Irinox Side Effects

The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan Hydrochloride concentrate for solution for injection have been reported from 765 patients at the recommended dose of 350 mg/m² in monotherapy, and from 145 patients treated by Irinotecan Hydrochloride concentrate for solution for injection in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m².
Gastrointestinal disorders: Delayed diarrhoea: Diarrhoea (occurring more than 24 hours after administration) is a dose-limiting toxicity of Irinotecan Hydrochloride concentrate for solution for injection.
In monotherapy: Severe diarrhoea was observed in 20 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 14 % have a severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of Irinotecan Hydrochloride concentrate for solution for injection.
In combination therapy: Severe diarrhoea was observed in 13.1 % of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 3.9 % have a severe diarrhoea.
Uncommon cases of pseudo-membranous colitis have been reported, one of which has been documented bacteriologically (Clostridium difficile).
Nausea and vomiting: In monotherapy: Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.
In combination therapy: A lower incidence of severe nausea and vomiting was observed (2.1% and 2.8% of patients respectively).
Dehydration: Episodes of dehydration commonly associated with diarrhoea and/or vomiting have been reported.
Infrequent cases of renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting.
Other gastrointestinal disorders: Constipation relative to Irinotecan Hydrochloride concentrate for solution for injection and/or loperamide has been observed, shared between: in monotherapy : in less than 10% of patients; in combination therapy: 3.4% of patients.
Infrequent cases of intestinal obstruction, ileus, or gastrointestinal haemorrhage and rare cases of colitis, including typhlitis, ischemic and ulcerative colitis, were reported. Rare cases of intestinal perforation were reported. Other mild effects include anorexia, abdominal pain and mucositis.
Rare cases of symptomatic or asymptomatic pancreatitis have been associated with irinotecan therapy.
Blood disorders: Neutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; the median day to nadir was 8 days whatever the use in monotherapy or in combination therapy.
In monotherapy: Neutropenia was observed in 78.7% of patients and was severe (neutrophil count < 500 cells/mm³) in 22.6% of patients.
Of the evaluable cycles, 18 % had a neutrophil count below 1,000 cells/mm3 including 7.6% with a neutrophil count < 500 cells/mm³.
Total recovery was usually reached by day 22.
Fever with severe neutropenia was reported in 6.2% of patients and in 1.7% of cycles.
Infectious episodes occurred in about 10.3% of patients (2.5% of cycles) and were associated with severe neutropenia in about 5.3% of patients (1.1% of cycles), and resulted in death in 2 cases.
Anaemia was reported in about 58.7% of patients (8% with haemoglobin < 8 g/dl and 0.9 % with haemoglobin < 6.5 g/dl).
Thrombocytopenia (< 100,000 cells/mm³) was observed in 7.4% of patients and 1.8% of cycles with 0.9% with platelets count 50,000 cells/mm³ and 0.2% of cycles.
Nearly all the patients showed a recovery by day 22.
In combination therapy: Neutropenia was observed in 82.5% of patients and was severe (neutrophil count < 500 cells/mm³) in 9.8 % of patients.
Of the evaluable cycles, 67.3% had a neutrophil count below 1,000 cells/mm³ including 2.7% with a neutrophil count < 500 cells/mm³.
Total recovery was usually reached within 7-8 days.
Fever with severe neutropenia was reported in 3.4% of patients and in 0.9% of cycles.
Infectious episodes occurred in about 2% of patients (0.5% of cycles) and were associated with severe neutropenia in about 2.1% of patients (0.5% of cycles), and resulted in death in 1 case.
Anaemia was reported in 97.2% of patients (2.1% with haemoglobin < 8 g/dl).
Thrombocytopenia (< 100,000 cells/mm³) was observed in 32.6% of patients and 21.8% of cycles. No severe thrombocytopenia (< 50,000 cells/mm³) has been observed.
One case of peripheral thrombocytopenia with antiplatelet antibodies has been reported in the post-marketing experience.
Infection and infestation: Infrequent cases of renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced sepsis.
General disorders and infusion site reactions: Acute cholinergic syndrome: Severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy and in 1.4 % of patients treated in combination therapy. The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilatation, sweating, chills, malaise, dizziness, visual disturbances, myosis, lachrimation and increased salivation occurring during or within the first 24 hours after the infusion of Irinotecan Hydrochloride concentrate for solution for injection. These symptoms disappear after atropine administration (see Precautions).
Asthenia was severe in less than 10 % of patients treated in monotherapy and in 6.2 % of patients treated in combination therapy. The causal relationship to Irinotecan Hydrochloride concentrate for solution for injection has not been clearly established. Fever in the absence of infection and without concomitant severe neutropenia, occurred in 12 % of patients treated in monotherapy and in 6.2 % of patients treated in combination therapy.
Mild infusion site reactions have been reported although uncommonly.
Cardiac disorder: Rare cases of hypertension during or following the infusion have been reported.
Respiratory disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnoea have been reported.
Skin and subcutaneous tissue disorders: Alopecia was very common and reversible. Mild cutaneous reactions have been reported although uncommonly.
Immune system disorders: Uncommon mild allergy reactions and rare cases of anaphylactic/anaphylactoid reactions have been reported.
Musculoskeletal disorders: Early effects such as muscular contraction or cramps and paresthesia have been reported.
Laboratory tests: In monotherapy, transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase or bilirubin were observed in 9.2%, 8.1% and 1.8% of the patients, respectively, in the absence of progressive liver metastasis.
Transient and mild to moderate increases of serum levels of creatinine have been observed in 7.3% of the patients.
In combination therapy transient serum levels (grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were observed in 15%, 11%, 11% and 10% of the patients, respectively, in the absence of progressive liver metastasis. Transient grade 3 was observed in 0%, 0%, 0% and 1% of the patients, respectively. No grade 4 was observed.
Increases of amylase and/or lipase have been very rarely reported.
Rare cases of hypokalemia and hyponatremia mostly related with diarrhea and vomiting have been reported.
Nervous system disorders: There have been very rare postmarketing reports of transient speech disorders associated with Irinotecan Hydrochloride concentrate for solution for injection infusions.
Post-marketing surveillance: Cardiac disorders: Myocardial ischemic events have been observed following irinotecan therapy predominantly in patients with underlying cardiac disease, other known risk factors for cardiac disease or previous cytotoxic chemotherapy.
Gastrointestinal disorders: Infrequent cases of intestinal obstruction, ileus, megacolon, or gastrointestinal hemorrhage, and rare cases of colitis, including typhlitis, ischemic and ulcerative colitis were reported. In some cases, colitis was complicated by ulceration, bleeding, ileus, or infection. Cases of ileus without preceding colitis have also been reported. Rare cases of intestinal perforation were reported.
Rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed.
Hypovolemia: There have been rare cases of renal impairment and acute renal failure, generally in patients who became infected and/or volume depleted from severe gastrointestinal toxicities. Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis.
Immune system disorders: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been reported.
Musculoskeletal and connective tissue disorders: Early effects such as muscular contraction or cramps and paresthesia have been reported.
Nervous system disorders: Speech disorders, generally transient in nature, have been reported in patients treated with irinotecan; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.
Respiratory, thoracic and mediastinal disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnea have been reported . Hiccups have also been reported.
Investigations: Rare cases of hyponatremia mostly related with diarrhea and vomiting have been reported. Increases in serum levels of transaminases (i.e., AST and AlT) in the absence of progressive liver metastasis have been very rarely reported.