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Selection of initial treatment for metastatic colorectal cancer

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  • 1. Pfizer Oncology Presents O  ptimizingTreatmentStrategiesin Colorectal Cancer Selection of initial treatment for metastatic colorectal cancer Considerations for patients who have progressed from stage III disease Charles D. Blanke, MD, FACP Professor of Medicine Oregon Health & Science University Cancer Institute Portland, Oregon
  • 2. Pfizer Oncology Presents O  ptimizingTreatmentStrategiesin Colorectal Cancer Selection of initial treatment for metastatic colorectal cancer Considerations for patients who have progressed from stage III disease Charles D. Blanke, MD, FACP Professor of Medicine Oregon Health & Science University Cancer Institute Portland, Oregon Editorial support and publishing was provided by Current Medicine Group LLC and funded by Pfizer Inc.
  • 3.  Selection of initial treatment for metastatic colorectal cancer: considerations for patients who have progressed from stage III disease Key Points • There is a need to strategically plan treatment in metastatic colorectal cancer (mCRC) since more than one option exists for the initial regimen and beyond. • Several factors may determine the appropriate selection of first-line mCRC treatment for previously treated stage III patients. • Prior treatment with adjuvant therapy can impact the selection of initial treatment options when the disease metastasizes. • FOLFOX is often used as adjuvant therapy for patients with stage III colorectal cancer (CRC). In these instances, clinicians may consider using FOLFIRI or other regimens as first-line treatment for those patients whose disease has become metastatic. Introduction CRC remains the fourth most frequently diagnosed cancer and the second leading cause of cancer-related death in Western countries. In a prospective study of 619 patients who had surgery and adjuvant treatment for CRC, it was found that 208 patients relapsed in the first three years.1 Some of these patients were initially diagnosed with stage III disease. To help lower the risk of recurrence, patients usually receive adjuvant chemotherapy following surgical resection. Adjuvant chemotherapy has been shown to increase 5-year survival rates in patients with stage III CRC compared with those who receive no adjuvant chemotherapy.2 However, unfortunately, some of these patients do relapse and develop metastatic disease. This bulletin highlights the various considerations for the selection of initial treatment in patients who have progressed from stage III colorectal cancer to mCRC. The need to strategically plan treatment in mCRC In the past, the standard chemotherapy regimen for patients with mCRC consisted of a bolus injection of 5-fluorouracil (5-FU) combined with leucovorin (LV). However, infusional 5-FU has been shown to be better tolerated than bolus 5-FU, while providing comparable response and survival.3 Advances in the treatment of mCRC have incorporated the use of two other cytotoxic agents, irinotecan and oxaliplatin, in combination with 5-FU and LV. Adding the targeted agent bevacizumab to a first-line irinotecan chemotherapy regimen further improves the overall survival of patients with mCRC.4 Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 6 to 11.
  • 4. In the recent 2007 clinical practice guidelines from the National Comprehensive Cancer  Network® (NCCN), the recommended combination regimens for initial therapy for patients with mCRC who can tolerate intensive therapy are:5 • Infusional 5-FU/LV/irinotecan (FOLFIRI) in combination with bevacizumab. • Infusional 5-FU/LV/oxaliplatin (FOLFOX) in combination with bevacizumab. • Capecitabine plus oxaliplatin (CapeOX) in combination with bevacizumab. • 5-FU/LV in combination with bevacizumab. For all patients with mCRC there are several factors that impact treatment selection, such as the patient’s eligibility for resection, the patient’s condition and characteristics, along with the safety and efficacy of the available regimens. This bulletin focuses on the most commonly used first-line regimens—FOLFOX and FOLFIRI.6 While efficacy is an important factor, toxicity is also a relevant consideration. In first-line FOLFIRI, the most common irinotecan-associated adverse events are diarrhea, neutropenia, leukopenia, emesis, and nausea.7 In first-line FOLFOX, the most common oxaliplatin-associated adverse events are peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.8 The toxicity patients experience may affect their ability and willingness during first-line treatment to continue treatment or affect their suitability to receive subsequent therapy with another regimen. Since some patients may not receive second-line therapy, choosing the most appropriate first-line regimen is often crucial.9 Due to all these considerations, there is a need to strategically plan and tailor the mCRC treatment strategy for each patient.10 This strategic approach can help to improve patient outcomes while addressing treatment toxicities. Impact of prior adjuvant treatment on the initial selection of mCRC treatment An additional factor in selecting the initial treatment regimen for mCRC should be whether the patient has received prior adjuvant therapy and which regimen. There exist several approved adjuvant treatment options, such as FOLFOX, 5-FU and LV, and capecitabine. Currently, there is a lack of trial data confirming which mCRC regimen to use following prior treatment with a specific adjuvant therapy. Nevertheless, for previously treated patients, mCRC treatment strategies should take into account the timing, efficacy, and toxicity of previous adjuvant treatment. This information can help determine which mCRC regimen could be most appropriate for each patient. A patient history that includes prior treatment with adjuvant chemotherapy raises several questions in treating mCRC, such as which combination of agents to use initially for metastatic disease and at what point in the course of treatment could a regimen used as adjuvant therapy be reintroduced. Some factors to be considered before immediate reuse of the adjuvant regimen as initial mCRC therapy include the timing of relapse from the completion of treatment, the extent of adverse events experienced on treatment, and the presence of any remaining residual toxicities. In light of these considerations, it may be appropriate to reintroduce an existing agent or switch to an alternative regimen for the initial treatment of metastatic disease. Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 6 to 11.
  • 5.  Appropriate selection of first-line mCRC treatment after FOLFOX adjuvant therapy Presently, there are no definitive answers regarding whether and when to reuse a regimen used previously during stage III disease when treating a patient now with metastatic disease. For example, the use of FOLFOX as adjuvant therapy has been increasing substantially.6 Consequently, for patients who develop metastatic disease after having been treated at some point with FOLFOX adjuvant therapy, the appropriate initial therapy for mCRC may differ depending upon how physicians consider the factors surrounding the prior treatment. The factors physicians must consider in treating patients with mCRC who have received prior adjuvant therapy include the following: • How long did the patient remain progression free? • Did the patient experience side effects, such as neuropathy? • Will the tumor respond to retreatment with FOLFOX? • Should the patient be treated initially with FOLFIRI and subsequently with FOLFOX? The increasing use of FOLFOX as adjuvant therapy may lead to increased consideration of FOLFIRI as initial therapy for mCRC. However, FOLFOX remains a viable initial mCRC alternative for some of these patients as well. Moreover, in the absence of clear clinical evidence, the physician’s judgment and consideration of all the factors remain important in determining the most appropriate clinical strategy for managing patients with metastatic disease. Conclusion For patients who can tolerate intensive therapies, regimens such as FOLFIRI and FOLFOX remain standards for initial mCRC therapy.5 Both FOLFOX and FOLFIRI continue to be recognized options in the NCCN guidelines. Since there is not one standard approach to treating mCRC, it is critical for clinicians to consider all of the treatment options for patients who have undergone prior adjuvant therapy. This includes the option, when appropriate, of using a different intensive regimen as initial mCRC treatment for patients who have received prior adjuvant therapy. Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 6 to 11.
  • 6. Important information (CAMPTOSAR)  CAMPTOSAR (irinotecan HCl) is indicated as a component of first-line therapy in ® combination with 5-FU/LV for the treatment of metastatic colorectal cancer (mCRC). CAMPTOSAR is also indicated in the treatment of patients with mCRC, whose disease has recurred or progressed following initial FU-based therapy. CAMPTOSAR is not indicated in the adjuvant setting. Both early and late forms of diarrhea can occur and may be life threatening. Late diarrhea should be managed promptly with loperamide and supportive care, including antibiotics as needed. CAMPTOSAR can induce severe myelosuppression. Depending on the severity of neutropenia, dose delay, dose reduction, or use of a colony-stimulating factor should be considered. Particular caution should be exercised in monitoring the effects of CAMPTOSAR in the elderly (>65 years), in patients who have previously received pelvic/abdominal irradiation, in patients with performance status of 2 or higher, and in patients known to be homozygous for the UGT1A1*28 allele. Rare cases of ileus, complicated colitis, or renal impairment have been observed. It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. Provided intolerable toxicity does not develop, treatment with additional courses may be continued indefinitely as long as patients continue to experience clinical benefits. Thromboembolic events have been observed, but the specific cause has not been determined. CAMPTOSAR should not be used in patients with severe bone marrow failure. In addition, patients with hereditary fructose intolerance should not be given CAMPTOSAR, as this product contains sorbitol. References 1 Arriola E, Navarro M, Parés D, et al. Imaging 5 National Comprehensive Cancer Network. techniques contribute to increased surgical rescue NCCN Clinical Practice Guidlines in Oncology – of relapse in the follow-up of colorectal cancer. Dis V.2.2007: Colon Cancer. Available at: www. Colon Rectum 2006;49(4):478–484. nccn.org/professionals/physician_gls/PDF/colon. 2 Jessup JM, Stewart A, Greene FL, et al. Adjuvant pdf. Accessed April 18, 2007. chemotherapy for stage III colon cancer: implica- 6 Data on file. Pfizer Inc, New York, NY. tions of race/ethnicity, age, and differentiation. 7 Camptosar (US prescribing information). New JAMA 2005;294(21):2703–2711. York, NY: Pfizer Inc; 2006. 3 Meta-analysis Group in Cancer. Efficacy of intra- 8 Eloxatin (US prescribing information). Bridge- venous continuous infusion of fluorouracil com- water, NJ: sanofi-aventis US LLC; 2006. pared with bolus administration in advanced 9 Saunders M, Iveson, T. Management of colorectal cancer. J Clin Oncol 1998;16(1): advanced colorectal cancer: state of the art. 301–308. Br J Cancer 2006;95(2):131–138. 4 Hurwitz H, Fehrenbacher L, Novotny W, et al. 10 Goldberg RM, Rothenberg ML, Van Cutsem E, Bevacizumab plus irinotecan, fluorouracil, and et al. The continuum of care: a paradigm for the leucovorin for metastatic colorectal cancer. management of metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–2342. Oncologist 2007;12(1):38–50. Please see the full CAMPTOSAR® (irinotecan HCl) prescribing information on pages 6 to 11.
  • 7.  Camptosar ® Camptosar ® Camptosar® irinotecan hydrochloride injection irinotecan hydrochloride injection irinotecan hydrochloride injection Table 1. Summary of Mean (±Standard Deviation) Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients Irinotecan and SN-38 Pharmacokinetic receiving concomitant ketoconazole have increased exposure to irinotecan and its Parameters in Patients with Solid Tumors active metabolite SN-38. Patients should discontinue ketoconazole at least 1 week Irinotecan SN-38 prior to starting irinotecan therapy and ketoconazole is contraindicated during For Intravenous Use Only irinotecan therapy. Dose (mg/m2) Cmax AUC0-24 t1/2 Vz CL Cmax AUC0-24 t1/2 Neuromuscular blocking agents. Interaction between irinotecan and WARNINGS neuromuscular blocking agents cannot be ruled out. Irinotecan has anti- CAMPTOSAR Injection should be administered only under the supervision (ng/mL) (ng·h/mL) (h) (L/m2) (L/h/m2) (ng/mL)(ng·h/mL) (h) cholinesterase activity, which may prolong the neuromuscular blocking effects of of a physician who is experienced in the use of cancer chemotherapeutic 125 1,660 10,200 5.8 a 110 13.3 26.3 229 10.4 a suxamethonium and the neuromuscular blockade of non-depolarizing drugs may agents. Appropriate management of complications is possible only when (N=64) ±797 ±3,270 ±0.7 ±48.5 ±6.01 ±11.9 ±108 ±3.1 be antagonized. adequate diagnostic and treatment facilities are readily available. Atazanavir sulfate: Coadministration of atazanavir sulfate, a CYP3A4 and CAMPTOSAR can induce both early and late forms of diarrhea that appear to 340 3,392 20,604 11.7b 234 13.9 56.0 474 21.0b UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the be mediated by different mechanisms. Both forms of diarrhea may be severe. (N=6) ±874 ±6,027 ±1.0 ±69.6 ±4.0 ±28.2 ±245 ±4.3 active metabolite of irinotecan. Physicians should take this into consideration Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) when co-administering these drugs. Cmax - Maximum plasma concentration may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperi- AUC0-24 - Area under the plasma concentration-time curve from time 0 to 24 CLINICAL STUDIES stalsis that can cause abdominal cramping. Early diarrhea and other hours after the end of the 90-minute infusion Irinotecan has been studied in clinical trials in combination with 5-fluorouracil cholinergic symptoms may be prevented or ameliorated by atropine (see t1/2 - Terminal elimination half-life (5-FU) and leucovorin (LV) and as a single agent (see DOSAGE AND ADMINIS- PRECAUTIONS, General). Late diarrhea (generally occurring more than 24 Vz - Volume of distribution of terminal elimination phase TRATION). When given as a component of combination-agent treatment, irinote- hours after administration of CAMPTOSAR) can be life threatening since it CL - Total systemic clearance can was either given with a weekly schedule of bolus 5-FU/LV or with an every- may be prolonged and may lead to dehydration, electrolyte imbalance, or a Plasma specimens collected for 24 hours following the end of the 90-minute 2-week schedule of infusional 5-FU/LV. Weekly and a once-every-3-week dosage sepsis. Late diarrhea should be treated promptly with loperamide. Patients schedules were used for the single-agent irinotecan studies. Clinical studies of infusion. with diarrhea should be carefully monitored and given fluid and electrolyte b Plasma specimens collected for 48 hours following the end of the 90-minute combination and single-agent use are described below. replacement if they become dehydrated or antibiotic therapy if they develop infusion. Because of the longer collection period, these values provide a First-Line Therapy in Combination with 5-FU/LV for the Treatment of Metastatic ileus, fever, or severe neutropenia (see WARNINGS). Administration of more accurate reflection of the terminal elimination half-lives of irinotecan and Colorectal Cancer CAMPTOSAR should be interrupted and subsequent doses reduced if severe SN-38. Two phase 3, randomized, controlled, multinational clinical trials support the diarrhea occurs (see DOSAGE AND ADMINISTRATION). use of CAMPTOSAR Injection as first-line treatment of patients with metastatic Severe myelosuppression may occur (see WARNINGS). Irinotecan exhibits moderate plasma protein binding (30% to 68% carcinoma of the colon or rectum. In each study, combinations of irinotecan with bound). SN-38 is highly bound to human plasma proteins (approximately 95% 5-FU and LV were compared with 5-FU and LV alone. Study 1 compared combi- DESCRIPTION bound). The plasma protein to which irinotecan and SN-38 predominantly binds nation irinotecan/bolus 5-FU/LV therapy given weekly with a standard bolus reg- CAMPTOSAR Injection (irinotecan hydrochloride injection) is an antineo- is albumin. imen of 5-FU/LV alone given daily for 5 days every 4 weeks; an irinotecan-alone plastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride was Metabolism and Excretion: The metabolic conversion of irinotecan to the active treatment arm given on a weekly schedule was also included. Study 2 evaluated clinically investigated as CPT-11. metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs two different methods of administering infusional 5-FU/LV, with or without CAMPTOSAR is supplied as a sterile, pale yellow, clear, aqueous solution. It is in the liver. SN-38 is subsequently conjugated predominantly by the enzyme UDP- irinotecan. In both studies, concomitant medications such as antiemetics, available in two single-dose sizes: 2 mL-fill vials contain 40 mg irinotecan glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. atropine, and loperamide were given to patients for prophylaxis and/or manage- hydrochloride and 5 mL-fill vials contain 100 mg irinotecan hydrochloride. Each UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead ment of symptoms from treatment. In Study 2, a 7-day course of fluoroquinolone milliliter of solution contains 20 mg of irinotecan hydrochloride (on the basis of to reduced enzyme activity such as the UGT1A1*28 polymorphism. antibiotic prophylaxis was given in patients whose diarrhea persisted for greater the trihydrate salt), 45 mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. Approximately 10% of the North American population is homozygous for the than 24 hours despite loperamide or if they developed a fever in addition to diar- The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium UGT1A1*28 allele. In a prospective study, in which irinotecan was administered rhea. Treatment with oral fluoroquinolone was also initiated in patients who devel- hydroxide or hydrochloric acid. CAMPTOSAR is intended for dilution with 5% as a single-agent on a once-every-3-week schedule, patients who were oped an absolute neutrophil count (ANC) <500/mm3, even in the absence of fever Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients with or diarrhea. Patients in both studies also received treatment with intravenous intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP. the wild-type UGT1A1 allele (See WARNINGS and DOSAGE AND ADMINISTRA- antibiotics if they had persistent diarrhea or fever or if ileus developed. