L/m 2 ) (L/h/m 2 ) (ng/mL) (ng•h/mL) (h)
125 1,660 10,200 5.8 a 110 13.3 26.3 229 10.4 a
(N=64) ±797 ±3,270 ±0.7 ±48.5 ±6.01 ±11.9 ±108 ±3.1
340 3,392 20,604 11.7 b 234 13.9 56.0 474 21.0 b
(N=6) ±874 ±6,027 ±1.0 ±69.6 ±4.0 ±28.2 ±245 ±4.3
C max - Maximum plasma concentration
AUC 0-24 - Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute infusion
t 1/2 - Terminal elimination half-life
V z - Volume of distribution of terminal elimination phase
CL - Total systemic clearance
a Plasma specimens collected for 24 hours following the end of the 90-minute infusion.
b Plasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide a more accurate reflection of the terminal elimination half-lives of irinotecan and SN-38.
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. SN-38 subsequently undergoes conjugation to form a glucuronide metabolite. 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/m 2 ) to 50% (300 mg/m 2 ).
Pharmacokinetics in Special Populations
Geriatric: In studies using the weekly schedule, the terminal half-life of irinotecan was 6.0 hours in patients who were 65 years or older and 5.5 hours in patients younger than 65 years. Dose-normalized AUC 0-24 for SN-38 in patients who were at least 65 years of age was 11% higher than in patients younger than 65 years. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan. The pharmacokinetics of irinotecan given once every 3 weeks has not been studied in the geriatric population; a lower starting dose is recommended in patients 70 years or older based on clinical toxicity experience with this schedule (see DOSAGE AND ADMINISTRATION ).
Pediatric: Information regarding the pharmacokinetics of irinotecan is not available.
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: The influence of hepatic insufficiency on the pharmacokinetic characteristics of irinotecan and its metabolites has not been formally studied. Among patients with known hepatic tumor involvement (a majority of patients), irinotecan and SN-38 AUC values were somewhat higher than values for patients without liver metastases (see PRECAUTIONS ).
Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of irinotecan has not been evaluated.
Drug-Drug Interactions
In a phase 1 clinical study involving irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid tumors, the disposition of irinotecan was not substantially altered when the drugs were co-administered. Although the C max and AUC 0-24 of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was followed by 5-FU and LV administration compared with when irinotecan was given alone, this sequence of administration was used in the combination trials and is recommended (see DOSAGE AND ADMINISTRATION ). Formal in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV have not been conducted.
Possible pharmacokinetic interactions of IRINOTEL with other concomitantly administered medications have not been formally investigated.
CLINICAL STUDIES
Irinotecan has been studied in clinical trials in combination with 5-fluorouracil (5-FU) and leucovorin (LV) and as a single agent (see DOSAGE AND ADMINISTRATION ). When given as a component of combination-agent treatment, irinotecan was either given with a weekly schedule of bolus 5-FU/LV or with an every-2-week schedule of infusional 5-FU/LV. Weekly and a once-every-3-week dosage schedules were used for the single-agent irinotecan studies. Clinical studies of combination and single-agent use are described below.
First-Line Therapy in Combination with 5-FU/LV for the Treatment of Metastatic Colorectal Cancer
Two phase 3, randomized, controlled, multinational clinical trials support the use of IRINOTEL Injection as first-line treatment of patients with metastatic carcinoma of the colon or rectum. In each study, combinations of irinotecan with 5-FU and LV were compared with 5-FU and LV alone. Study 1 compared combination irinotecan/bolus 5-FU/LV therapy given weekly with a standard bolus regimen of 5-FU/LV alone given daily for 5 days every 4 weeks; an irinotecan-alone treatment arm given on a weekly schedule was also included. Study 2 evaluated two different methods of administering infusional 5-FU/LV, with or without irinotecan. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. In Study 2, a 7-day course of fluoroquinolone antibiotic prophylaxis was given in patients whose diarrhea persisted for greater than 24 hours despite loperamide or if they developed a fever in addition to diarrhea. Treatment with oral fluoroquinolone was also initiated in patients who developed an absolute neutrophil count (ANC) <500/mm 3 , even in the absence of fever or diarrhea. Patients in both studies also received treatment with intravenous antibiotics if they had persistent diarrhea or fever or if ileus developed.
