Camptosar Drug Information

• CAMPTOSAR is indicated as a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum.
• CAMPTOSAR is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. CAMPTOSAR is a topoisomerase inhibitor indicated for:
• First-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. ( 1 )
• Patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. ( 1 )

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions (≥30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia. Common adverse reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia.

First-Line Combination Therapy A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan alone . 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 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 5 and 6 list the clinically relevant adverse events reported in Studies 1 and 2, respectively. Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies Severity of adverse events based on NCI CTC (version 1.0) Adverse Event Study 1 Irinotecan + Bolus 5-FU/LV weekly × 4 every 6 weeks N=225 Bolus 5-FU/LV daily × 5 every 4 weeks N=219 Irinotecan weekly × 4 every 6 weeks 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

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 --

Early 45.8 4.9 31.5 1.4 43.0 6.7 Nausea 79.1 15.6 67.6 8.2

81.6

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

Anorexia 34.2 5.8 42.0 3.7 43.9 7.2 Constipation 41.3 3.1 31.5 1.8

32.3

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 --

Leukopenia 96.9 37.8 98.6 23.3 96.4 21.5 Anemia 96.9 8.4 98.6 5.5

96.9

Neutropenic fever -- 7.1 -- 14.6 -- 5.8 Thrombocytopenia 96.0 2.6 98.6

2.7 96.0

Neutropenic infection -- 1.8 -- 0 -- 2.2

BODY AS A WHOLE Asthenia 70.2 19.5 64.4 11.9 69.1

Pain 30.7 3.1 26.9 3.6 22.9 2.2 Fever 42.2 1.7 32.4 3.6

43.5

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

DERMATOLOGIC Exfoliative dermatitis 0.9 0 3.2 0.5 0 0 Rash 19.1 0

26.5 0.9 14.3

Alopecia Complete hair loss = Grade 2 43.1 -- 26.5 -- 46.1

-- RESPIRATORY Dyspnea 27.6 6.3 16.0 0.5 22.0

Cough 26.7 1.3 18.3 0 20.2 0.4 Pneumonia 6.2 2.7 1.4 1.0

3.6

NEUROLOGIC Dizziness 23.1 1.3 16.4 0 21.1 1.8 Somnolence 12.4 1.8 4.6

1.8 9.4

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

Thromboembolic events 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. 9.3 -- 11.4 -- 5.4 -- Table 6. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies Severity of adverse events based on NCI CTC (version 1.0) Adverse Event Study 2 Irinotecan + 5-FU/LV infusional days 1&2 every 2 weeks N= 145 5-FU/LV infusional days 1&2 every 2 weeks N=143 Grades 1–4 Grades 3&4 Grades 1–4 Grades 3&4 TOTAL Adverse Events 100 72.4 100

GASTROINTESTINAL Diarrhea late 72.4 14.4 44.8 6.3 grade 3 -- 10.3 --

4.2 grade 4 -- 4.1 --

Cholinergic syndrome Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping

or diarrhea (occurring during or shortly after infusion of irinotecan) 28.3 1.4 0.7 0 Nausea 66.9 2.1 55.2