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an TION). SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity In both studies, the combination of irinotecan/5-FU/LV therapy resulted in alkaloid extract from plants such as Camptotheca acuminata or is chemically syn- assays using two cell lines in vitro. The disposition of irinotecan has not been fully significant improvements in objective tumor response rates, time to tumor pro- thesized. The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy- elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, gression, and survival when compared with 5-FU/LV alone. These differences in 3,14-dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4’bipiperidine]- <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion survival were observed in spite of second-line therapy in a majority of patients on 1’-carboxylate, monohydrochloride, trihydrate. Its structural formula is as of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of both arms, including crossover to irinotecan-containing regimens in the control follows: 48 hours following administration of irinotecan in two patients ranged from arm. Patient characteristics and major efficacy results are shown in Table 2. approximately 25% (100 mg/m2) to 50% (300 mg/m2). 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 AUC0-24 for SN-38 in patients who were at least 65 years of age was 11% higher than in patients younger than 65 years. Irinotecan Hydrochloride No change in the starting dose is recommended for geriatric patients receiving Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the the weekly dosage schedule of irinotecan. The pharmacokinetics of irinotecan empirical formula C33H38N4O6•HCl•3H2O and a molecular weight of 677.19. It is given once every 3 weeks has not been studied in the geriatric population; a lower slightly soluble in water and organic solvents. starting dose is recommended in patients 70 years or older based on clinical tox- CLINICAL PHARMACOLOGY icity experience with this schedule (see DOSAGE AND ADMINISTRATION). Irinotecan is a derivative of camptothecin. Camptothecins interact specifically Pediatric: See Pediatric Use under PRECAUTIONS. with the enzyme topoisomerase I which relieves torsional strain in DNA by induc- Gender: The pharmacokinetics of irinotecan do not appear to be influenced by ing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 gender. bind to the topoisomerase I-DNA complex and prevent religation of these single- Race: The influence of race on the pharmacokinetics of irinotecan has not been strand breaks. Current research suggests that the cytotoxicity of irinotecan is due evaluated. to double-strand DNA damage produced during DNA synthesis when replication Hepatic Insufficiency: Irinotecan clearance is diminished in patients with hepatic enzymes interact with the ternary complex formed by topoisomerase I, DNA, and dysfunction while exposure to the active metabolite SN-38 is increased relative to either irinotecan or SN-38. Mammalian cells cannot efficiently repair these that in patients with normal hepatic function. The magnitude of these effects is double-strand breaks. proportional to the degree of liver impairment as measured by elevations in total Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. bilirubin and transaminase concentrations. However, the tolerability of irinotecan SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been carbamate bond between the camptothecin moiety and the dipiperidino side assessed sufficiently, and no recommendations for dosing can be made (see chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor DOSAGE AND ADMINISTRATION and PRECAUTIONS: Patients at Particular Risk of topoisomerase I purified from human and rodent tumor cell lines. In vitro Sections). cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics from 2- to 2000-fold. However, the plasma area under the concentration versus of irinotecan has not been evaluated. Therefore, caution should be undertaken in time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% patients with impaired renal function. Irinotecan is not recommended for use in bound to plasma proteins compared to approximately 50% bound to plasma pro- patients on dialysis. teins for irinotecan (see Pharmacokinetics). The precise contribution of SN-38 to Drug-Drug Interactions the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in 5-fluorouracil (5-FU) and leucovorin (LV): In a phase 1 clinical study involving an active lactone form and an inactive hydroxy acid anion form. A pH-dependent irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid Improvement was noted with irinotecan-based combination therapy relative to equilibrium exists between the two forms such that an acid pH promotes the for- tumors, the disposition of irinotecan was not substantially altered when the drugs 5-FU/LV when response rates and time to tumor progression were examined mation of the lactone, while a more basic pH favors the hydroxy acid anion form. were co-administered. Although the Cmax and AUC0-24 of SN-38, the active across the following demographic and disease-related subgroups (age, gender, Administration of irinotecan has resulted in antitumor activity in mice metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was ethnic origin, performance status, extent of organ involvement with cancer, time bearing cancers of rodent origin and in human carcinoma xenografts of various followed by 5-FU and LV administration compared with when irinotecan was from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory abnor- histological types. given alone, this sequence of administration was used in the combination trials malities). Figures 1 and 2 illustrate the Kaplan-Meier survival curves for the com- and is recommended (see DOSAGE AND ADMINISTRATION). Formal in vivo or parison of irinotecan/5-FU/LV versus 5-FU/LV in Studies 1 and 2, respectively. Pharmacokinetics After intravenous infusion of irinotecan in humans, irinotecan plasma concen- in vitro drug interaction studies to evaluate the influence of irinotecan on the dis- Second-Line Treatment for Recurrent or Progressive Metastatic Colorectal trations decline in a multiexponential manner, with a mean terminal elimination position of 5-FU and LV have not been conducted. Cancer After 5-FU-Based Treatment half-life of about 6 to 12 hours. The mean terminal elimination half-life of the Anticonvulsants: Exposure to irinotecan and its active metabolite SN-38 is Weekly Dosage Schedule active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone substantially reduced in adult and pediatric patients concomitantly receiving the Data from three open-label, single-agent, clinical studies, involving a total of (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carba- 304 patients in 59 centers, support the use of CAMPTOSAR in the treatment of SN-38, as the lactone and hydroxy acid forms are in equilibrium. mazepine. The appropriate starting dose for patients taking these anticonvulsants patients with metastatic cancer of the colon or rectum that has recurred or pro- Over the recommended dose range of 50 to 350 mg/m2, the AUC of has not been formally defined. The following drugs are also CYP3A4 inducers: gressed following treatment with 5-FU-based therapy. These studies were irinotecan increases linearly with dose; the AUC of SN-38 increases less than pro- rifampin, rifabutin. For patients requiring anticonvulsant treatment, consideration designed to evaluate tumor response rate and do not provide information on portionally with dose. Maximum concentrations of the active metabolite SN-38 should be given to substituting non-enzyme inducing anticonvulsants at least 2 actual clinical benefit, such as effects on survival and disease-related symptoms. are generally seen within 1 hour following the end of a 90-minute infusion of weeks prior to initiation of irinotecan therapy. Dexamethasone does not appear to In each study, CAMPTOSAR was administered in repeated 6-week cycles consist- irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following a alter the pharmacokinetics of irinotecan. ing of a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m2 determined St. John’s Wort: St. John’s Wort is an inducer of CYP3A4 enzymes. Exposure 2-week rest period. Starting doses of CAMPTOSAR in these trials were 100, 125, in two clinical studies in patients with solid tumors are summarized in Table 1: to the active metabolite SN-38 is reduced in patients receiving concomitant St. or 150 mg/m2, but the 150-mg/m2 dose was poorly tolerated (due to unaccept- John’s Wort. St. John’s Wort should be discontinued at least 2 weeks prior to the ably high rates of grade 4 late diarrhea and febrile neutropenia). Study 1 enrolled first cycle of irinotecan, and St. John’s Wort is contraindicated during irinotecan 48 patients and was conducted by a single investigator at several regional hospi- therapy. tals. 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
  • 8. Camptosar ® Camptosar ® Camptosar ®  irinotecan hydrochloride injection irinotecan hydrochloride injection irinotecan hydrochloride injection performance status and other baseline prognostic factors, survival among Table 2. Combination Dosage Schedule: Study Results patients treated with irinotecan remained significantly longer than in the control Study 1 Study 2 populations (p=0.001 for Study 1 and p=0.017 for Study 2). Measurements of Irinotecan + pain, performance status, and weight loss were collected prospectively in the two Bolus 5-FU/LV Bolus 5-FU/LV Irinotecan Irinotecan + studies; however, the plan for the analysis of these data was defined retrospec- weekly x 4 q daily x 5 q weekly x 4 q Infusional Infusional tively. When comparing irinotecan with best supportive care in Study 1, this 6 weeks 4 weeks 6 weeks 5-FU/LV 5-FU/LV analysis showed a statistically significant advantage for irinotecan, with longer Number of Patients 231 226 226 198 187 time to development of pain (6.9 months versus 2.0 months), time to perform- Demographics and Treatment Administration ance 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 Female/Male (%) 34/65 45/54 35/64 33/67 47/53 patients with a baseline performance status of 1 or 2 showed an improvement in Median Age in years (range) 62 (25-85) 61 (19-85) 61 (30-87) 62 (27-75) 59 (24-75) performance status when treated with irinotecan versus 11.3% (7/62) of patients Performance Status (%) receiving best supportive care (p=0.002). Because of the inclusion of patients 0 39 41 46 51 51 with non-measurable disease, intent-to-treat response rates could not be 1 46 45 46 42 41 assessed. 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 Rateb (%) (p<0.0001)c (p<0.005)c Median Time to Tumor Progressiond 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 be greater than that seen in previous studies. All patients in these studies had In the intent-to-treat analysis of the pooled data across all three studies, metastatic colorectal cancer, and the majority had disease that recurred or 193 of the 304 patients began therapy at the recommended starting dose of progressed following a 5-FU-based regimen administered for metastatic disease. 125 mg/m2. Among these 193 patients, 2 complete and 27 partial responses were The results of the individual studies are shown in Table 3. observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], Table 3. Weekly Dosage Schedule: Study Results 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 Study 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 In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. 1 2 3 median response duration for patients beginning therapy at 125 mg/m2 was At the start of each cycle of therapy, patients completed a questionnaire consist- Number of Patients 48 90 64 102 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three ing of 30 questions, such as “Did pain interfere with daily activities?” (1 = Not at Starting Dose studies, response rates to CAMPTOSAR were similar in males and females and All, to 4 = Very Much) and “Do you have any trouble taking a long walk?” (Yes (mg/m2/wk x 4) 125 a 125 125 100 among patients older and younger than 65 years. Rates were also similar in or No). The answers from the 30 questions were converted into 15 subscales, patients with cancer of the colon or cancer of the rectum and in patients with that were scored from 0 to 100, and the global health status subscale that was Demographics and Treatment Administration single and multiple metastatic sites. The response rate was 18.5% in patients with derived from two questions about the patient’s sense of general well being in the Female/Male (%) 46/54 36/64 50/50 51/49 a performance status of 0 and 8.2% in patients with a performance status past week. In addition to the global health status subscale, there were five func- of 1 or 2. Patients with a performance status of 3 or 4 have not been studied. tional (i.e., cognitive, emotional, social, physical, role) and nine symptom (i.e., Median Age in years (range) 63 (29-78) 63 (32-81) 61 (42-84) 64 (25-84) fatigue, appetite loss, pain assessment, insomnia, constipation, dyspnea, nau- Over half of the patients responding to CAMPTOSAR had not responded to prior Ethnic Origin (%) 5-FU. Patients who had received previous irradiation to the pelvis responded to sea/vomiting, financial impact, diarrhea) subscales. The results as summarized in White 79 96 81 91 CAMPTOSAR at approximately the same rate as those who had not previously Table 5 are based on patients’ worst post-baseline scores. In Study 1, a multivari- African American 12 4 11 5 received irradiation. ate analysis and univariate analyses of the individual subscales were performed Hispanic 8 0 8 2 and corrected for multivariate testing. Patients receiving irinotecan reported sig- Oriental/Asian 0 0 0 2 Once-Every-3-Week Dosage Schedule nificantly better results for the global health status, on two of five functional sub- Single-Arm Studies: Data from an open-label, single-agent, single-arm, multicen- Performance Status (%) scales, and on four of nine symptom subscales. As expected, patients receiving ter, clinical study involving a total of 132 patients support a once-every-3-week 0 60 38 59 44 irinotecan noted significantly more diarrhea than those receiving best supportive dosage schedule of irinotecan in the treatment of patients with metastatic cancer 1 38 48 33 51 care. In Study 2, the multivariate analysis on all 15 subscales did not indicate a of the colon or rectum that recurred