In both studies, the combination of irinotecan/5-FU/LV therapy resulted in significant improvements in objective tumor response rates, time to tumor progression, and survival when compared with 5-FU/LV alone. These differences in survival were observed in spite of second-line therapy in a majority of patients on both arms, including crossover to irinotecan-containing regimens in the control arm. Patient characteristics and major efficacy results are shown in Table 2.
Table 2. Combination Dosage Schedule: Study Results
Study 1 Study 2
Irinotecan + Bolus 5-FU/LV Irinotecan Irinotecan + Infusional
Bolus 5-FU/LV daily × 5 q weekly × 4 q Infusional 5-FU/LV
weekly × 4 q 4 weeks 6 weeks 5-FU/LV
6 weeks
Number of Patients 231 226 226 198 187
Demographics and Treatment Administration
Female/Male (%) 34/65 45/54 35/64 33/67 47/53
Median Age in years (range) 62 (25-85) 61 (19-85) 61 (30-87) 62 (27-75) 59 (24-75)
Performance Status (%)
0 39 41 46 51 51
1 46 45 46 42 41
2 15 13 8 7 8
Primary Tumor (%)
Colon 81 85 84 55 65
Rectum 17 14 15 45 35
Median Time from Diagnosis
to Randomization 1.9 1.7 1.8 4.5 2.7
(months, range) (0-161) (0-203) (0.1-185) (0-88) (0-104)
Prior Adjuvant 5-FU Therapy (%)
No 89 92 90 74 76
Yes 11 8 10 26 24
Median Duration of Study
Treatment a (months) 5.5 4.1 3.9 5.6 4.5
Median Relative Dose Intensity (%) a
Irinotecan 72 -- 75 87 --
5-FU 71 86 -- 86 93
Efficacy Results
Confirmed Objective Tumor 39 21 18 35 22
Response Rate b (%) (p<0.0001) c (p<0.005) c
Median Time to Tumor Progression d 7.0 4.3 4.2 6.7 4.4
(months) (p=0.004) d (p<0.001) d
Median Survival 14.8 12.6 12.0 17.4 14.1
(months) (p<0.05) d (p<0.05) d
a Study 1: N=225 (irinotecan/5-FU/LV), N=219 (5-FU/LV), N=223 (irinotecan)
Study 2: N=199 (irinotecan/5-FU/LV), N=186 (5-FU/LV)
b Confirmed >/=4 to 6 weeks after first evidence of objective response
c Chi-square test
d Log-rank test
Improvement was noted with irinotecan-based combination therapy relative to 5-FU/LV when response rates and time to tumor progression were examined across the following demographic and disease-related subgroups (age, gender, ethnic origin, performance status, extent of organ involvement with cancer, time from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory abnormalities). Figures 1 and 2 illustrate the Kaplan-Meier survival curves for the comparison of irinotecan/5-FU/LV versus 5-FU/LV in Studies 1 and 2, respectively.
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 IRINOTEL 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, IRINOTEL 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 IRINOTEL in these trials were 100, 125, or 150 mg/m 2 , but the 150-mg/m 2 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/m 2 . Study 3 was a multicenter study that enrolled 166 patients from 30 institutions. The initial dose in Study 3 was 125 mg/m 2 but was reduced to 100 mg/m 2 because the toxicity seen at the 125-mg/m 2 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 3.
Table 3. Weekly Dosage Schedule: Study Results
Study
1 2 3
Number of Patients 48 90 64 102
Starting Dose (mg/m 2 /wk × 4) 125 a 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
IRINOTEL (median, months) 5 4 4 3
Relative Dose Intensity b
(median%) 74 67 73 81
Efficacy
Confirmed Objective Response 21 13 14 9
Rate (%) c(95% CI) (9.3-32.3) (6.3-20.4) (5.5-22.6) (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
a Nine patients received 150 mg/m 2 as a starting dose; two (22.2%) responded to IRINOTEL.
b Relative dose intensity for IRINOTEL based on planned dose intensity of 100, 83.3, and 66.7 mg/m 2 /wk corresponding with 150, 125, and 100 mg/m 2 starting doses, respectively.
c Confirmed >/= 4 to 6 weeks after first evidence of objective response.
