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 [see Dosage and Administration (2)].
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.
| 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 | 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 |
Alopecia† | 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 events‡ | 9.3 | -- | 11.4 | -- | 5.4 | -- |
| 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 | 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 syndrome† | 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 AND NUTRITIONAL | ||||
Bilirubin | 19.1 | 3.5 | 35.9 | 10.6 |
DERMATOLOGIC | ||||
Hand and foot syndrome | 10.3 | 0.7 | 12.6 | 0.7 |
Cutaneous signs | 17.2 | 0.7 | 20.3 | 0 |
Alopecia‡ | 56.6 | -- | 16.8 | -- |
RESPIRATORY | ||||
Dyspnea | 9.7 | 1.4 | 4.9 | 0 |
CARDIOVASCULAR | ||||
Hypotension | 3.4 | 1.4 | 0.7 | 0 |
Thromboembolic events§ | 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/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 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies (14.1).
| % of Patients Reporting | ||
|---|---|---|
| Body System & Event | NCI Grades 1–4 | NCI Grades 3 & 4 |
GASTROINTESTINAL | ||
Diarrhea (late)† | 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)‡ | 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 infection§ | 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¶ |
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 (14.1).
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| Adverse Event | Irinotecan N=189 | BSC † N=90 | Irinotecan N=127 | 5-FU N=129 |
| ||||
TOTAL Grade 3/4 | 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 ‡ | 9 | 7 | 9 | 6 |
DERMATOLOGIC | ||||
Hand and foot syndrome | 0 | 0 | 0 | 5 |
Cutaneous signs § | 2 | 0 | 1 | 3 |
RESPIRATORY ¶ | 10 | 8 | 5 | 7 |
NEUROLOGIC # | 12 | 13 | 9 | 4 |
CARDIOVASCULAR Þ | 9 | 3 | 4 | 2 |
OTHER ß | 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.
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.
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 [see Dosage and Administration (2)].
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.
| 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 | 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 |
Alopecia† | 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 events‡ | 9.3 | -- | 11.4 | -- | 5.4 | -- |
| 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 | 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 syndrome† | 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 AND NUTRITIONAL | ||||
Bilirubin | 19.1 | 3.5 | 35.9 | 10.6 |
DERMATOLOGIC | ||||
Hand and foot syndrome | 10.3 | 0.7 | 12.6 | 0.7 |
Cutaneous signs | 17.2 | 0.7 | 20.3 | 0 |
Alopecia‡ | 56.6 | -- | 16.8 | -- |
RESPIRATORY | ||||
Dyspnea | 9.7 | 1.4 | 4.9 | 0 |
CARDIOVASCULAR | ||||
Hypotension | 3.4 | 1.4 | 0.7 | 0 |
Thromboembolic events§ | 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/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 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies (14.1).
| % of Patients Reporting | ||
|---|---|---|
| Body System & Event | NCI Grades 1–4 | NCI Grades 3 & 4 |
GASTROINTESTINAL | ||
Diarrhea (late)† | 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)‡ | 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 infection§ | 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¶ |
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 (14.1).
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| Adverse Event | Irinotecan N=189 | BSC † N=90 | Irinotecan N=127 | 5-FU N=129 |
| ||||
TOTAL Grade 3/4 | 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 ‡ | 9 | 7 | 9 | 6 |
DERMATOLOGIC | ||||
Hand and foot syndrome | 0 | 0 | 0 | 5 |
Cutaneous signs § | 2 | 0 | 1 | 3 |
RESPIRATORY ¶ | 10 | 8 | 5 | 7 |
NEUROLOGIC # | 12 | 13 | 9 | 4 |
CARDIOVASCULAR Þ | 9 | 3 | 4 | 2 |
OTHER ß | 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.
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.
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