or progressed following treatment with 2 2 14 8 5 statistically significant difference between irinotecan and infusional 5-FU. 5-FU. Patients received a starting dose of 350 mg/m2 given by 30-minute intra- Primary Tumor (%) venous infusion once every 3 weeks. Among the 132 previously treated patients Table 4. Once-Every-3-Week Dosage Schedule: Study Results Colon 100 71 89 87 in this trial, the intent-to-treat response rate was 12.1% (95% CI, 7.0% to 18.1%). Study 1 Study 2 Rectum 0 29 11 8 Randomized Trials: Two multicenter, randomized, clinical studies further support Unknown 0 0 0 5 the use of irinotecan given by the once-every-3-week dosage schedule in patients Irinotecan BSCa Irinotecan 5-FU Prior 5-FU Therapy (%) with metastatic colorectal cancer whose disease has recurred or progressed fol- Number of Patients 189 90 127 129 For Metastatic Disease 81 66 73 68 lowing 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 Demographics and Treatment Administration ≤ 6 months after Adjuvant 15 7 27 28 > 6 months after Adjuvant 2 16 0 2 second study, second-line irinotecan therapy was compared with infusional 5-FU- Female/Male (%) 32/68 42/58 43/57 35/65 Classification Unknown 2 12 0 3 based therapy. In both studies, irinotecan was administered intravenously at a Median Age in years (range) 59 (22-75) 62 (34-75) 58 (30-75) 58 (25-75) starting dose of 350 mg/m2 over 90 minutes once every 3 weeks. The starting Prior Pelvic/Abdominal dose was 300 mg/m2 for patients who were 70 years and older or who had a Performance Status (%) Irradiation (%) performance status of 2. The highest total dose permitted was 700 mg. 0 47 31 58 54 Yes 3 29 0 0 Dose reductions and/or administration delays were permitted in the event of 1 39 46 35 43 Other 0 9 2 4 2 14 23 8 3 severe hematologic and/or nonhematologic toxicities while on treatment. Best None 97 62 98 96 supportive care was provided to patients in both arms of Study 1 and included Primary Tumor (%) Duration of Treatment with antibiotics, analgesics, corticosteroids, transfusions, psychotherapy, or any other Colon 55 52 57 62 CAMPTOSAR (median, months) 5 4 4 3 symptomatic therapy as clinically indicated. In both studies, concomitant med- Rectum 45 48 43 38 Relative Dose Intensityb ications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. If late diarrhea Prior 5-FU Therapy (%) (median %) 74 67 73 81 persisted for greater than 24 hours despite loperamide, a 7-day course of fluoro- For Metastatic Disease 70 63 58 68 Efficacy quinolone antibiotic prophylaxis was given. Patients in the control arm of the As Adjuvant Treatment 30 37 42 32 Confirmed Objective Response 21 13 14 9 second study received one of the following 5-FU regimens: (1) LV, 200 mg/m2 IV Prior Irradiation (%) 26 27 18 20 Rate (%)c (95% CI) (9.3-32.3) (6.3-20.4) (5.5-22.6) (3.3 -14.3) 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; Duration of Study Treatment Time to Response (median, months) 4.1 — 4.2 2.8 (2) 5-FU, 250 to 300 mg/m2/day protracted continuous IV infusion until toxicity; (median, months) 2.6 1.5 2.8 2.8 (Log-rank test) (p=0.02) (3) 5-FU, 2.6 to 3 g/m2 IV over 24 hours every week for 6 weeks with or without Response Duration LV, 20 to 500 mg/m2/day every week IV for 6 weeks with 2-week rest between Relative Dose Intensity (median, months) 6.4 5.9 5.6 6.4 cycles. Patients were to be followed every 3 to 6 weeks for 1 year. (median %)b 94 — 95 81-99 Survival (median, months) 10.4 8.1 10.7 9.3 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 sig- Survival 1-Year Survival (%) 46 31 45 43 nificant overall survival advantage for irinotecan compared with best supportive Survival (median, months) 9.2 6.5 10.8 8.5 a Nine patients received 150 mg/m2 as a starting dose; two (22.2%) responded to care (p=0.0001) and infusional 5-FU-based therapy (p=0.035) as shown in (Log-rank test) (p=0.0001) (p=0.035) CAMPTOSAR. Figures 3 and 4. In Study 1, median survival for patients treated with irinotecan a was 9.2 months compared with 6.5 months for patients receiving best support- BSC = best supportive care b Relative dose intensity for CAMPTOSAR based on planned dose intensity of 100, b Relative dose intensity for irinotecan based on planned dose intensity of 116.7 83.3, and 66.7 mg/m2/wk corresponding with 150, 125, and 100 mg/m2 starting ive care. In Study 2, median survival for patients treated with irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional and 100 mg/m2/wk corresponding with 350 and 300 mg/m2 starting doses, doses, respectively. respectively. c Confirmed ≥ 4 to 6 weeks after first evidence of objective response. 5-FU-based therapy. Multiple regression analyses determined that patients’ base- line characteristics also had a significant effect on survival. When adjusted for
  • 9.  Camptosar ® Camptosar ® Camptosar ® irinotecan hydrochloride injection irinotecan hydrochloride injection irinotecan hydrochloride injection Table 5. EORTC QLQ-C30: Mean Worst Post-Baseline Scorea Colitis/Ileus stools; symptoms of dehydration such as lightheadedness, dizziness, or faint- Cases of colitis complicated by ulceration, bleeding, ileus, and infection have ness; inability to take fluids by mouth due to nausea or vomiting; inability to get QLQ-C30 Subscale Study 1 Study 2 been observed. Patients experiencing ileus should receive prompt antibiotic sup- diarrhea under control within 24 hours; or fever or evidence of infection. port (see PRECAUTIONS). Patients should be warned about the potential for dizziness or visual Irinotecan Irinotecan Renal Impairment/Renal Failure disturbances which may occur within 24 hours following the administration of p-value p-value Rare cases of renal impairment and acute renal failure have been identified, CAMPTOSAR, and advised not to drive or operate machinery if these symptoms 5-FU BSC usually in patients who became volume depleted from severe vomiting and/or occur. diarrhea. Patients should be alerted to the possibility of alopecia. Global Health Status 47 37 0.03 53 52 0.9 Laboratory Tests Thromboembolism Functional Scales Thromboembolic events have been observed in patients receiving irinotecan- Careful monitoring of the white blood cell count with differential, hemoglobin, Cognitive 77 68 0.07 79 83 0.9 containing regimens; the specific cause of these events has not been determined. and platelet count is recommended before each dose of CAMPTOSAR. Drug Interactions Emotional 68 64 0.4 64 68 0.9 Pregnancy The adverse effects of CAMPTOSAR, such as myelosuppression and diarrhea, CAMPTOSAR may cause fetal harm when administered to a pregnant woman. Social 58 47 0.06 65 67 0.9 would be expected to be exacerbated by other antineoplastic agents having Radioactivity related to 14C-irinotecan crosses the placenta of rats following intra- Physical 60 40 0.0003 66 66 0.9 similar adverse effects. venous administration of 10 mg/kg (which in separate studies produced an Patients who have previously received pelvic/abdominal irradiation are Role 53 35 0.02 54 57 0.9 irinotecan Cmax and AUC about 3 and 0.5 times, respectively, the corresponding at increased risk of severe myelosuppression following the administration of Symptom Scales values in patients administered 125 mg/m2). Administration of 6 mg/kg/day intra- CAMPTOSAR. The concurrent administration of CAMPTOSAR with irradiation venous irinotecan to rats (which in separate studies produced an irinotecan Cmax Fatigue 51 63 0.03 47 46 0.9 has not been adequately studied and is not recommended. and AUC about 2 and 0.2 times, respectively, the corresponding values in patients Lymphocytopenia has been reported in patients receiving CAMPTOSAR, and Appetite Loss 37 57 0.0007 35 38 0.9 administered 125 mg/m2) and rabbits (about one-half the recommended human it is possible that the administration of dexamethasone as antiemetic prophylaxis Pain Assessment 41 56 0.009 38 34 0.9 weekly starting dose on a mg/m2 basis) during the period of organogenesis, is may have enhanced the likelihood of this effect. However, serious opportunistic embryotoxic as characterized by increased post-implantation loss and decreased Insomnia 39 47 0.3 39 33 0.9 infections have not been observed, and no complications have specifically been numbers of live fetuses. Irinotecan was teratogenic in rats at doses greater than Constipation 28 41 0.03 25 19 0.9 attributed to lymphocytopenia. 1.2 mg/kg/day (which in separate studies produced an irinotecan Cmax and AUC Hyperglycemia has also been reported in patients receiving CAMPTOSAR. Dyspnea 31 40 0.2 25 24 0.9 about 2/3 and 1/40th, respectively, of the corresponding values in patients Usually, this has been observed in patients with a history of diabetes mellitus or administered 125 mg/m2) and in rabbits at 6.0 mg/kg/day (about one-half the rec- Nausea/Vomiting 27 29 0.5 25 16 0.09 evidence of glucose intolerance prior to administration of CAMPTOSAR. It is ommended human weekly starting dose on a mg/m2 basis). Teratogenic effects Financial Impact 22 26 0.5 24 15 0.3 probable that dexamethasone, given as antiemetic prophylaxis, contributed to included a variety of external, visceral, and skeletal abnormalities. Irinotecan hyperglycemia in some patients. Diarrhea 32 19 0.01 32 22 0.2 administered to rat dams for the period following organogenesis through wean- The incidence of akathisia in clinical trials of the weekly dosage schedule was ing at doses of 6 mg/kg/day caused decreased learning ability and decreased a For the five functional subscales and global health status subscale, higher greater (8.5%, 4/47 patients) when prochlorperazine was administered on the female body weights in the offspring. There are no adequate and well-controlled scores imply better functioning, whereas, on the nine symptom subscales, same day as CAMPTOSAR than when these drugs were given on separate days studies of irinotecan in pregnant women. If the drug is used during pregnancy, higher scores imply more severe symptoms. The subscale scores of each (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the or if the patient becomes pregnant while receiving this drug, the patient should patient were collected at each visit until the patient dropped out of the study. range reported for use of prochlorperazine when given as a premedication for be apprised of the potential hazard to the fetus. Women of childbearing potential other chemotherapies. INDICATIONS AND USAGE should be advised to avoid becoming pregnant while receiving treatment with It would be expected that laxative use during therapy with CAMPTOSAR would CAMPTOSAR Injection is indicated as a component of first-line therapy CAMPTOSAR. worsen the incidence or severity of diarrhea, but this has not been studied. in combination with 5-fluorouracil and leucovorin for patients with metastatic PRECAUTIONS In view of the potential risk of dehydration secondary to vomiting and/or carcinoma of the colon or rectum. CAMPTOSAR is also indicated for patients General diarrhea induced by CAMPTOSAR, the physician may wish to withhold diuretics with metastatic carcinoma of the colon or rectum whose disease has recurred or Care of Intravenous Site: CAMPTOSAR Injection is administered by intravenous during dosing with CAMPTOSAR and, certainly, during periods of active vomit- progressed following initial fluorouracil-based therapy. infusion. Care should be taken to avoid extravasation, and the infusion site should ing or diarrhea. CONTRAINDICATIONS be monitored for signs of inflammation. Should extravasation occur, flushing the Drug-Laboratory Test Interactions CAMPTOSAR Injection is contraindicated in patients with a known hypersen- site with sterile water and applications of ice are recommended. There are no known interactions between CAMPTOSAR and laboratory tests. sitivity to the drug or its excipients. Premedication with Antiemetics: Irinotecan is emetigenic. It is recommended that Carcinogenesis, Mutagenesis & Impairment of Fertility WARNINGS patients receive premedication with antiemetic agents. In clinical studies of the Long-term carcinogenicity studies with irinotecan were not conducted. Rats General weekly dosage schedule, the majority of patients received 10 mg of dexametha- were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinote- Outside of a well-designed clinical study, CAMPTOSAR Injection should not be sone given in conjunction with another type of antiemetic agent, such as a 5-HT3 can once per week for 13 weeks (in separate studies, the 25 mg/kg dose pro- used in combination with the “Mayo Clinic” regimen of 5-FU/LV (administration blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given duced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the for 4-5 consecutive days every 4 weeks) because of reports of increased toxicity, on the day of treatment, starting at least 30 minutes before administration of respective values in patients administered 125 mg/m2 weekly) and were then including toxic deaths. CAMPTOSAR should be used as recommended (see CAMPTOSAR. Physicians should also consider providing patients with an allowed to recover for 91 weeks. Under these conditions, there was a significant DOSAGE AND ADMINISTRATION, Table 10). antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed. linear trend with dose for the incidence of combined uterine horn endometrial In patients receiving either irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, Treatment of Cholinergic Symptoms: Prophylactic or therapeutic administration stromal polyps and endometrial stromal sarcomas. Neither irinotecan nor SN-38 higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered was mutagenic in the in vitro Ames assay. Irinotecan was clastogenic both in vitro treatment discontinuation, and early deaths were observed in patients with a (unless clinically contraindicated) in patients experiencing rhinitis, increased (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronu- baseline performance status of 2 than in patients with a baseline performance salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping, or cleus test in mice). No significant adverse effects on fertility and general repro- status of 0 or 1. diarrhea (occurring during or shortly after infusion of CAMPTOSAR). These ductive performance were observed after intravenous administration of irinote- symptoms are expected to occur more frequently with higher irinotecan doses. can in doses of up to 6 mg/kg/day to rats and rabbits. However, atrophy of male Diarrhea Patients at Particular Risk: In patients receiving either irinotecan/5-FU/LV or CAMPTOSAR can induce both early and late forms of diarrhea that appear to reproductive organs was observed after multiple daily irinotecan doses both in 5-FU/LV in the clinical trials, higher rates of hospitalization, neutropenic fever, rodents at 20 mg/kg (which in separate studies produced an irinotecan Cmax and be mediated by different mechanisms. Early diarrhea (occurring during or shortly thromboembolism, first-cycle treatment discontinuation, and early deaths were after infusion of CAMPTOSAR) is cholinergic in nature. It is usually transient and AUC about 5 and 1 times, respectively, the corresponding values in patients observed in patients with a baseline performance status of 2 than in patients with administered 125 mg/m2 weekly) and dogs at 0.4 mg/kg (which in separate stud- only infrequently is severe. It may be accompanied by symptoms of rhinitis, a baseline performance status of 0 or 1. Patients who had previously received increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal ies produced an irinotecan Cmax and AUC about one-half and 1/15 th, respectively, pelvic/abdominal radiation and elderly patients with comorbid conditions should the corresponding values in patients administered 125 mg/m2 weekly). hyperperistalsis that can cause abdominal cramping. Early diarrhea and other be closely monitored. cholinergic symptoms may be prevented or ameliorated by administration of Pregnancy The use of CAMPTOSAR in patients with significant hepatic dysfunction has Pregnancy Category D—see WARNINGS. atropine (see PRECAUTIONS, General, for dosing recommendations for not been established. In clinical trials of either dosing schedule, irinotecan was atropine). Nursing Mothers not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase Late diarrhea (generally occurring more than 24 hours after administration of Radioactivity appeared in rat milk within 5 minutes of intravenous administra- >3 times the upper limit of normal if no liver metastasis, or transaminase CAMPTOSAR) can be life threatening since it may be prolonged and may lead to tion of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after >5 times the upper limit of normal with liver metastasis. In clinical trials of the dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated administration relative to plasma concentrations. Because many drugs are weekly dosage schedule, patients with modestly elevated baseline serum total promptly with loperamide (see PRECAUTIONS, Information for Patients, for dos- excreted in human milk and because of the potential for serious adverse reac- bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experi- ing recommendations for loperamide). Patients with diarrhea should be carefully tions in nursing infants, it is recommended that nursing be discontinued when encing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that monitored, should be given fluid and electrolyte replacement if they become receiving therapy with CAMPTOSAR. were less than 1.0 mg/dL (50.