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CAMPTOSAR® (irinotecan HCl) Adverse Reactions

6 ADVERSE REACTIONS

6.1 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 [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.

Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies*
Adverse EventStudy 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 1–4Grade 3&4Grade 1–4Grade 3&4Grade 1–4Grade 3&4
*
Severity of adverse events based on NCI CTC (version 1.0)
Complete hair loss = Grade 2
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.
TOTAL Adverse Events10053.310045.799.645.7
GASTROINTESTINAL
  Diarrhea84.922.769.413.283.031.0
    Late--15.1--5.9--18.4
      grade 3--7.6--7.3--12.6
      grade 445.84.931.51.443.06.7
    Early
  Nausea79.115.667.68.281.616.1
  Abdominal pain63.114.650.211.567.713.0
  Vomiting60.49.746.14.162.812.1
  Anorexia34.25.842.03.743.97.2
  Constipation41.33.131.51.832.30.4
  Mucositis32.42.276.316.929.62.2
HEMATOLOGIC
  Neutropenia96.953.898.666.796.431.4
    grade 3--29.8--23.7--19.3
    grade 4--24.0--42.5--12.1
  Leukopenia96.937.898.623.396.421.5
  Anemia96.98.498.65.596.94.5
  Neutropenic fever--7.1--14.6--5.8
  Thrombocytopenia96.02.698.62.796.01.7
  Neutropenic infection--1.8--0--2.2
BODY AS A WHOLE
  Asthenia70.219.564.411.969.113.9
  Pain30.73.126.93.622.92.2
  Fever42.21.732.43.643.50.4
  Infection22.2016.01.413.90.4
METABOLIC & NUTRITIONAL
  Bilirubin87.67.192.28.283.97.2
DERMATOLOGIC0.903.20.500
  Exfoliative dermatitis19.1026.50.914.30.4
  Rash43.1--26.5--46.1--
  Alopecia
RESPIRATORY
  Dyspnea27.66.316.00.522.02.2
  Cough26.71.318.3020.20.4
  Pneumonia6.22.71.41.03.61.3
NEUROLOGIC
  Dizziness23.11.316.4021.11.8
  Somnolence12.41.84.61.89.41.3
  Confusion7.11.84.102.70
CARDIOVASCULAR9.30.95.009.00
  Vasodilatation5.81.32.30.55.81.7
  Hypotension9.3--11.4--5.4--
  Thromboembolic events
Table 6. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies*
Adverse EventStudy 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 1–4Grades 3&4Grades 1–4Grades 3&4
*
Severity of adverse events based on NCI CTC (version 1.0)
Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan)
Complete hair loss = Grade 2
§
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.
TOTAL Adverse Events10072.410039.2
GASTROINTESTINAL
  Diarrhea72.414.444.86.3
    late--10.3--4.2
      grade 3--4.1--2.1
      grade 428.31.40.70
  Cholinergic syndrome
  Nausea66.92.155.23.5
  Abdominal pain17.22.116.80.7
  Vomiting44.83.532.22.8
  Anorexia35.22.118.90.7
  Constipation30.30.725.21.4
  Mucositis40.04.128.72.8
HEMATOLOGIC
  Neutropenia82.546.247.913.4
    grade 3--36.4--12.7
    grade 4--9.8--0.7
  Leukopenia81.317.442.03.5
  Anemia97.22.190.92.1
  Neutropenic fever--3.4--0.7
  Thrombocytopenia32.6032.20
  Neutropenic infection--2.1--0
BODY AS A WHOLE
  Asthenia57.99.048.34.2
  Pain64.19.761.58.4
  Fever22.10.725.90.7
  Infection35.97.633.63.5
METABOLIC AND NUTRITIONAL
  Bilirubin19.13.535.910.6
DERMATOLOGIC10.30.712.60.7
  Hand and foot syndrome17.20.720.30
  Cutaneous signs56.6--16.8--
  Alopecia
RESPIRATORY
  Dyspnea9.71.44.90
CARDIOVASCULAR3.41.40.70
  Hypotension11.7--5.6--
  Thromboembolic events§

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).

Table 7. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum*
% of Patients Reporting
Body System & EventNCI Grades 1–4NCI Grades 3 & 4
*
Severity of adverse events based on NCI CTC (version 1.0)
Occurring >24 hours after administration of CAMPTOSAR
Occurring ≤24 hours after administration of CAMPTOSAR
§
Primarily upper respiratory infections
Not applicable; complete hair loss = NCI grade 2
GASTROINTESTINAL
  Diarrhea (late)8831
    7–9 stools/day (grade 3)(16)
    ≥10 stools/day (grade 4)(14)
  Nausea8617
  Vomiting6712
  Anorexia556
  Diarrhea (early)518
  Constipation302
  Flatulence120
  Stomatitis121
  Dyspepsia100
HEMATOLOGIC
  Leukopenia6328
  Anemia607
  Neutropenia5426
    500 to <1000/mm3 (grade 3)(15)
    <500/mm3 (grade 4)(12)
BODY AS A WHOLE
  Asthenia7612
  Abdominal cramping/pain5716
  Fever451
  Pain242
  Headache171
  Back pain142
  Chills140
  Minor infection§140
  Edema101
  Abdominal enlargement100
METABOLIC AND NUTRITIONAL
  ↓ Body weight301
  Dehydration154
  ↑ Alkaline phosphatase134
  ↑ SGOT101
DERMATOLOGIC
  Alopecia60NA
  Sweating160
  Rash131
RESPIRATORY
  Dyspnea224
  ↑ Coughing170
  Rhinitis160
NEUROLOGIC
  Insomnia190
  Dizziness150
CARDIOVASCULAR
  Vasodilation (flushing)110

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).

Table 8: Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapy*
Study 1Study 2
Adverse EventIrinotecan
N=189
BSC
N=90
Irinotecan
N=127
5-FU
N=129
*
Severity of adverse events based on NCI CTC (version 1.0)
BSC = best supportive care
Hepatic includes events such as ascites and jaundice
§
Cutaneous signs include events such as rash
Respiratory includes events such as dyspnea and cough
#
Neurologic includes events such as somnolence
Þ
Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction
ß
Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss
TOTAL Grade 3/4 Adverse Events79676954
GASTROINTESTINAL
  Diarrhea2262211
  Vomiting148145
  Nausea143114
  Abdominal pain141698
  Constipation10886
  Anorexia5764
  Mucositis2125
HEMATOLOGIC
  Leukopenia/Neutropenia220142
  Anemia7663
  Hemorrhage5313
  Thrombocytopenia1042
Infection
  without grade 3/4 neutropenia8314
  with grade 3/4 neutropenia1020
Fever
  without grade 3/4 neutropenia2120
  with grade 3/4 neutropenia2042
BODY AS A WHOLE
  Pain19221713
  Asthenia15191312
METABOLIC AND NUTRITIONAL
Hepatic 9796
DERMATOLOGIC
  Hand and foot syndrome0005
  Cutaneous signs §2013
RESPIRATORY 10857
NEUROLOGIC #121394
CARDIOVASCULAR Þ9342
OTHER ß32281214

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.

6.2 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.

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