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

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 --

Leukopenia 81.3 17.4 42.0 3.5 Anemia 97.2 2.1 90.9 2.1 Neutropenic fever

-- 3.4 --

Thrombocytopenia 32.6 0 32.2 0 Neutropenic infection -- 2.1 -- 0

BODY AS A WHOLE Asthenia 57.9 9.0 48.3

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

METABOLIC

AND NUTRITIONAL Bilirubin 19.1 3.5 35.9

DERMATOLOGIC Hand and foot syndrome 10.3 0.7 12.6 0.7 Cutaneous signs 17.2

0.7 20.3 0 Alopecia Complete hair loss = Grade 2 56.6 -- 16.8 -- RESPIRATORY Dyspnea 9.7 1.4 4.9 0 CARDIOVASCULAR Hypotension 3.4 1.4 0.7 0 Thromboembolic events 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. 11.7 -- 5.6 -- 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. One of the 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 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%). The first dose of at least one cycle of CAMPTOSAR was reduced for 67% of patients who began the studies at the 125-mg/m 2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m 2 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 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies . Table 7. Adverse Events Occurring in >10% of 304 Previously Treated Patients With Metastatic Carcinoma of the Colon or Rectum Severity of adverse events based on NCI CTC (version 1.0) % of Patients Reporting Body System & Event NCI Grades 1–4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late) Occurring >24 hours after administration of CAMPTOSAR 88 31 7–9 stools/day (grade 3) — ≥10 stools/day (grade 4) — Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early) Occurring ≤24 hours after administration of CAMPTOSAR 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/mm 3 (grade 3) — <500/mm 3 (grade 4) — 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 infection Primarily upper respiratory infections 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC AND NUTRITIONAL ↓ Body weight 30 1 Dehydration 15 4 ↑ Alkaline phosphatase 13 4 ↑ SGOT 10 1 DERMATOLOGIC Alopecia 60 NA Not applicable; complete hair loss = NCI grade 2 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 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 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 8 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in Clinical Studies . Table 8. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapy Severity of adverse events based on NCI CTC (version 1.0) Study 1 Study 2 Adverse Event Irinotecan N=189 BSC BSC = best supportive care N=90 Irinotecan N=127 5-FU 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 AND NUTRITIONAL Hepatic Hepatic includes events such as ascites and jaundice 9 7 9 6 DERMATOLOGIC Hand and foot syndrome 0 0 0 5 Cutaneous signs Cutaneous signs include events such as rash 2 0 1 3 RESPIRATORY Respiratory includes events such as dyspnea and cough 10 8 5 7 NEUROLOGIC Neurologic includes events such as somnolence 12 13 9 4 CARDIOVASCULAR Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction 9 3 4 2 OTHER Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss 32 28 12 14 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of CAMPTOSAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Myocardial ischemic events have been observed following CAMPTOSAR therapy. Thromboembolic events have been observed in patients receiving CAMPTOSAR. Symptomatic pancreatitis, asymptomatic pancreatic enzyme elevation have been reported.

Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis have been observed. Hyponatremia, mostly with diarrhea and vomiting, has been reported. Transient dysarthria has been reported in patients treated with CAMPTOSAR; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.

Interaction between CAMPTOSAR 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. Infections: fungal and viral infections have been reported.

• Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with CAMPTOSAR. ( 7.2 )
• Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with CAMPTOSAR. ( 7.3 ) 7.1 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 C max and AUC 0–24 of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was followed by 5-FU and LV administration compared with when irinotecan was given alone, this sequence of administration was used in the combination trials and is recommended [see Dosage and Administration (2) ] . 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. 7.2 Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of CAMPTOSAR therapy. Do not administer strong CYP3A4 inducers with CAMPTOSAR unless there are no therapeutic alternatives. 7.3 Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively, [see Clinical Pharmacology (12.3) ] . Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of CAMPTOSAR with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting CAMPTOSAR therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with CAMPTOSAR unless there are no therapeutic alternatives.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, CAMPTOSAR can cause fetal harm when administered to a pregnant woman . Available postmarketing and published data reporting the use of CAMPTOSAR in pregnant women, are insufficient and confounded by the concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, intravenous administration of irinotecan to rats and rabbits during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on AUC at the clinical dose of 125 mg/m 2 ( see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data Radioactivity related to 14 C-irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan to rats at a dose of 6 mg/kg/day (approximately 0.2 times the clinical exposure (AUC) at the 125 mg/m 2 dose based on exposure data from a separate rat study) during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses; at doses ≥ 1.2 mg/kg/day (approximately 0.03 times the clinical exposure (AUC) at the 125 mg/m 2 dose based on exposure data from a separate rat study) there were increases in a variety of external, visceral, and skeletal abnormalities. Administration of irinotecan to pregnant rabbits at a dose of 6 mg/kg (approximately half of the clinical dose of 125 mg/m 2 based on BSA) resulted in similar findings to those in rats, with increased post-implantation loss, decreased live fetuses, and increased 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.

L/h/m 2 for the 50mg/m 2 dose and 16.2 ± 4.6 L/h/m

2 for the 125 mg/m 2 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.

• CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
• Hypersensitivity to CAMPTOSAR or its excipients ( 4 )

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.