% [19/38] versus 18% [47/226]; p<0.001). (Also dehydrated, and should be given antibiotic support if they develop ileus, fever, or see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations: Pediatric Use severe neutropenia. After the first treatment, subsequent weekly chemotherapy Hepatic Insufficiency). Patients with deficient glucuronidation of bilirubin, such as The effectiveness of irinotecan in pediatric patients has not been established. treatments should be delayed in patients until return of pretreatment bowel func- those with Gilbert’s syndrome, may be at greater risk of myelosuppression when Results from two open-label, single arm studies were evaluated. One hundred and tion for at least 24 hours without need for antidiarrhea medication. If grade 2, 3, receiving therapy with CAMPTOSAR. seventy children with refractory solid tumors were enrolled in one phase 2 trial in or 4 late diarrhea occurs subsequent doses of CAMPTOSAR should be decreased Ketoconazole, enzyme-inducing anticonvulsants and St. John’s Wort are which 50 mg/m2 of irinotecan was infused for 5 consecutive days every 3 weeks. within the current cycle (see DOSAGE AND ADMINISTRATION). known to have drug-drug interactions with irinotecan therapy. (See Drug-Drug Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was Neutropenia Interactions sub-section under CLINICAL PHARMACOLOGY) complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 Deaths due to sepsis following severe neutropenia have been reported Irinotecan commonly causes neutropenia, leucopenia, and anemia, any of (20.6%) patients. This adverse event profile was comparable to that observed in in patients treated with CAMPTOSAR. Neutropenic complications should be which may be severe and therefore should not be used in patients with severe adults. In the second phase 2 trial of 21 children with previously untreated rhab- managed promptly with antibiotic support (see PRECAUTIONS). Therapy with bone marrow failure. domyosarcoma, 20 mg/m2 of irinotecan was infused for 5 consecutive days on CAMPTOSAR should be temporarily omitted during a cycle of therapy if Patients must not be treated with irinotecan until resolution of the bowel obstruc- weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal ther- neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3. tion. Patients with hereditary fructose intolerance should not be given apy. Accrual to the single agent irinotecan phase was halted due to the high rate After the patient recovers to an absolute neutrophil count ≥1000/mm3, subse- CAMPTOSAR, as this product contains sorbitol. (28.6%) of progressive disease and the early deaths (14%). The adverse event pro- quent doses of CAMPTOSAR should be reduced depending upon the level of Information for Patients file was different in this study from that observed in adults; the most significant neutropenia observed (see DOSAGE AND ADMINISTRATION). Patients and patients’ caregivers should be informed of the expected toxic grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) Routine administration of a colony-stimulating factor (CSF) is not necessary, effects of CAMPTOSAR, particularly of its gastrointestinal complications, such as associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 but physicians may wish to consider CSF use in individual patients experiencing nausea, vomiting, abdominal cramping, diarrhea, and infection. Each patient patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) significant neutropenia. should be instructed to have loperamide readily available and to begin treatment (across all courses of therapy and irrespective of causal relationship). Patients with Reduced UGT1A1 Activity for late diarrhea (generally occurring more than 24 hours after administration of Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 Individuals who are homozygous for the UGT1A1*28 allele are at increased CAMPTOSAR) at the first episode of poorly formed or loose stools or the earli- pediatric solid-tumor trials at dose levels of 50 mg/m2 (60-min infusion, n=48) risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced est onset of bowel movements more frequent than normally expected for the and 125 mg/m2 (90-min infusion, n=6). Irinotecan clearance (mean ± S.D.) was initial dose should be considered for patients known to be homozygous for the patient. One dosage regimen for loperamide used in clinical trials consisted of the 17.3 ± 6.7 L/h/m2 for the 50 mg/m2 dose and 16.2 ± 4.6 L/h/m2 for the 125 UGT1A1*28 allele (see DOSAGE AND ADMINISTRATION). Heterozygous patients following (Note: This dosage regimen exceeds the usual dosage mg/m2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC (carriers of one variant allele and one wild-type allele which results in intermedi- recommendations for loperamide.): 4 mg at the first onset of late diarrhea and values were comparable between adults and children. Minimal accumulation of ate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. irinotecan and SN-38 was observed in children on daily dosing regimens [daily x results have been variable and such patients have been shown to tolerate normal Loperamide is not recommended to be used for more than 48 consecutive hours 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks]. starting doses. at these doses, because of the risk of paralytic ileus. During the night, the patient Geriatric Use Hypersensitivity may take 4 mg of loperamide every 4 hours. Premedication with loperamide is Patients greater than 65 years of age should be closely monitored because of Hypersensitivity reactions including severe anaphylactic or anaphylactoid not recommended. The use of drugs with laxative properties should be avoided a greater risk of late diarrhea in this population (see CLINICAL PHARMACOLOGY , reactions have been observed. because of the potential for exacerbation of diarrhea. Patients should be advised Pharmacokinetics in Special Populations and ADVERSE REACTIONS, Overview to contact their physician to discuss any laxative use. of Adverse Events). The starting dose of CAMPTOSAR in patients 70 years and Patients should be instructed to contact their physician or nurse if any of the older for the once-every-3-week dosage schedule should be 300 mg/m2 (see following occur: diarrhea for the first time during treatment; black or bloody DOSAGE AND ADMINISTRATION).
  • 10. Camptosar ® Camptosar ® Camptosar ®  irinotecan hydrochloride injection irinotecan hydrochloride injection irinotecan hydrochloride injection Table 6. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa Table 7. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa (continued) Study 1 Study 2 Irinotecan + Bolus 5-FU/LV Bolus 5-FU/LV Irinotecan weekly x 4 daily x 5 weekly x 4 Irinotecan + q 6 weeks q 4 weeks q 6 weeks Adverse Event N=225 N=219 N=223 5-FU/LV 5-FU/LV Infusional d 1&2 Infusional d 1&2 Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 q 2 weeks q 2 weeks TOTAL Adverse Events 100 53.3 100 45.7 99.6 45.7 Adverse Event N=145 N=143 GASTROINTESTINAL Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 Diarrhea late 84.9 22.7 69.4 13.2 83.0 31.0 DERMATOLOGIC grade 3 — 15.1 — 5.9 — 18.4 grade 4 — 7.6 — 7.3 — 12.6 Hand & foot syndrome 10.3 0.7 12.6 0.7 early 45.8 4.9 31.5 1.4 43.0 6.7 Cutaneous signs 17.2 0.7 20.3 0 Nausea 79.1 15.6 67.6 8.2 81.6 16.1 Alopecia c 56.6 — 16.8 — Abdominal pain 63.1 14.6 50.2 11.5 67.7 13.0 Vomiting 60.4 9.7 46.1 4.1 62.8 12.1 RESPIRATORY Anorexia 34.2 5.8 42.0 3.7 43.9 7.2 Dyspnea 9.7 1.4 4.9 0 Constipation 41.3 3.1 31.5 1.8 32.3 0.4 CARDIOVASCULAR Mucositis 32.4 2.2 76.3 16.9 29.6 2.2 Hypotension 3.4 1.4 0.7 0 HEMATOLOGIC Thromboembolic events d 11.7 — 5.6 — Neutropenia 96.9 53.8 98.6 66.7 96.4 31.4 grade 3 — 29.8 — 23.7 — 19.3 a Severity of adverse events based on NCI CTC (version 1.0) grade 4 — 24.0 — 42.5 — 12.1 b Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flush- Leukopenia 96.9 37.8 98.6 23.3 96.4 21.5 ing, abdominal cramping or diarrhea (occurring during or shortly after infu- Anemia 96.9 8.4 98.6 5.5 96.9 4.5 Neutropenic fever — 7.1 — 14.6 — 5.8 sion of irinotecan) c Complete hair loss = Grade 2 Thrombocytopenia 96.0 2.6 98.6 2.7 96.0 1.7 Neutropenic infection — 1.8 — 0 — 2.2 d Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular BODY AS A WHOLE accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myo- Asthenia 70.2 19.5 64.4 11.9 69.1 13.9 cardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary Pain 30.7 3.1 26.9 3.6 22.9 2.2 embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder. Fever 42.2 1.7 32.4 3.6 43.5 0.4 Infection 22.2 0 16.0 1.4 13.9 0.4 Adjustments in the dose of CAMPTOSAR were made during the cycle of treat- ment and for subsequent cycles based on individual patient tolerance. The first METABOLIC & NUTRITIONAL ↑ Bilirubin 87.6 7.1 92.2 8.2 83.9 7.2 dose of at least one cycle of CAMPTOSAR was reduced for 67% of patients who began the studies at the 125-mg/m2 starting dose. Within-cycle dose reductions DERMATOLOGIC were required for 32% of the cycles initiated at the 125-mg/m2 dose level. The Exfoliative dermatitis 0.9 0 3.2 0.5 0 0 Rash 19.1 0 26.5 0.9 14.3 0.4 most common reasons for dose reduction were late diarrhea, neutropenia, and Alopecia b 43.1 — 26.5 — 46.1 — leukopenia. Thirteen (4.3%) patients discontinued treatment with CAMPTOSAR because of adverse events. The adverse events in Table 8 are based on the expe- RESPIRATORY Dyspnea 27.6 6.3 16.0 0.5 22.0 2.2 rience of the 304 patients enrolled in the three studies described in the CLINICAL Cough 26.7 1.3 18.3 0 20.2 0.4 STUDIES, Studies Evaluating the Weekly Dosage Schedule, section. Pneumonia 6.2 2.7 1.4 1.0 3.6 1.3 Table 8. Adverse Events Occurring in >10% of 304 Previously NEUROLOGIC Treated Patients with Metastatic Carcinoma Dizziness 23.1 1.3 16.4 0 21.1 1.8 of the Colon or Rectuma Somnolence 12.4 1.8 4.6 1.8 9.4 1.3 Confusion 7.1 1.8 4.1 0 2.7 0 % of Patients Reporting CARDIOVASCULAR Body System & Event Vasodilation 9.3 0.9 5.0 0 9.0 0 NCI Grades 1-4 NCI Grades 3 & 4 Hypotension 5.8 1.3 2.3 0.5 5.8 1.7 GASTROINTESTINAL Thromboembolic events c 9.3 — 11.4 — 5.4 — Diarrhea (late)b 88 31 a Severity of adverse events based on NCI CTC (version 1.0) 7-9 stools/day (grade 3) — (16) b Complete hair loss = Grade 2 ≥10 stools/day (grade 4) — (14) c Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, Nausea 86 17 myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder. Vomiting 67 12 Anorexia 55 6 ADVERSE REACTIONS One hundred nineteen (39.1%) of the 304 patients were hospitalized a total of Diarrhea (early) c 51 8 First-Line Combination Therapy 156 times because of adverse events; 81 (26.6%) patients were hospitalized for Constipation 30 2 A total of 955 patients with metastatic colorectal cancer received the recom- events judged to be related to administration of CAMPTOSAR. The primary rea- Flatulence 12 0 mended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or sons for drug-related hospitalization were diarrhea, with or without nausea and/or Stomatitis 12 1 irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever Dyspepsia 10 0 combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients (8.2%); and nausea and/or vomiting (4.9%). received irinotecan alone. (See Table 10 in DOSAGE AND ADMINISTRATION for Table 7. Study 2: Percent (%) of Patients Experiencing Clinically HEMATOLOGIC recommended combination-agent regimens.) Relevant Adverse Events in Combination Therapiesa Leukopenia 63 28 In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: Anemia 60 7 21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received Study 2 Neutropenia 54 26 5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related 500 to <1000/mm 3 (grade 3) — (15) Irinotecan + to treatment occurred in 2 (0.9%) patients who received irinotecan in combina- <500/mm3 (grade 4) — (12) 5-FU/LV 5-FU/LV tion with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received Infusional d 1&2 Infusional d 1&2 BODY AS A WHOLE 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocy- q 2 weeks q 2 weeks Asthenia 76 12 topenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neu- Adverse Event N=145 N=143 Abdominal cramping/pain 57 16 tropenic fever). Deaths from any cause within 60 days of first study treatment Fever 45 1 were reported for 15 (6.7%) patients who received irinotecan in combination with Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 Pain 24 2 5-FU/LV, 16 (7.3%) patients who received 5-FU/LV alone, and 15 (6.7%) patients TOTAL Adverse Events 100 72.4 100 39.2 Headache 17 1 who received irinotecan alone. Discontinuations due to adverse events were Back pain 14 2 reported for 17 (7.6%) patients who received irinotecan in combination with GASTROINTESTINAL Diarrhea Chills 14 0 5-FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26 (11.7%) patients Minor infection d 14 0 who received irinotecan alone. late 72.4 14.4 44.8 6.3 grade 3 — 10.3 — 4.2 Edema 10 1 In Study 2, 10 (3.5%) patients died within 30 days of last study treatment: Abdominal enlargement 10 0 grade 4 — 4.1 — 2.1 6 (4.1%) received irinotecan in combination with 5-FU/LV and 4 (2.8%) received Cholinergic syndrome b 28.3 1.4 0.7 0 METABOLIC & NUTRITIONAL 5-FU/LV alone. There was one potentially treatment-related death, which occurred Nausea 66.9 2.1 55.2 3.5 ↓ Body weight 30 1 in a patient who received irinotecan in combination with 5-FU/LV (0.7%, neu- Abdominal pain 17.2 2.1 16.8 0.7 Dehydration 15 4 tropenic sepsis). Deaths from any cause within 60 days of first study treatment Vomiting 44.8 3.5 32.2 2.8 ↑ Alkaline phosphatase 13 4 were reported for 3 (2.1%) patients who received irinotecan in combination with Anorexia 35.2 2.1 18.9 0.7 ↑ SGOT 10 1 5-FU/LV and 2 (1.4%) patients who received 5-FU/LV alone. Discontinuations due Constipation 30.3 0.7 25.2 1.4 to adverse events were reported for 9 (6.2%) patients who received irinotecan in DERMATOLOGIC Mucositis 40.0 4.1 28.7 2.8 combination with 5-FU/LV and 1 (0.7%) patient who received 5-FU/LV alone. Alopecia 60 NA e The most clinically significant adverse events for patients receiving irinotecan- HEMATOLOGIC Sweating 16 0 based therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The Neutropenia 82.5 46.2 47.9 13.4 Rash 13 1 most clinically significant adverse events for patients receiving 5-FU/LV therapy grade 3 — 36.4 — 12.7 RESPIRATORY were diarrhea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade grade 4 — 9.8 — 0.7 Dyspnea 22 4 4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutrope- Leukopenia 81.3 17.4 42.0 3.5 ↑ Coughing 17 0 nia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than Anemia 97.2 2.1 90.9 2.1 Rhinitis 16 0 with monthly administration of 5-FU/LV. Neutropenic fever — 3.4 — 0.7 Tables 6 and 7 list the clinically relevant adverse events reported in Studies 1 Thrombocytopenia 32.6 0 32.2 0 NEUROLOGIC and 2, respectively. Neutropenic infection — 2.1 — 0 Insomnia 19 0 Second-Line Single-Agent Therapy Dizziness 15 0 BODY AS A WHOLE Weekly Dosage Schedule Asthenia 57.9 9.0 48.3 4.2 CARDIOVASCULAR In three clinical studies evaluating the weekly dosage schedule, 304 patients Pain 64.1 9.7 61.5 8.4 Vasodilation (flushing) 11 0 with metastatic carcinoma of the colon or rectum that had recurred or progressed Fever 22.1 0.7 25.9 0.7 a Severity of adverse events based on NCI CTC (version 1.0) following 5-FU-based therapy were treated with CAMPTOSAR. Seventeen of the Infection 35.9 7.6 33.6 3.5 b Occurring >24 hours after administration of CAMPTOSAR patients died within 30 days of the administration of CAMPTOSAR; in five cases c Occurring ≤24 hours after administration of CAMPTOSAR METABOLIC & NUTRITIONAL (1.6%, 5/304), the deaths were potentially drug-related. These five patients d Primarily upper respiratory infections ↑ Bilirubin 19.1 3.5 35.9 10.6 experienced a constellation of medical events that included known effects of e Not applicable; complete hair loss = NCI grade 2 CAMPTOSAR. One of these patients died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other patients; these patients recov- ered with supportive care.