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/m 2 . 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/m 2 . 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/m 2 was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to IRINOTEL 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 IRINOTEL had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to IRINOTEL 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/m 2 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/m 2 over 90 minutes once every 3 weeks. The starting dose was 300 mg/m 2 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/m 2 IV over 2 hours; followed by 5-FU, 400 mg/m 2 IV bolus; followed by 5-FU, 600 mg/m 2 continuous IV infusion over 22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to 300 mg/m 2 /day protracted continuous IV infusion until toxicity; (3) 5-FU, 2.6 to 3 g/m 2 IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m 2 /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 5 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.
Table 4. Once-Every-3-Week Dosage Schedule: Study Results
Study 1 Study 2
Irinotecan BSC a 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) 4.1 -- 4.2 2.8
(Log-rank test) (p=0.02)
Relative Dose Intensity
(median %) b 94 -- 95 81-99
Survival
Survival (median, months)
(Log-rank test) 9.2 6.5 10.8 8.5
(p=0.0001) (p=0.035)
a BSC = best supportive care
b Relative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m 2 /wk corresponding with 350 and 300 mg/m 2 starting doses, respectively.
Table 5. EORTC QL Q-C30: Mean Worst Post-Baseline Score a
QLQ-C30 Subscale Study 1 Study 2
Irinotecan BSC p-value Irinotecan 5-FU p-value
Global Health Status 47 37 0.03 53 52 0.9
Functional Scales
Cognitive 77 68 0.07 79 83 0.9
Emotional 68 64 0.4 64 68 0.9
Social 58 47 0.06 65 67 0.9
Physical 60 40 0.0003 66 66 0.9
Role 53 35 0.02 54 57 0.9
Symptom Scales
Fatigue 51 63 0.03 47 46 0.9
Appetite Loss 37 57 0.0007 35 38 0.9
Pain Assessment 41 56 0.009 38 34 0.9
Insomnia 39 47 0.3 39 33 0.9
Constipation 28 41 0.03 25 19 0.9
Dyspnea 31 40 0.2 25 24 0.9
Nausea/Vomiting 27 29 0.5 25 16 0.09
Financial Impact 22 26 0.5 24 15 0.3
Diarrhea 32 19 0.01 32 22 0.2
a For the five functional subscales and global health status subscale, higher scores imply better functioning, whereas, on the nine symptom subscales, higher scores imply more severe symptoms. The subscale scores of each patient were collected at each visit until the patient dropped out of the study.
INDICATIONS AND USAGE
IRINOTEL Injection is indicated as a component of first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. IRINOTEL is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
CONTRAINDICATIONS
IRINOTEL Injection is contraindicated in patients with a known hypersensitivity to the drug.
WARNINGS
General
Outside of a well-designed clinical study, IRINOTEL Injection should not be used in combination with the "Mayo Clinic" regimen of 5-FU/LV (administration for 4-5 consecutive days every 4 weeks) because of reports of increased toxicity, including toxic deaths. IRINOTEL should be used as recommended (see DOSAGE AND ADMINISTRATION , Table 10).
In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, higher rates of hospitalization, 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.
Diarrhea
IRINOTEL can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Early diarrhea (occurring during or shortly after infusion of IRINOTEL) is cholinergic in nature. It is usually transient and only infrequently is severe. It may be accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyper-peristalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by administration of atropine (see PRECAUTIONS , General , for dosing recommendations for atropine).
Late diarrhea (generally occurring more than 24 hours after administration of IRINOTEL) 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 (see PRECAUTIONS , Information for Patients , for dosing recommendations for loperamide). Patients with diarrhea should be carefully monitored, should be given fluid and electrolyte replacement if they become dehydrated, and should be given antibiotic support if they develop ileus, fever, or severe neutropenia. After the first treatment, subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without need for antidiarrhea medication. If grade 2, 3, or 4 late diarrhea occurs subsequent doses of IRINOTEL should be decreased within the current cycle (see DOSAGE AND ADMINISTRATION ).
Neutropenia
Deaths due to sepsis following severe neutropenia have been reported in patients treated with IRINOTEL. Neutropenic complications should be managed promptly with antibiotic support (see PRECAUTIONS ). Therapy with IRINOTEL should be temporarily omitted during a cycle of therapy if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm 3 . After the patient recovers to an absolute neutrophil count >/=1000/mm 3 , subsequent doses of IRINOTEL should be reduced depending upon the level of neutropenia observed (see DOSAGE AND ADMINISTRATION ).
