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Camptosar Inj

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Camptosar Injection

Side Effects
Interactions

SIDE EFFECTS

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.

Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.

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].

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 5FU/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 Therapiesa

Adverse Event Study 1
Irinotecan + Bolus 5-FU/LV weekly x 4 every 6 weeks
N=225
Bolus 5-FU/LV daily x 5 every 4 weeks
N=219
Irinotecan weekly x 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 84.9 22.7 69.4 13.2 83 31
   late -- 15.1 -- 5.9 -- 18.4
    grade 3 -- 7.6 -- 7.3 -- 12.6
    grade 4 45.8 4.9 31.5 1.4 43 6.7
   early
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
Vomiting 60.4 9.7 46.1 4.1 62.8 12.1
Anorexia 34.2 5.8 42 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 -- 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 2.6 98.6 2.7 96 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 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 --
aSeverity of adverse events based on NCI CTC (version 1.0)
bComplete hair loss = Grade 2
cIncludes 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.

Table 6: Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa

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 72.4 14.4 44.8 6.3
    late -- 10.3 -- 4.2
    grade 3 -- 4.1 -- 2.1
    grade 4 28.3 1.4 0.7 0
  Cholinergic syndromeb
  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 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 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 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
  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 --
aSeverity of adverse events based on NCI CTC (version 1.0)
bIncludes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan)
cComplete hair loss = Grade 2
dIncludes 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.

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 Rectuma

Body System & Event % of Patients Reporting
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 AND 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
aSeverity of adverse events based on NCI CTC (version 1.0)
bOccurring > 24 hours after administration of CAMPTOSAR
cOccurring ≤ 24 hours after administration of CAMPTOSAR
dPrimarily upper respiratory infections
eNot applicable; complete hair loss = NCI grade 2

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 Therapya

Adverse Event Study 1 Study 2
Irinotecan
N=189
BSCb
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 8 3 1 4
  neutropenia with grade 3/4 neutropenia 1 0 2 0
Fever
  without grade 3/4 2 1 2 0
  neutropenia 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
  Hepaticc 9 7 9 6
DERMATOLOGIC
  Hand and foot syndrome 0 0 0 5
  Cutaneous signsd 2 0 1 3
RESPIRATORYe 10 8 5 7
NEUROLOGICf 12 13 9 4
CARDIOVASCULARg 9 3 4 2
OTHERh 32 28 12 14
aSeverity of adverse events based on NCI CTC (version 1.0)
bBSC = best supportive care
cHepatic includes events such as ascites and jaundice
dCutaneous signs include events such as rash
eRespiratory includes events such as dyspnea and cough
fNeurologic includes events such as somnolence
gCardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction
hOther includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss

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 irinotecan 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 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.

Read the Camptosar Injection (irinotecan hydrochloride) Side Effects Center for a complete guide to possible side effects

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 5FU 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.

Strong CYP 3A4 Inducers

Anticonvulsants and other strong inducers: 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 or other strong inducers such as rifampin and rifabutin has not been defined. Consideration should be given to substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy.

St. John's wort: 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.

Dexamethasone, a moderate CYP3A4 inducer, does not appear to alter the pharmacokinetics of irinotecan.

Strong CYP 3A4 Inhibitors

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.

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.

Drug-Laboratory Test Interactions

There are no known interactions between CAMPTOSAR and laboratory tests.

Read the Camptosar Injection Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 8/9/2012
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
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