  • 11. 10 Camptosar ® Camptosar ® Camptosar ® irinotecan hydrochloride injection irinotecan hydrochloride injection irinotecan hydrochloride injection Once-Every-3-Week Dosage Schedule icantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than OVERDOSAGE A total of 535 patients with metastatic colorectal cancer whose disease had those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus In U.S. phase 1 trials, single doses of up to 345 mg/m2 of irinotecan were recurred or progressed following prior 5-FU therapy participated in the two phase 18% [47/266]; p<0.001). There were no significant differences in the frequency administered to patients with various cancers. Single doses of up to 750 mg/m2 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best sup- of grade 3 and 4 neutropenia by age or gender. In the clinical studies evaluating of irinotecan have been given in non-U.S. trials. The adverse events in these portive care. Eleven (3.5%) patients treated with irinotecan died within 30 days the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neu- patients were similar to those reported with the recommended dosage and regi- of treatment. In three cases (1%, 3/316), the deaths were potentially related to tropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% men. There have been reports of overdosage at doses up to approximately twice irinotecan treatment and were attributed to neutropenic infection, grade 4 diar- of patients received G-CSF for the treatment of neutropenia. NCI grade 3 or 4 the recommended therapeutic dose, which may be fatal. The most significant rhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died anemia was noted in 7% of the patients receiving weekly treatment; blood trans- adverse reactions reported were severe neutropenia and severe diarrhea. There within 30 days of treatment; this death was attributed to grade 4 diarrhea. fusions were given to 10% of the patients in these trials. is no known antidote for overdosage of CAMPTOSAR. Maximum supportive care Hospitalizations due to serious adverse events (whether or not related to study Body as a Whole: Asthenia, fever, and abdominal pain are generally the most should be instituted to prevent dehydration due to diarrhea and to treat any infec- treatment) occurred at least once in 60% (188/316) of patients who received common events of this type. tious complications. irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) Cholinergic Symptoms: Patients may have cholinergic symptoms of rhinitis, DOSAGE AND ADMINISTRATION who received 5-FU-based therapy. Eight percent of patients treated with irinote- increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal Dosage in Patients with Reduced UGT1A1 Activity can and 7% treated with 5-FU-based therapy discontinued treatment due to hyperperistalsis that can cause abdominal cramping and early diarrhea. If these When administered in combination with other agents, or as a single-agent, a adverse events. symptoms occur, they manifest during or shortly after drug infusion. They are reduction in the starting dose by at least one level of CAMPTOSAR should be con- Of the 316 patients treated with irinotecan, the most clinically significant thought to be related to the anticholinesterase activity of the irinotecan parent sidered for patients known to be homozygous for the UGT1A1*28 allele (see adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea compound and are expected to occur more frequently with higher irinotecan CLINICAL PHARMACOLOGY and WARNINGS). However, the precise dose reduc- (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). doses. tion in this patient population is not known and subsequent dose modifications Table 9 lists the grade 3 and 4 adverse events reported in the patients enrolled to Hepatic: In the clinical studies evaluating the weekly dosage schedule, NCI grade should be considered based on individual patient tolerance to treatment (see all treatment arms of the two studies described in the CLINICAL STUDIES, 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. Tables 10-13). Studies Evaluating the Once-Every-3-Week Dosage Schedule, section. These events typically occur in patients with known hepatic metastases. Dermatologic: Alopecia has been reported during treatment with CAMPTOSAR. Combination-Agent Dosage Table 9. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Rashes have also been reported but did not result in discontinuation of treatment. Dosage Regimens Comparative Studies Of Once-Every-3-Week Irinotecan Therapya Respiratory: Severe pulmonary events are infrequent. In the clinical studies eval- CAMPTOSAR Injection in Combination with 5-Fluorouracil (5-FU) and Study 1 Study 2 uating the weekly dosage schedule, NCI grade 3 or 4 dyspnea was reported in Leucovorin (LV) 4% of patients. Over half the patients with dyspnea had lung metastases; the CAMPTOSAR should be administered as an intravenous infusion over 90 min- Irinotecan BSCb Irinotecan 5-FU extent to which malignant pulmonary involvement or other preexisting lung dis- utes (see Preparation of Infusion Solution). For all regimens, the dose of LV Adverse Event N=189 N=90 N=127 N=129 ease may have contributed to dyspnea in these patients is unknown. should be administered immediately after CAMPTOSAR, with the administration TOTAL Grade 3/4 Interstitial pulmonary disease presenting as pulmonary infiltrates is uncom- of 5-FU to occur immediately after receipt of LV. CAMPTOSAR should be used as Adverse Events 79 67 69 54 mon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk recommended; the currently recommended regimens are shown in Table 10. GASTROINTESTINAL factors possibly associated with the development of interstitial pulmonary dis- Dosing for patients with bilirubin >2 mg/dL cannot be recommended because Diarrhea 22 6 22 11 ease include pre-existing lung disease, use of pneumotoxic drugs, radiation ther- there is insufficient information to recommend a dose in these patients. It is rec- Vomiting 14 8 14 5 apy, and colony stimulating factors. Patients with risk factors should be closely ommended that patients receive premedication with antiemetic agents. Nausea 14 3 11 4 monitored for respiratory symptoms before and during irinotecan therapy. Prophylactic or therapeutic administration of atropine should be considered in Abdominal pain 14 16 9 8 Neurologic: Insomnia and dizziness can occur, but are not usually considered to patients experiencing cholinergic symptoms. See PRECAUTIONS, General. Constipation 10 8 8 6 be directly related to the administration of CAMPTOSAR. Dizziness may some- Dose Modifications Anorexia 5 7 6 4 times represent symptomatic evidence of orthostatic hypotension in patients with Patients should be carefully monitored for toxicity and assessed prior to each Mucositis 2 1 2 5 dehydration. treatment. Doses of CAMPTOSAR and 5-FU should be modified as necessary to Cardiovascular: Vasodilation (flushing) may occur during administration of accommodate individual patient tolerance to treatment. Based on the HEMATOLOGIC CAMPTOSAR. Bradycardia may also occur, but has not required intervention. recommended dose-levels described in Table 10, Combination-Agent Dosage Leukopenia/Neutropenia 22 0 14 2 These effects have been attributed to the cholinergic syndrome sometimes Regimens & Dose Modifications, subsequent doses should be adjusted as sug- Anemia 7 6 6 3 observed during or shortly after infusion of CAMPTOSAR. Thromboembolic gested in Table 11, Recommended Dose Modifications for Combination Hemorrhage 5 3 1 3 events have been observed in patients receiving CAMPTOSAR; the specific cause Schedules. All dose modifications should be based on the worst Thrombocytopenia 1 0 4 2 of these events has not been determined. preceding toxicity. After the first treatment, patients with active diarrhea should Infection Other Non-U.S. Clinical Trials return to pre-treatment bowel function without requiring anti-diarrhea medica- without grade 3/4 neutropenia 8 3 1 4 Irinotecan has been studied in over 1100 patients in Japan. Patients in these tions for at least 24 hours before the next chemotherapy administration. with grade 3/4 neutropenia 1 0 2 0 studies had a variety of tumor types, including cancer of the colon or rectum, and A new cycle of therapy should not begin until the toxicity has recovered to NCI Fever were treated with several different doses and schedules. In general, the types of grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery without grade 3/4 neutropenia 2 1 2 0 toxicities observed were similar to those seen in U.S. trials with CAMPTOSAR. from treatment-related toxicity. If the patient has not recovered, consideration with grade 3/4 neutropenia 2 0 4 2 There is some information from Japanese trials that patients with considerable should be given to discontinuing therapy. Provided intolerable toxicity does not BODY AS A WHOLE ascites or pleural effusions were at increased risk for neutropenia or diarrhea. A develop, treatment with additional cycles of CAMPTOSAR/5-FU/LV may be con- Pain 19 22 17 13 potentially life-threatening pulmonary syndrome, consisting of dyspnea, fever, tinued indefinitely as long as patients continue to experience clinical benefit. Asthenia 15 19 13 12 and a reticulonodular pattern on chest x-ray, was observed in a small percentage Single-Agent Dosage Schedules of patients in early Japanese studies. The contribution of irinotecan to these pre- Dosage Regimens METABOLIC & NUTRITIONAL liminary events was difficult to assess because these patients also had lung Hepaticc 9 7 9 6 CAMPTOSAR should be administered as an intravenous infusion over 90 min- tumors and some had preexisting nonmalignant pulmonary disease. As a result utes for both the weekly and once-every-3-week dosage schedules (see DERMATOLOGIC of these observations, however, clinical studies in the United States have enrolled Preparation of Infusion Solution). Single-agent dosage regimens are shown in Hand & foot syndrome 0 0 0 5 few patients with compromised pulmonary function, significant ascites, or pleu- Table 12. Cutaneous signs d 2 0 1 3 ral effusions. A reduction in the starting dose by one dose level of CAMPTOSAR may be RESPIRATORY e 10 8 5 7 Post-Marketing Experience considered for patients with any of the following conditions: age ≥65 years, prior The following events have been identified during postmarketing use of pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin NEUROLOGIC f 12 13 9 4 CAMPTOSAR in clinical practice. Infrequent cases of ulcerative and ischemic coli- levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended CARDIOVASCULAR g 9 3 4 2 tis have been observed. This can be complicated by ulceration, bleeding, ileus, because there is insufficient information to recommend a dose in these patients. obstruction, and infection, including typhlitis. Patients experiencing ileus should It is recommended that patients receive premedication with antiemetic agents. OTHER h 32 28 12 14 receive prompt antibiotic support (see PRECAUTIONS). Rare cases of intestinal Prophylactic or therapeutic administration of atropine should be considered in a Severity of adverse events based on NCI CTC (version 1.0) perforation have been reported. Rare cases of symptomatic pancreatitis or patients experiencing cholinergic symptoms. See PRECAUTIONS, General. b BSC = best supportive care asymptomatic elevated pancreatic enzymes have been observed. Dose Modifications c Hepatic includes events such as ascites and jaundice Hypersensitivity reactions including severe anaphylactic or anaphylactoid Patients should be carefully monitored for toxicity and doses of CAMPTOSAR d Cutaneous signs include events such as rash reactions have also been observed (see WARNINGS). should be modified as necessary to accommodate individual patient tolerance to e Respiratory includes events such as dyspnea and cough Rare cases of hyponatremia mostly related with diarrhea and vomiting have treatment. Based on recommended dose-levels described in Table 12, Single- f Neurologic includes events such as somnolence been reported. Transient and mild to moderate increases in serum levels of Agent Regimens of CAMPTOSAR and Dose Modifications, subsequent doses g Cardiovascular includes events such as dysrhythmias, ischemia, and transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis; should be adjusted as suggested in Table 13, Recommended Dose Modifications mechanical cardiac dysfunction transient increase of amylase and occasionally transient increase of lipase have for Single-Agent Schedules. All dose modifications should be based on the worst h Other includes events such as accidental injury, hepatomegaly, syncope, been very rarely reported. preceding toxicity. vertigo, and weight loss Infrequent cases of renal insufficiency including acute renal failure, hypoten- A new cycle of therapy should not begin until the toxicity has recovered to NCI sion or circulatory failure have been observed in patients who experienced grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from Overview of Adverse Events episodes of dehydration associated with diarrhea and/or vomiting, or sepsis (see treatment-related toxicity. If the patient has not recovered, consideration should Gastrointestinal: Nausea, vomiting, and diarrhea are common adverse events fol- WARNINGS). be given to discontinuing this combination therapy. Provided intolerable toxicity lowing treatment with CAMPTOSAR and can be severe. When observed, nausea Early effects such as muscular contraction or cramps and paresthesia have does not develop, treatment with additional cycles of CAMPTOSAR may be con- and vomiting usually occur during or shortly after infusion of CAMPTOSAR. In been reported. tinued indefinitely as long as patients continue to experience clinical benefit. 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 Table 10. Combination-Agent Dosage Regimens & Dose Modifications a diarrhea was 11 days following administration of CAMPTOSAR. For patients Regimen 1 CAMPTOSAR 125 mg/m2 IV over 90 min, d 1,8,15,22 starting treatment at the 125-mg/m2 weekly dose, the median duration of any 6-wk cycle with LV 20 mg/m2 IV bolus, d 1,8,15,22 grade of late diarrhea was 3 days. Among those patients treated at the 125-mg/m2 bolus 5-FU/LV 5-FU 500 mg/m2 IV bolus, d 1,8,15,22 weekly dose who experienced grade 3 or 4 late diarrhea, the median duration of (next cycle begins on Starting Dose & Modified Dose Levels (mg/m2) the entire episode of diarrhea was 7 days. The frequency of grade 3 or 4 late diar- rhea was somewhat greater in patients starting treatment at 125 mg/m2 than in day 43) Starting Dose Dose Level -1 Dose Level -2 patients given a 100-mg/m2 weekly starting dose (34% [65/193] versus 23% CAMPTOSAR 125 100 75 [24/102]; p=0.08). The frequency of grade 3 and 4 late diarrhea by age was sig- LV 20 20 20 nificantly greater in patients ≥65 years than in patients <65 years (40% [53/133] 5-FU 500 400 300 versus 23% [40/171]; p=0.002). In one study of the weekly dosage treatment, the frequency of grade 3 and 4 late diarrhea was significantly greater in male than Regimen 2 CAMPTOSAR 180 mg/m2 IV over 90 min, d 1,15,29 6-wk cycle LV 200 mg/m2 IV over 2 h, d 1,2,15,16,29,30 in female patients (43% [25/58] versus 16% [5/32]; p=0.01), but there were no with infusional 5-FU Bolus 400 mg/m2 IV bolus, d 1,2,15,16,29,30 gender differences in the frequency of grade 3 and 4 late diarrhea in the other two 5-FU/LV 5-FU Infusion b 600 mg/m2 IV over 22 h, d 1,2,15,16,29,30 studies of the weekly dosage treatment schedule. Colonic ulceration, sometimes (next cycle Starting Dose & Modified Dose Levels (mg/m2) with gastrointestinal bleeding, has been observed in association with administra- begins on tion of CAMPTOSAR. day 43) Starting Dose Dose Level -1 Dose Level -2 Hematology: CAMPTOSAR commonly causes neutropenia, leukopenia (including CAMPTOSAR 180 150 120 lymphocytopenia), and anemia. Serious thrombocytopenia is uncommon. When LV 200 200 200 evaluated in the trials of weekly administration, the frequency of grade 3 and 4 5-FU Bolus 400 320 240 neutropenia was significantly higher in patients who received previous 5-FU Infusionb 600 480 360 pelvic/abdominal irradiation than in those who had not received such irradiation a Dose reductions beyond dose level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does (48% [13/27] versus 24% [67/277]; p=0.04). In these same studies, patients not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a signif- b Infusion follows bolus administration.
