Irinotecan Hydrochloride
Generic: IRINOTECAN HYDROCHLORIDE
Basic Information
Manufacturer
Hikma Pharmaceuticals USA Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
9c6aa884-750e-4b11-9955-bc7ab6e9c2ad
Indications & Usage
1 INDICATIONS AND USAGE Irinotecan Hydrochloride Injection, USP is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
Irinotecan Hydrochloride Injection, USP is a topoisomerase inhibitor indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
Irinotecan Hydrochloride Injection, USP is a topoisomerase inhibitor indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
Adverse Reactions
6 ADVERSE REACTIONS 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, alopecia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.
at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 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.
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 irinotecan hydrochloride injection.
Seventeen of the patients died within 30 days of the administration of irinotecan hydrochloride injection; 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 irinotecan hydrochloride injection.
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 irinotecan hydrochloride injection 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 irinotecan hydrochloride injection because of adverse events.
The adverse events in Table 3 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies ( 14.1 ).
Table 3.
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 irinotecan hydrochloride injection 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) Occurring ≤24 hours after administration of irinotecan hydrochloride injection 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) - (15) <500/mm 3 (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 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 4 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 4.
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) Adverse Event Study 1 Study 2 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 irinotecan hydrochloride injection 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 irinotecan hydrochloride injection.
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 hydrochloride injection therapy.
Thromboembolic events have been observed in patients receiving irinotecan hydrochloride injection.
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 irinotecan hydrochloride injection; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.
Interaction between irinotecan hydrochloride injection 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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.
at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 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.
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 irinotecan hydrochloride injection.
Seventeen of the patients died within 30 days of the administration of irinotecan hydrochloride injection; 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 irinotecan hydrochloride injection.
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 irinotecan hydrochloride injection 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 irinotecan hydrochloride injection because of adverse events.
The adverse events in Table 3 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies ( 14.1 ).
Table 3.
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 irinotecan hydrochloride injection 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) Occurring ≤24 hours after administration of irinotecan hydrochloride injection 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) - (15) <500/mm 3 (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 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 4 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 4.
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) Adverse Event Study 1 Study 2 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 irinotecan hydrochloride injection 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 irinotecan hydrochloride injection.
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 hydrochloride injection therapy.
Thromboembolic events have been observed in patients receiving irinotecan hydrochloride injection.
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 irinotecan hydrochloride injection; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.
Interaction between irinotecan hydrochloride injection 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.