Routine administration of a colony-stimulating factor (CSF) is not necessary, but physicians may wish to consider CSF use in individual patients experiencing significant neutropenia.
Hypersensitivity
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed.
Colitis/Ileus
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed. Patients experiencing ileus should receive prompt antibiotic support (see PRECAUTIONS ).
Renal Impairment/Renal Failure
Rare cases of renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.
Thromboembolism
Thromboembolic events have been observed in patients receiving irinotecan-containing regimens; the specific cause of these events has not been determined.
Pregnancy
IRINOTEL may cause fetal harm when administered to a pregnant woman. Radioactivity related to 14 C-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/m 2 ). Administration of 6 mg/kg/day intravenous irinotecan to rats (which in separate studies produced an irinotecan C max and AUC about 2 and 0.2 times, respectively, the corresponding values in patients administered 125 mg/m 2 ) and rabbits (about one-half the recommended human weekly starting dose on a mg/m 2 basis) during the period of organogenesis, is embryotoxic as characterized by increased post-implantation loss and decreased numbers of live fetuses. 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 1/40th, respectively, of the corresponding values in patients administered 125 mg/m 2 ) and in rabbits at 6.0 mg/kg/day (about one-half the recommended human weekly starting dose on a mg/m 2 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. There are no adequate and well-controlled studies of irinotecan in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with IRINOTEL.
PRECAUTIONS
General
Care of Intravenous Site: IRINOTEL Injection is administered by intravenous infusion. 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.
Premedication with Antiemetics: Irinotecan is emetigenic. 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 IRINOTEL. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.
Treatment of Cholinergic Symptoms: Prophylactic or therapeutic administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping, or diarrhea (occurring during or shortly after infusion of IRINOTEL). These symptoms are expected to occur more frequently with higher irinotecan doses.
Patients at Particular Risk: In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, higher rates of hospitalization, 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. Patients who had previously received pelvic/abdominal radiation and elderly patients with comorbid conditions should be closely monitored.
The use of IRINOTEL in patients with significant hepatic dysfunction has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. However in clinical trials of the weekly dosage schedule, it has been noted that patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) 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 (50.0% [19/38] versus 17.7% [47/226]; p<0.001). Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's syndrome, may also be at greater risk of myelosuppression when receiving therapy with IRINOTEL. An association between baseline bilirubin elevations and an increased risk of late diarrhea has not been observed in studies of the weekly dosage schedule.
Information for Patients
Patients and patients' caregivers should be informed of the expected toxic effects of IRINOTEL, particularly of its gastrointestinal complications, such as nausea, vomiting, abdominal cramping, diarrhea, and infection. Each patient should be instructed to have loperamide readily available and to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of IRINOTEL) 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. One dosage regimen for loperamide used in clinical trials consisted of the following (Note: This dosage regimen exceeds the usual dosage recommendations for loperamide.): 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. Premedication with loperamide is not recommended. The use of drugs with laxative properties should be avoided because of the potential for exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any laxative use.
Patients should be instructed to contact their physician or nurse if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; inability to get diarrhea under control within 24 hours; or fever or evidence of infection.
Patients should be alerted to the possibility of alopecia.
Laboratory Tests
Careful monitoring of the white blood cell count with differential, hemoglobin, and platelet count is recommended before each dose of IRINOTEL.
Drug Interactions
The adverse effects of IRINOTEL, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects.
Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of IRINOTEL. The concurrent administration of IRINOTEL with irradiation has not been adequately studied and is not recommended.
Lymphocytopenia has been reported in patients receiving IRINOTEL, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect. However, serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.
Hyperglycemia has also been reported in patients receiving IRINOTEL. Usually, this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of IRINOTEL. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients.
The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as IRINOTEL than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies.
It would be expected that laxative use during therapy with IRINOTEL would worsen the incidence or severity of diarrhea, but this has not been studied.
In view of the potential risk of dehydration secondary to vomiting and/or diarrhea induced by IRINOTEL, the physician may wish to withhold diuretics during dosing with IRINOTEL and, certainly, during periods of active vomiting or diarrhea.
Drug-Laboratory Test Interactions
There are no known interactions between IRINOTEL and laboratory tests.
Carcinogenesis, Mutagenesis & Impairment of Fertility
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/m 2 weekly) 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. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). 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 and rabbits. 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/m 2 weekly) 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/m 2 weekly).