  • 12. Camptosar ® Camptosar ® Camptosar ® 11 irinotecan hydrochloride injection irinotecan hydrochloride injection irinotecan hydrochloride injection Table 11. Recommended Dose Modifications for CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules Preparation & Administration Precautions As with other potentially toxic anticancer agents, care should be exercised in Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administra- the handling and preparation of infusion solutions prepared from CAMPTOSAR tion. 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 Injection. The use of gloves is recommended. If a solution of CAMPTOSAR con- 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 therapy. tacts the skin, wash the skin immediately and thoroughly with soap and water. If CAMPTOSAR contacts the mucous membranes, flush thoroughly with water. Toxicity During a Cycle of Therapy At the Start of Subsequent Several published guidelines for handling and disposal of anticancer agents are NCI CTC Grade a (Value) Cycles of Therapy b available.1-7 No toxicity Maintain dose level Maintain dose level Preparation of Infusion Solution Inspect vial contents for particulate matter and repeat inspection when drug Neutropenia product is withdrawn from vial into syringe. 1 (1500 to 1999/mm 3) Maintain dose level Maintain dose level CAMPTOSAR Injection must be diluted prior to infusion. CAMPTOSAR should 2 (1000 to 1499/mm 3) ↓ 1 dose level Maintain dose level be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride 3 (500 to 999/mm 3) Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓ 1 dose level Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL. In most clin- 4 (<500/mm 3) Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels ical trials, CAMPTOSAR was administered in 250 mL to 500 mL of 5% Dextrose Injection, USP. Neutropenic fever Omit dose until resolved, then ↓ 2 dose levels The solution is physically and chemically stable for up to 24 hours at room temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions Other hematologic toxicities Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. (approximately 2° to 8°C), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visi- Diarrhea ble particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR may 1 (2-3 stools/day > pretx c) Delay dose until resolved to baseline, then give same dose Maintain dose level result in precipitation of the drug and should be avoided. Because 2 (4-6 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 1 dose level Maintain dose level 3 (7-9 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 1 dose level ↓ 1 dose level of possible microbial contamination during dilution, it is advisable to use the 4 (≥10 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 2 dose levels ↓ 2 dose levels admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refriger- ated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should Other nonhematologic toxicities d be used within 6 hours if kept at room temperature (15° to 30°C, 59° to 86°F). 1 Maintain dose level Maintain dose level 2 Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level Maintain dose level Other drugs should not be added to the infusion solution. Parenteral drug 3 Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓ 1 dose level products should be inspected visually for particulate matter and discoloration 4 Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels prior to administration whenever solution and container permit. For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR For mucositis/stomatitis decrease only HOW SUPPLIED 5-FU, not CAMPTOSAR Each mL of CAMPTOSAR Injection contains 20 mg irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic acid. When necessary, a National Cancer Institute Common Toxicity Criteria (version 1.0) pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or b Relative to the starting dose used in the previous cycle hydrochloric acid. c Pretreatment CAMPTOSAR Injection is available in single-dose amber glass vials in the d Excludes alopecia, anorexia, asthenia following package sizes: 2 mL NDC 0009-7529-02 5 mL NDC 0009-7529-01 Table 12. Single-Agent Regimens of CAMPTOSAR and Dose Modifications This is packaged in a backing/plastic blister to protect against inadvertent Weekly Regimena 125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest breakage and leakage. The vial should be inspected for damage and visible signs Starting Dose & Modified Dose Levels c (mg/m2) of leaks before removing the backing/plastic blister. If damaged, incinerate the unopened package. Starting Dose Dose Level -1 Dose Level -2 Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from 125 100 75 light. It is recommended that the vial (and backing/plastic blister) should remain Once-Every-3-Week 350 mg/m2 IV over 90 min, once every 3 wks c in the carton until the time of use. Regimenb Starting Dose & Modified Dose Levels (mg/m2) Starting Dose Dose Level -1 Dose Level -2 350 300 250 REFERENCES a Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance. 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and b Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. 1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. Table 13. Recommended Dose Modifications For Single-Agent Schedules a US Dept of Health and Human Services, Public Health Service publication NIH A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3, and the platelet count has recovered 83-2621. to ≥100,000/mm 3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment- 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineo- related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR. plastics. JAMA. 1985;253:1590-1592. At the Start of the Next Cycles of Therapy 4. National Study Commission on Cytotoxic Exposure. Recommendations for Worst Toxicity During a Cycle of Therapy (After Adequate Recovery), Compared with the handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, NCI Grade b (Value) Starting Dose in the Previous Cyclea National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Weekly Weekly Once Every 3 Weeks Boston, MA 02115. No toxicity Maintain dose level 5. Clinical Oncological Society of Australia. Guidelines and recommendations for ↑ 25 mg/m2 up to a maximum Maintain dose level dose of 150 mg/m2 safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a Neutropenia report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1 (1500 to 1999/mm3) Maintain dose level Maintain dose level Maintain dose level 1983;33:258-263. 2 (1000 to 1499/mm3) ↓ 25 mg/m2 Maintain dose level Maintain dose level Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin 3 (500 to 999/mm3) ↓ 25 mg/m2 ↓ 50 mg/m2 4 (<500/mm3) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. ↓ 50 mg/m2 ↓ 50 mg/m2 1990;47:1033-1049. Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m2 when resolved ↓ 50 mg/m2 ↓ 50 mg/m2 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work- Practice Guidelines.) Am J Health-SystPharm. 1996;53;1669-1685. Other hematologic Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of toxicities therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Camptosar brand of irinotecan hydrochloride injection Diarrhea Distributed by 1 (2-3 stools/day > pretx c) Maintain dose level Maintain dose level Maintain dose level 2 (4-6 stools/day > pretx) ↓ 25 mg/m2 Maintain dose level Maintain dose level 3 (7-9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 Pharmacia & Upjohn Co 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 Division of P zer Inc, NY, NY 10017 Other nonhematologicd toxicities Licensed from Yakult Honsha Co., LTD, Japan, and Daiichi Pharmaceutical Co., 1 Maintain dose level Maintain dose level Maintain dose level LTD, Japan 2 ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 3 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 Revised June 2006 4 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 LAB-0134-10.0 a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia
  • 13. Camptosar® irinotecan hydrochloride injection For Intravenous Use Only WARNINGS CAMPTOSAR 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.CAMPTOSAR 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 CAMPTOSAR) 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 CAMPTOSAR) 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 CAMPTOSAR should be interrupted and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND ADMINISTRATION). Severe myelosuppression may occur (see WARNINGS). DESCRIPTION CAMPTOSAR Injection (irinotecan hydrochloride injection) is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride was clinically investigated as CPT-11. CAMPTOSAR 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. CAMPTOSAR 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 or is chemically synthesized. The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H- 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:
  • 14. Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the empirical formula C 33H38N4O6•HCl•3H2O 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 CAMPTOSAR 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
  • 15. 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: Table 1.Summary of Mean (±Standard Deviation) Irinotecan and SN-38 Pharmacokinetic Parameters in Patients with Solid Tumors Irinotecan SN-38 Dose (mg/m2) Cmax AUC0-24 t1/2 Vz CL Cmax AUC0-24 t1/2 (ng/mL) (ng·h/mL) (h) (L/m2) (L/h/m2) (ng/mL) (ng·h/mL) (h) 125 1,660 10,200 5.8a 110 13.3 26.3 229 10.4a (N=64) ±797 ±3,270 ±0.7 ±48.5 ±6.01 ±11.9 ±108 ±3.1 340 3,392 20,604 11.7b 234 13.9 56.0 474 21.0b (N=6) ±874 ±6,027 ±1.0 ±69.6 ±4.0 ±28.2 ±245 ±4.3 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 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 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. In a prospective study, in which irinotecan was administered as a single-agent on a once-every-3-week schedule, patients who were homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele (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
  • 16. 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 AUC0-24 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: 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 5-fluorouracil (5-FU) and leucovorin (LV): 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 Cmax and AUC0-24 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. 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.
  • 17. 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 co-administering these drugs. 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 CAMPTOSAR 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/mm3, 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
  • 18. 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 Bolus 5-FU/LV Irinotecan Irinotecan + weekly x 4 q daily x 5 q weekly x 4 q Infusional Infusional 6 weeks 4 weeks 6 weeks 5-FU/LV 5-FU/LV 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 5.5 4.1 3.9 5.6 4.5 Treatmenta (months) 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 Rateb (%) (p<0.0001)c (p<0.005)c Median Time to Tumor Progressiond 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.
  • 19. Figure 1. Survival First-Line Irinotecan/5-FU/LV vs 5-FU/LV Study 1 1.0 0.9 0.8 Probability 0.7 Irinotecan/5-FU/LV 0.6 0.5 0.4 5-FU/LV 0.3 0.2 0.1 p<0.05* 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months *log-rank test
  • 20. Figure 2. Survival First-Line Irinotecan/5-FU/LV vs 5-FU/LV Study 2 1.0 0.9 0.8 Irinotecan/5-FU/LV 0.7 Probability 0.6 0.5 5-FU/LV 0.4 0.3 0.2 0.1 p<0.05* 0.0 0 3 6 9 12 15 18 21 24 27 30 Months *log-rank test 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 CAMPTOSAR 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
  • 21. 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, CAMPTOSAR 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 CAMPTOSAR 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 3.
  • 22. Table 3. Weekly Dosage Schedule: Study Results Study 1 2 3 Number of Patients 48 90 64 102 Starting Dose (mg/m2/wk x 4) 125a 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 CAMPTOSAR (median, months) 5 4 4 3 b Relative Dose Intensity (median %) 74 67 73 81 Efficacy Confirmed Objective Response Rate (%)c 21 13 14 9 (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/m2 as a starting dose; two (22.2%) responded to CAMPTOSAR. b Relative dose intensity for CAMPTOSAR based on planned dose intensity of 100, 83.3, and 66.7 mg/m2/wk corresponding with 150, 125, and 100 mg/m2 starting doses, respectively. c Confirmed ≥ 4 to 6 weeks after first evidence of objective response.
  • 23. 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 CAMPTOSAR 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 CAMPTOSAR had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to CAMPTOSAR 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)
  • 24. LV, 200 mg/m 2 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.
  • 25. Figure 3. Survival Second-Line Irinotecan vs Best Supportive Care (BSC) Study 1 1.0 0.9 Irinotecan BSC 0.8 N 189 90 Median follow-up 13 mo 0.7 Probability Median (mo) 9.2 6.5 0.6 0.5 0.4 Irinotecan 0.3 BSC 0.2 0.1 p=0.0001* 0.0 0 3 6 9 12 15 18 21 Months *log-rank test Figure 4. Survival Second-Line Irinotecan vs Infusional 5-FU Study 2 1.0 Irinotecan 5-FU N 127 129 0.9 Median follow-up 15 mo 0.8 Median (mo) 10.8 8.5 Probability 0.7 0.6 0.5 Irinotecan 0.4 0.3 5-FU 0.2 0.1 p=0.035* 0.0 0 3 6 9 12 15 18 21 *log-rank test Months
  • 26. 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.
  • 27. Table 4. Once-Every-3-Week Dosage Schedule: Study Results Study 1 Study 2 Irinotecan BSCa 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) 9.2 6.5 10.8 8.5 (Log-rank test) (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/m2/wk corresponding with 350 and 300 mg/m2 starting doses, respectively.
  • 28. Table 5. EORTC QLQ-C30: Mean Worst Post-Baseline Scorea 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 CAMPTOSAR 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. CAMPTOSAR 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 CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients. WARNINGS General Outside of a well-designed clinical study, CAMPTOSAR 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. CAMPTOSAR 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 CAMPTOSAR 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 CAMPTOSAR) 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 hyperperistalsis that
  • 29. 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 CAMPTOSAR) 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 anti- diarrhea medication. If grade 2, 3, or 4 late diarrhea occurs subsequent doses of CAMPTOSAR 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 CAMPTOSAR. Neutropenic complications should be managed promptly with antibiotic support (see PRECAUTIONS). Therapy with CAMPTOSAR should be temporarily omitted during a cycle of therapy if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3 . After the patient recovers to an absolute neutrophil count ≥1000/mm3 , subsequent doses of CAMPTOSAR 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. Patients with Reduced UGT1A1 Activity Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele (see DOSAGE AND ADMINISTRATION). Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses. 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
  • 30. Thromboembolic events have been observed in patients receiving irinotecan-containing regimens; the specific cause of these events has not been determined. Pregnancy CAMPTOSAR 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 Cmax and AUC about 3 and 0.5 times, respectively, the corresponding values in patients administered 125 mg/m2 ). Administration of 6 mg/kg/day intravenous irinotecan to rats (which in separate studies produced an irinotecan Cmax and AUC about 2 and 0.2 times, respectively, the corresponding values in patients administered 125 mg/m2 ) and rabbits (about one-half the recommended human weekly starting dose on a mg/m2 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/m2 ) and in rabbits at 6.0 mg/kg/day (about one-half the recommended human weekly starting 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. 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 CAMPTOSAR. PRECAUTIONS General Care of Intravenous Site: CAMPTOSAR 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-HT3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of CAMPTOSAR. 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 CAMPTOSAR). These symptoms are expected to occur more frequently with higher irinotecan doses.
