Undesirable effects detailed in this section refer to irinotecan. There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In combination with cetuximab, additional reported undesirable effects were those expected with cetuximab (such as acneiform rash 88%). Therefore also refer to the product information of cetuximab.
For information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.
The following adverse reactions considered to be possibly or probably related to the administration of irinotecan hydrochloride trihydrate have been reported from 765 patients at the recommended dose of 350 mg/m
2 in monotherapy, and from 145 patients treated by irinotecan hydrochloride trihydrate in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m
2.
Frequency estimate: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000).
Gastrointestinal disorders: Delayed diarrhoea: Diarrhoea occurring more than 24 hours after administration) is a dose-limiting toxicity of Irinotesin.
In monotherapy:
Very Common: Severe diarrhoea was observed in 20% of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 14% have severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of irinotecan hydrochloride trihydrate.
In combination therapy: Very common: severe diarrhoea was observed in 13.1% of patients who follow recommendations for the management of diarrhoea. Of the evaluable cycles, 3.9% have severe diarrhoea.
Uncommon: Cases of pseudo-membranous colitis have been reported, one of which has been documented bacteriologically (
Clostridium difficile).
Nausea and vomiting: Monotherapy: Very common: Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.
In combination therapy: Common: A lower incidence of severe nausea and vomiting was observed (2.1% and 2.8% of patients respectively).
Dehydration: Common: Episodes of dehydration associated with diarrhoea and/or vomiting.
Uncommon: 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: Common: Constipation relative to irinotecan and/or loperamide has been observed, shared between: in monotherapy: in less than 10% of patients; in combination therapy: 3.4% of patients.
Uncommon: Intestinal obstruction, ileus, or gastrointestinal haemorrhage.
Rare: Colitis, including typhlitis, ischaemic and ulcerative colitis and intestinal perforation. Cases of symptomatic or asymptomatic pancreatitis have been associated with irinotecan therapy. Other mild effects include anorexia, abdominal pain and mucositis.
Blood and lymphatic system 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: Very common: Neutropenia was observed in 78.7% of patients and was severe (neutrophil count <500 cells/mm
3) in 22.6% of patients. Of the evaluable cycles, 18% had a neutrophil count below 1,000 cells/mm
3 including 76% with a neutrophil count <500 cells/mm
3. Total recovery was usually reached by day 22. Anaemia was reported in about 58.7% of patients (8% with haemoglobin <80 g/l and 0.9% with haemoglobin <65 g/l).
Common: 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.
Thrombocytopenia (<100,000 cells/mm
3) was observed in 7.4% of patients and 1.8% of cycles with 0.9% with platelets count ≤50,000 cells/mm
3 and 0.2% of cycles. Nearly all the patients showed a recovery by day 22.
In combination therapy: Very common: Neutropenia was observed in 82.5% of patients and was severe (neutrophil count <500 cells/mm
3) in 9.8% of patients. Of the evaluable cycles, 67.3% has a neutrophil count below 1,000 cells/mm
3 including 2.7% with a neutrophil count <500 cells/mm
3. Total recovery was usually reached within 7-8 days.
Anaemia was reported in 97.2% of patients (2.1% with haemoglobin <80 g/l).
Thrombocytopenia (<100,000 cells/mm
3) was observed in 32.6% of patients and 21.8% of cycles. No severe thrombocytopenia (<50,000 cells/mm
3) has been observed. One case of peripheral thrombocytopenia with antiplatelet antibodies has been reported.
Common: 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.
Infections and infestations: Uncommon: Renal insufficiency, hypotension or cardio-circulatory failure have been observed in patients who experienced sepsis.
General disorders and administration site conditions: Acute cholinergic syndrome: Common: 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, lacrimation and increased salivation occurring during or within the first 24 hours after the infusion of irinotecan hydrochloride trihydrate. 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 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.
Uncommon: Mild infusion site reactions have been reported.
Cardiac disorders: Rare: Hypertension during or following the infusion.
Respiratory, thoracic and mediastinal disorders: Uncommon: Interstitial pulmonary disease presenting as pulmonary infiltrates. Early effects such as dyspnoea have been reported (see Precautions).
Skin and subcutaneous tissue disorders: Very common: Reversible alopecia.
Uncommon: Mild cutaneous reactions.
Immune system disorders: Uncommon: Mild allergy reactions.
Rare: Anaphylactic/anaphylactoid reactions.
Musculoskeletal and connective tissue disorders: Rare: Early effects such as muscular contraction or cramps and paresthesia have been reported.
Investigations: Very common: In combination therapy transient serum levels (grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were observed in 15%, 11% and 10% of the patients, respectively, in the absence of progressive liver metastasis. Transient grade 3 were observed in 0%, 0%, 0% and 1% of the patients, respectively. No grade 4 was observed.
Common: 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.
Rare: Hypokalemia and hyponatremia mostly related with diarrhea and vomiting.
Very Rare: Increases of amylase and/or lipase.
Nervous system disorders: Very rare: Transient speech disorders associated with infusion of irinotecan.