  • 31. Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including CAMPTOSAR, 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. 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 CAMPTOSAR 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. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) 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% [19/38] versus 18% [47/226]; p<0.001). (Also see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations: Hepatic Insufficiency). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with CAMPTOSAR. Ketoconazole, enzyme-inducing anticonvulsants and St. John’s Wort are known to have drug-drug interactions with irinotecan therapy. (See Drug-Drug Interactions sub-section under CLINICAL PHARMACOLOGY) Irinotecan commonly causes neutropenia, leucopenia, and anemia, any of which may be severe and therefore should not be used in patients with severe bone marrow failure. Patients must not be treated with irinotecan until resolution of the bowel obstruction. Patients with hereditary fructose intolerance should not be given CAMPTOSAR, as this product contains sorbitol. Information for Patients Patients and patients’ caregivers should be informed of the expected toxic effects of CAMPTOSAR, 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 CAMPTOSAR) 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. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Premedication with loperamide is not recommended. The
  • 32. 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 warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of CAMPTOSAR, and advised not to drive or operate machinery if these symptoms occur. 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 CAMPTOSAR. Drug Interactions The adverse effects of CAMPTOSAR, 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 CAMPTOSAR. The concurrent administration of CAMPTOSAR with irradiation has not been adequately studied and is not recommended. Lymphocytopenia has been reported in patients receiving CAMPTOSAR, 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 CAMPTOSAR. Usually, this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of CAMPTOSAR. 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 CAMPTOSAR 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 CAMPTOSAR 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 CAMPTOSAR, the physician may wish to withhold diuretics during dosing with CAMPTOSAR and, certainly, during periods of active vomiting or diarrhea. Drug-Laboratory Test Interactions There are no known interactions between CAMPTOSAR and laboratory tests.
  • 33. 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 Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m2 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 Cmax and AUC about 5 and 1 times, respectively, the corresponding values in patients administered 125 mg/m2 weekly) and dogs at 0.4 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about one-half and 1/15th, respectively, the corresponding values in patients administered 125 mg/m2 weekly). Pregnancy Pregnancy Category D—see WARNINGS. Nursing Mothers Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving therapy with CAMPTOSAR. Pediatric Use The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/ 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 hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship). Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric
  • 34. 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 50mg/m2 dose and 16.2 ± 4.6 L/h/m2 for the 125 mg/m2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks]. Geriatric Use Patients greater than 65 years of age should be closely monitored because of a greater risk of late diarrhea in this population (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and ADVERSE REACTIONS, Overview of Adverse Events). The starting dose of CAMPT OS AR i n p at i en t s 7 0 years an d o l d er fo r t h e o n ce-ev ery-3-week-dosage schedule should be 300 mg/m2 (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Fi rst-L i n e Comb i n ati o n T h erap y A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in co m b i n at i o n wi t h 5 -FU/ LV, 5 -FU/ LV al o n e, o r i ri not ecan al one. In t h e t wo phase 3 st udi es, 370 pat i ent s recei ved irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan alone. (See Table 10 in DOSAGE AND ADMINISTRATION for recommended combination-agent regimens.) In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: 21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related to treatment occurred in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any cause within 60 days of first study treatment were reported for 15 (6.7%) patients who received irinotecan in combination with 5-FU/LV, 16 (7.3%) patients who received 5- FU/LV alone, and 15 (6.7%) patients who received irinotecan alone. Discontinuations due to adverse events were reported for 17 (7.6%) patients who received irinotecan in combination with 5FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who received irinotecan alone. In Study 2, 10 (3.5%) patients died within 30 days of last study treatment: 6 (4.1%) received irinotecan in combination with 5-FU/LV and 4 (2.8%) received 5-FU/LV alone. There was one potentially treatment-related death, which occurred in a patient who received irinotecan in combination with 5-FU/LV (0.7%, neutropenic sepsis). Deaths from any cause within 60 days of first study treatment were reported for 3 (2.1%) patients who received irinotecan in combination with 5-FU/LV and 2 (1.4%) patients who received 5-FU/LV alone. Discontinuations due to adverse events were reported for 9 (6.2%) patients who received irinotecan in combination with 5FU/LV and 1 (0.7%) patient who received 5-FU/LV alone. The most clinically significant adverse events for patients receiving irinotecan-based therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The most clinically
  • 35. significant adverse events for patients receiving 5-FU/LV therapy were diarrhea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than with monthly administration of 5-FU/LV. Tables 6 and 7 list the clinically relevant adverse events reported in Studies 1 and 2, respectively.
  • 36. Table 6. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa Study 1 Irinotecan + Bolus 5-FU/LV Bolus 5-FU/LV Irinotecan weekly x 4 daily x 5 weekly x 4 Adverse Event q 6 weeks q 4 weeks q 6 weeks N=225 N=219 N=223 Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 TOTAL Adverse Events 100 53.3 100 45.7 99.6 45.7 GASTROINTESTINAL Diarrhea late 84.9 22.7 69.4 13.2 83.0 31.0 grade 3 -- 15.1 -- 5.9 -- 18.4 grade 4 -- 7.6 -- 7.3 -- 12.6 early 45.8 4.9 31.5 1.4 43.0 6.7 Nausea 79.1 15.6 67.6 8.2 81.6 16.1 Abdominal pain 63.1 14.6 50.2 11.5 67.7 13.0 Vomiting 60.4 9.7 46.1 4.1 62.8 12.1 Anorexia 34.2 5.8 42.0 3.7 43.9 7.2 Constipation 41.3 3.1 31.5 1.8 32.3 0.4 Mucositis 32.4 2.2 76.3 16.9 29.6 2.2 HEMATOLOGIC Neutropenia 96.9 53.8 98.6 66.7 96.4 31.4 grade 3 -- 29.8 -- 23.7 -- 19.3 grade 4 -- 24.0 -- 42.5 -- 12.1 Leukopenia 96.9 37.8 98.6 23.3 96.4 21.5 Anemia 96.9 8.4 98.6 5.5 96.9 4.5 Neutropenic fever -- 7.1 -- 14.6 -- 5.8 Thrombocytopenia 96.0 2.6 98.6 2.7 96.0 1.7 Neutropenic infection -- 1.8 -- 0 -- 2.2 BODY AS A WHOLE Asthenia 70.2 19.5 64.4 11.9 69.1 13.9 Pain 30.7 3.1 26.9 3.6 22.9 2.2 Fever 42.2 1.7 32.4 3.6 43.5 0.4 Infection 22.2 0 16.0 1.4 13.9 0.4 METABOLIC & NUTRITIONAL ↑ Bilirubin 87.6 7.1 92.2 8.2 83.9 7.2 DERMATOLOGIC Exfoliative dermatitis 0.9 0 3.2 0.5 0 0 Rash 19.1 0 26.5 0.9 14.3 0.4 Alopeciab 43.1 -- 26.5 -- 46.1 -- RESPIRATORY Dyspnea 27.6 6.3 16.0 0.5 22.0 2.2 Cough 26.7 1.3 18.3 0 20.2 0.4 Pneumonia 6.2 2.7 1.4 1.0 3.6 1.3 NEUROLOGIC Dizziness 23.1 1.3 16.4 0 21.1 1.8 Somnolence 12.4 1.8 4.6 1.8 9.4 1.3 Confusion 7.1 1.8 4.1 0 2.7 0 CARDIOVASCULAR Vasodilatation 9.3 0.9 5.0 0 9.0 0 Hypotension 5.8 1.3 2.3 0.5 5.8 1.7 Thromboembolic eventsc 9.3 -- 11.4 -- 5.4 -- a Severity of adverse events based on NCI CTC (version 1.0) b Complete hair loss = Grade 2 c Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
  • 37. Table 7. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa Study 2 Irinotecan + 5-FU/LV 5-FU/LV infusional d 1&2 infusional d 1&2 q 2 weeks q 2 weeks Adverse Event N= 145 N=143 Grade 1-4 Grade 3&4 Grade 1-4 Grade 3&4 TOTAL Adverse Events 100 72.4 100 39.2 GASTROINTESTINAL Diarrhea late 72.4 14.4 44.8 6.3 grade 3 -- 10.3 -- 4.2 grade 4 -- 4.1 -- 2.1 Cholinergic syndromeb 28.3 1.4 0.7 0 Nausea 66.9 2.1 55.2 3.5 Abdominal pain 17.2 2.1 16.8 0.7 Vomiting 44.8 3.5 32.2 2.8 Anorexia 35.2 2.1 18.9 0.7 Constipation 30.3 0.7 25.2 1.4 Mucositis 40.0 4.1 28.7 2.8 HEMATOLOGIC Neutropenia 82.5 46.2 47.9 13.4 grade 3 -- 36.4 -- 12.7 grade 4 -- 9.8 -- 0.7 Leukopenia 81.3 17.4 42.0 3.5 Anemia 97.2 2.1 90.9 2.1 Neutropenic fever -- 3.4 -- 0.7 Thrombocytopenia 32.6 0 32.2 0 Neutropenic infection -- 2.1 -- 0 BODY AS A WHOLE Asthenia 57.9 9.0 48.3 4.2 Pain 64.1 9.7 61.5 8.4 Fever 22.1 0.7 25.9 0.7 Infection 35.9 7.6 33.6 3.5 METABOLIC & NUTRITIONAL ↑ Bilirubin 19.1 3.5 35.9 10.6 DERMATOLOGIC Hand & foot syndrome 10.3 0.7 12.6 0.7 Cutaneous signs 17.2 0.7 20.3 0 Alopeciac 56.6 -- 16.8 -- RESPIRATORY Dyspnea 9.7 1.4 4.9 0 CARDIOVASCULAR Hypotension 3.4 1.4 0.7 0 Thromboembolic eventsd 11.7 -- 5.6 -- a Severity of adverse events based on NCI CTC (version 1.0) b Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan) c Complete hair loss = Grade 2 d Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
  • 38. Second-Line Single-Agent Therapy Weekly Dosage Schedule In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5- FU-based therapy were treated with CAMPTOSAR. Seventeen of the patients died within 30 days of the administration of CAMPTOSAR; in five cases (1.6%, 5/304), the deaths were potentially drug-related. These five patients experienced a constellation of medical events that included known effects of CAMPTOSAR. One of these patients died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care. One hundred nineteen (39.1%) of the 304 patients were hospitalized a total of 156 times because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of CAMPTOSAR. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%). Adjustments in the dose of CAMPTOSAR were made during the cycle of treatment and for subsequent cycles based on individual patient tolerance. The first dose of at least one cycle of CAMPTOSAR was reduced for 67% of patients who began the studies at the 125-mg/m2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with CAMPTOSAR because of adverse events. The adverse events in Table 8 are based on the experience of the 304 patients enrolled in the three studies described in the CLINICAL STUDIES, Studies Evaluating the Weekly Dosage Schedule, section.
  • 39. Table 8. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectuma % of Patients Reporting Body System & Event NCI Grades 1-4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late)b 88 31 7-9 stools/day (grade 3)  (16) ≥10 stools/day (grade 4)  (14) Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early)c 51 8 Constipation 30 2 Flatulence 12 0 Stomatitis 12 1 Dyspepsia 10 0 HEMATOLOGIC Leukopenia 63 28 Anemia 60 7 Neutropenia 54 26 500 to <1000/mm3 (grade 3)  (15) <500/mm3 (grade 4)  (12) BODY AS A WHOLE Asthenia 76 12 Abdominal cramping/pain 57 16 Fever 45 1 Pain 24 2 Headache 17 1 Back pain 14 2 Chills 14 0 Minor infectiond 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC & NUTRITIONAL ↓ Body weight 30 1 Dehydration 15 4 ↑ Alkaline phosphatase 13 4 ↑ SGOT 10 1 DERMATOLOGIC Alopecia 60 NAe Sweating 16 0 Rash 13 1 RESPIRATORY Dyspnea 22 4 ↑ Coughing 17 0 Rhinitis 16 0 NEUROLOGIC Insomnia 19 0 Dizziness 15 0 CARDIOVASCULAR Vasodilation (flushing) 11 0 a Severity of adverse events based on NCI CTC (version 1.0) b Occurring > 24 hours after administration of CAMPTOSAR c Occurring ≤24 hours after administration of CAMPTOSAR d Primarily upper respiratory infections e Not applicable; complete hair loss = NCI grade 2
  • 40. Once-Every-3-Week Dosage Schedule A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea. Hospitalizations due to serious adverse events (whether or not related to study treatment) occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU- based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5- FU-based therapy discontinued treatment due to adverse events. Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 9 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in the CLINICAL STUDIES, Studies Evaluating the Once-Every-3- Week Dosage Schedule, section.
  • 41. Table 9. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapya Study 1 Study 2 Irinotecan BSC b Irinotecan 5-FU Adverse Event N=189 N=90 N=127 N=129 TOTAL Grade 3/4 Adverse Events 79 67 69 54 GASTROINTESTINAL Diarrhea 22 6 22 11 Vomiting 14 8 14 5 Nausea 14 3 11 4 Abdominal pain 14 16 9 8 Constipation 10 8 8 6 Anorexia 5 7 6 4 Mucositis 2 1 2 5 HEMATOLOGIC Leukopenia/Neutropenia 22 0 14 2 Anemia 7 6 6 3 Hemorrhage 5 3 1 3 Thrombocytopenia 1 0 4 2 Infection without grade 3/4 neutropenia 8 3 1 4 with grade 3/4 neutropenia 1 0 2 0 Fever without grade 3/4 neutropenia 2 1 2 0 with grade 3/4 neutropenia 2 0 4 2 BODY AS A WHOLE Pain 19 22 17 13 Asthenia 15 19 13 12 METABOLIC & NUTRITIONAL Hepatic c 9 7 9 6 DERMATOLOGIC Hand & foot syndrome 0 0 0 5 Cutaneous signs d 2 0 1 3 RESPIRATORY e 10 8 5 7 NEUROLOGIC f 12 13 9 4 CARDIOVASCULAR g 9 3 4 2 OTHER h 32 28 12 14 a Severity of adverse events based on NCI CTC (version 1.0) b BSC = best supportive care c Hepatic includes events such as ascites and jaundice d Cutaneous signs include events such as rash e Respiratory includes events such as dyspnea and cough f Neurologic includes events such as somnolence g Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction h Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss Overview of Adverse Events Gastrointestinal: Nausea, vomiting, and diarrhea are common adverse events following treatment with CAMPTOSAR and can be severe. When observed, nausea and vomiting usually occur during or shortly after infusion of CAMPTOSAR. 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 CAMPTOSAR. 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
  • 42. 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. The frequency of grade 3 or 4 late diarrhea was somewhat greater in patients starting treatment at 125 mg/m2 than in patients given a 100-mg/m2 weekly starting dose (34% [65/193] versus 23% [24/102]; p=0.08). The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002). In one study of the weekly dosage treatment, the frequency of grade 3 and 4 late diarrhea was significantly greater in male than in female patients (43% [25/58] versus 16% [5/32]; p=0.01), but there were no gender differences in the frequency of grade 3 and 4 late diarrhea in the other two studies of the weekly dosage treatment schedule. Colonic ulceration, sometimes with gastrointestinal bleeding, has been observed in association with administration of CAMPTOSAR. Hematology: CAMPTOSAR commonly causes neutropenia, leukopenia (including lymphocytopenia), and anemia. Serious thrombocytopenia is uncommon. When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). In these same studies, patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also 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% [19/38] versus 18% [47/266]; p<0.001). There were no significant differences in the frequency of grade 3 and 4 neutropenia by age or gender. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. NCI grade 3 or 4 anemia was noted in 7% of the patients receiving weekly treatment; blood transfusions were given to 10% of the patients in these trials. Body as a Whole: Asthenia, fever, and abdominal pain are generally the most common events of this type. Cholinergic Symptoms: Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea. If these symptoms occur, they manifest during or shortly after drug infusion. They 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. Hepatic: In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastases. Dermatologic: Alopecia has been reported during treatment with CAMPTOSAR. Rashes have also been reported but did not result in discontinuation of treatment. Respiratory: Severe pulmonary events are infrequent. In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 dyspnea was reported in
  • 43. 4% of patients. Over half the patients with dyspnea had lung metastases; the extent to which malignant pulmonary involvement or other preexisting lung disease may have contributed to dyspnea in these patients is unknown. 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. Neurologic: Insomnia and dizziness can occur, but are not usually considered to be directly related to the administration of CAMPTOSAR. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration. Cardiovascular: Vasodilation (flushing) may occur during administration of CAMPTOSAR. Bradycardia may also occur, but has not required intervention. These effects have been attributed to the cholinergic syndrome sometimes observed during or shortly after infusion of CAMPTOSAR. Thromboembolic events have been observed in patients receiving CAMPTOSAR; the specific cause of these events has not been determined. Other Non-U.S. Clinical Trials Irinotecan has been studied in over 1100 patients in Japan. Patients in these studies had a variety of tumor types, including cancer of the colon or rectum, and were treated with several different doses and schedules. In general, the types of toxicities observed were similar to those seen in U.S. trials with CAMPTOSAR. There is some information from Japanese trials that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea. 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 preexisting nonmalignant pulmonary disease. As a result of these observations, however, clinical studies in the United States have enrolled few patients with compromised pulmonary function, significant ascites, or pleural effusions. Post-Marketing Experience The following events have been identified during postmarketing use of CAMPTOSAR in clinical practice. 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 7, thromboembolic events). Infrequent cases of ulcerative and ischemic colitis have been observed. This can be complicated by ulceration, bleeding, ileus, obstruction, and infection, including typhlitis. Patients experiencing ileus should receive prompt antibiotic support (see PRECAUTIONS). Rare cases of megacolon and intestinal perforation have been reported. Rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed. Hypersensitivity reactions including severe anaphylactic or anaphylactoid
  • 44. reactions have also been observed (see WARNINGS). 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; transient increase of amylase and occasionally transient increase of lipase have been very rarely reported. Infrequent cases of renal insufficiency including acute renal failure, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis (see WARNINGS). Early effects such as muscular contraction or cramps and paresthesia have been reported. Hiccups have been reported. OVERDOSAGE In U.S. phase 1 trials, single doses of up to 345 mg/m 2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m 2 of irinotecan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for overdosage of CAMPTOSAR. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications. DOSAGE AND ADMINISTRATION Dosage in Patients with Reduced UGT1A1 Activity When administered in combination with other agents, or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele (see CLINICAL PHARMACOLOGY and WARNINGS). However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see Tables 10-13). Combination-Agent Dosage Dosage Regimens CAMPTOSAR Injection in Combination with 5-Fluorouracil (5-FU) and Leucovorin (LV) C A M P T O S A R s h o u l d b e a d m i n i s t e r e d a s a n i n t r a v e n o u s infusion over 90 minutes (see Preparation of Infusion Solution). For all regimens, the dose of LV should be administered immediately after CAMPTOSAR, with the a d m i n i s t r a t i o n o f 5-FU to occur immediately after receipt of LV. CAMPTOSAR should be used as recommended; the currently recommended regimens are shown in Table 10. Table 10. Combination-Agent Dosage Regimens & Dose Modificationsa Regimen 1 CAMPTOSAR 125 mg/m2 IV over 90 min, d 1,8,15,22 6-wk cycle with LV 20 mg/m2 IV bolus, d 1,8,15,22 bolus 5-FU/LV 5-FU 500 mg/m2 IV bolus, d 1,8,15,22 (next cycle begins Starting Dose & Modified Dose Levels (mg/m2) on day 43) Starting Dose Dose Level -1 Dose Level -2
  • 45. CAMPTOSAR 125 100 75 LV 20 20 20 5-FU 500 400 300 2 Regimen 2 CAMPTOSAR 180 mg/m IV over 90 min, d 1,15,29 6-wk cycle with LV 200 mg/m2 IV over 2 h, d 1,2,15,16,29,30 infusional 5-FU Bolus 400 mg/m2 IV bolus, d 1,2,15,16,29,30 5-FU/LV 5-FU Infusionb 600 mg/m2 IV over 22 h, d 1,2,15,16,29,30 (next cycle begins on day 43) Starting Dose & Modified Dose Levels (mg/m2) Starting Dose Dose Level -1 Dose Level -2 CAMPTOSAR 180 150 120 LV 200 200 200 5-FU Bolus 400 320 240 5-FU Infusionb 600 480 360 a Dose reductions beyond dose level –2 by decrements of ≈20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. b Infusion follows bolus administration. Dosing for patients with bilirubin >2 mg/dL cannot be recommended b e c a u s e t h e r e is insufficient information to recommend a dose in these patients. It i s r e c o m m e n d e d t h a t p a t i e n t s r e c e i v e premedication with antiemetic agents. Prophylactic or t h e r a p e u t i c a d m i n i s t r a t i o n o f a t r o p i n e s h o u l d b e consi dered i n pat i ent s ex peri enci ng chol i nergi c sym pt om s . S ee PRECAUTIONS, General. Dose Modifications Patients should be carefully monitored for toxicity and assessed prior to each treatment. Doses of CAMPTOSAR and 5-FU should be modified as necessary to accommod a t e i n d i v i d u a l p a t i e n t t o l e r a n c e t o t r e a t m e n t . B a s e d o n the recommended dose-levels described in Table 10, C o m b i n a t i o n - A g e n t D o s a g e R e g i m e n s & Dose Modifications, subsequent doses should be adjusted as s u g g e s t e d in Table 11, Recommended Dose Modifications for C o m b i n a t i o n S c h e d u l e s . A l l d o s e m o d i f i c a t i o n s s h o u l d b e based on the worst preceding toxicity. After the first t r e a t m e n t , p a t i e n t s w i t h a c t i v e d i a r r h e a s h o u l d r e t u r n t o pre-treatment bowel function without requiring anti-diarrhea medications for at least 24 hours before the n e x t c h e m o t h e r a p y a d m i n i s t r a t i o n . A new cycle of therapy should not begi n until the tox i city has recovered to NCI grade 1 or less. Treatment maybe delayed 1 to 2 w e e k s t o a l l o w f o r r e c o v e r y f r o m t r e a t m en t -rel at ed t o x i ci t y. If t h e p at i en t h as n o t reco v ered , c o n s i d e r a t i o n s h o u l d b e g i v e n t o discontinuing therapy. Provided intolerable tox i city does not d e v e l o p , t r e a t m e n t with additional cycles of CAMPTOSAR/5-FU/LV may be continued indefinitely as long as patients continue to e x p e r i e n c e c l i n i c a l benefit.
  • 46. Table 11. Recommended Dose Modifications for CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules 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 therapy Toxicity During a Cycle of Therapy At the Start of Subsequent Cycles NCI CTC Gradea (Value) of Therapyb No toxicity Maintain dose level Maintain dose level Neutropenia 1 (1500 to 1999/mm3) Maintain dose level Maintain dose level 2 (1000 to 1499/mm3) ↓ 1 dose level Maintain dose level 3 (500 to 999/mm3) Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓ 1 dose level 3 4 (<500/mm ) Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels Neutropenic fever Omit dose until resolved, then ↓ 2 dose levels Other hematologic toxicities Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Diarrhea 1 (2-3 stools/day > pretxc) Delay dose until resolved to baseline, then give same dose Maintain dose level 2 (4-6 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 1 dose level Maintain dose level 3 (7-9 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 1 dose level ↓ 1 dose level 4 (≥10 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 2 dose levels ↓ 2 dose levels Other nonhematologic toxicitiesd 1 Maintain dose level Maintain dose level 2 Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level Maintain dose level 3 Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓ 1 dose level 4 Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels For mucositis/stomatitis decrease only 5-FU, not For mucositis/stomatitis decrease CAMPTOSAR only 5-FU, not CAMPTOSAR. a National Cancer Institute Common Toxicity Criteria (version 1.0) b Relative to the starting dose used in the previous cycle c Pretreatment d Excludes alopecia, anorexia, asthenia Single-Agent Dosage Schedules Dosage Regimens CAMPTOSAR should be administered as an intravenous infusion o v e r 9 0 m i n u t e s f o r b o t h t h e w e e k l y a n d o n c e - every-3-week dosage schedules (see Preparation of Infusion Solution). Single-agent dosage regimens are shown in Table 12. Table 12. Single-Agent Regimens of CAMPTOSAR and Dose Modifications Weekly Regimena 125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest Starting Dose & Modified Dose Levelsc (mg/m2) Starting Dose Dose Level -1 Dose Level -2 125 100 75 b 2 c Once-Every-3-Week Regimen 350 mg/m IV over 90 min, once every 3 wks Starting Dose & Modified Dose Levels (mg/m2) Starting Dose Dose Level -1 Dose Level -2 350 300 250
  • 47. a Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. A reduction in the starting dose by one dose level of C A M P T O S A R m a y b e c o n s i d e r e d f o r p a t i e n t s w i t h a n y o f the following conditions: age ≥65 years, prior pelvic/abdominal radiotherapy, performance status of 2, o r i n creas ed b i l i ru b i n l ev el s . Do s i n g fo r p at i en t s wi t h bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients. It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in p at i en t s ex peri enci ng chol i n ergi c sym p t o m s . S ee P R ECAUTIONS, General. Dose Modifications Patients should be carefully monitored for toxicity and doses of CAMPTOSAR should be modified as necessary to accom m odat e i n di vi dual pat i ent t o l erance t o t r e a t m e n t . Bas e d o n r e c o m m e n d e d d o s e- l e v e l s d e s c r i b e d i n T a b l e 1 2 , S i n gl e - A gen t R e gi m e n s o f C A M P T OS AR an d Do s e Modifications, subsequent doses should be adjusted as suggested in Table 13, Recommended Dose Modifications for Single-Agent Schedules. 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 NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatm en t - rel at ed t o x i ci t y. If t h e p at i en t h as n o t reco v ered , consideration should be given to discontinuing this combination therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of CAMPTOSAR may be continued indefinitely as long as patients continue to experience clinical benefit.
  • 48. Table 13. Recommended Dose Modifications For Single-Agent Schedulesa 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 CAMPTOSAR. At the Start of the Next Cycles of Therapy Worst Toxicity During a Cycle of Therapy (After Adequate Recovery), Compared with b NCI Grade (Value) the Starting Dose in the Previous Cyclea Weekly Weekly Once Every 3 Weeks No toxicity Maintain dose level ↑ 25 mg/m2 up to a Maintain dose level maximum dose of 150 mg/m2 Neutropenia 1 (1500 to 1999/mm3) Maintain dose level Maintain dose level Maintain dose level 2 (1000 to 1499/mm3) ↓ 25 mg/m2 Maintain dose level Maintain dose level ↓ 25 mg/m2 ↓ 50 mg/m2 3 3 (500 to 999/mm ) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 4 (<500/mm3) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m2 when resolved ↓ 50 mg/m2 ↓ 50 mg/m2 Other hematologic Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent toxicities cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Diarrhea 1 (2-3 stools/day > pretxc) Maintain dose level Maintain dose level Maintain dose level 2 (4-6 stools/day > pretx) ↓ 25 mg/m2 Maintain dose level Maintain dose level 3 (7-9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 Other nonhematologicd toxicities 1 Maintain dose level Maintain dose level Maintain dose level 2 ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 3 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 4 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia Prep arati o n & Ad mi n i strati on Precau ti o n s As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from CAMPTOSAR Injection. The use of gloves is recommended. If a solution of CAMPTOSAR contacts the skin, wash the skin immediately and t h o r o u gh l y w i t h s o a p a n d w a t e r . If C AM P TOS AR co n t act s the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.1-7 Preparation of Infusion Solution Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe. CAMPTOSAR Injection must be diluted prior to infusion. CAMPTOSAR should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL. In most clinical trials, CAMPTOSAR was administered in 2 5 0 m L t o 5 0 0 m L o f 5 % D e x t r o s e In j e c t i o n , U S P . T h e s o l u t i o n i s p h ys i c a l l y a n d c h e m i c a l l y s t a b l e f o r u p to 24 hours at room temperature (approximately 25°C) a n d i n a m b i e n t f l u o r e s c e n t l i g h t i n g . S o l u t i o n s d i l u t e d i n 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium C h l o r i d e In j e c t i o n , U S P , i s n o t r e c o m m e n d e d d u e t o a l o w and sporadic
  • 49. incidence of visible particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR may result in p r e c i p i t a t i o n o f t h e d r u g a n d s h o u l d b e avoided. Because of possible microbial contamination during d i l u t i o n , i t i s advisable to use the admixture prepared with 5%Dex trose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 6 hours if kept at room temperature (15° to 30°C, 5 9 ° t o 8 6 ° F ) . Other drugs should not be added to the infusion solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. HOW SUPPLIED Each mL of CAMPTOSAR Injection contains 20 mg irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. CAMPTOSAR Injection is available in single-dose amber glass vials in the following package sizes: 2 mL NDC 0009-7529-02 5 mL NDC 0009-7529-01 The vial should be inspected for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package. Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. It is recommended that the vial should remain in the carton until the time of use. Rx only REFERENCES 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32- 41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621. 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1592. 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study
  • 50. Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines). Am J Health-SystPharm. 1996;53;1669-1685. Licensed from Yakult Honsha Co., LTD, Japan, and Daiichi Pharmaceutical Co., LTD, Japan Revised July 2008 LAB-0134-13.0
  • 51. © 2007 Current Medicine Group LLC CQ278602B