Irinocan 40/Irinocan 100 Adverse Reactions

Adverse reaction data have been extensively collected from studies in metastatic colorectal cancer; the frequencies are presented as follows.
The most common (≥1/10), dose limiting adverse reactions of Irinotecan are delayed diarrhoea (occurring more than 24 hours after administration) and blood disorders including neutropenia, anaemia and thrombocytopenia.
Neutropenia is a dose limiting toxic effect. Neutropenia was reversible and not cumulative. The median day to nadir was 8 days whether in monotherapy or in combination therapy.
Very commonly severe transient acute cholinergic syndrome was observed. The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, sweating, myosis and increased salivation occurring during or within the first 24 hours after the infusion of Irinotecan. These symptoms disappear after atropine administration.
Monotherapy: The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan have been reported from 765 patients at the recommended dose of 350 mg/m² in monotherapy. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: 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), and very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 1.)

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Description of selected adverse reactions (monotherapy): Severe diarrhoea was observed in 20 % of patients who followed the recommendations for the management of diarrhoea. Of the evaluable cycles, 14 % had severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion of Irinotecan.
Nausea and vomiting were severe in approximately 10 % of patients treated with antiemetics.
Constipation was observed in less than 10% of patients.
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.
Severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy.
Asthenia was severe in less than 10 % of patients treated in monotherapy. 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.
Laboratory tests: 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.
Combination Therapy: Adverse reactions 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 adverse reactions were those expected with Cetuximab (such as acneiform rash 88%). For information on adverse reactions on Irinotecan in combination with Cetuximab, also refer to their respective summaries of product characteristics.
Adverse drug reactions reported in patients treated with Capecitabine in combination with Irinotecan in addition to those seen with Capecitabine monotherapy or seen at a higher frequency grouping compared to Capecitabine monotherapy include: Very common, all grade adverse drug reactions: thrombosis/embolism; Common, all grade adverse drug reactions: hypersensitivity reaction, cardiac ischemia/infarction; Common, grade 3 and grade 4 adverse drug reactions: febrile neutropenia. For complete information on adverse reactions of Capecitabine, refer to the Capecitabine summary product of characteristics.
Grade 3 and Grade 4 adverse drug reactions reported in patients treated with Capecitabine in combination with Irinotecan and Bevacizumab in addition to those seen with Capecitabine monotherapy or seen at a higher frequency grouping compared to Capecitabine monotherapy include: Common, grade 3 and grade 4 adverse drug reactions: neutropenia, thrombosis/embolism, hypertension, and cardiac ischemia/infarction. For complete information on adverse reactions of Capecitabine and Bevacizumab, refer to the respective Capecitabine and Bevacizumab summary of product characteristics.
Grade 3-hypertension was the principal significant risk involved with the addition of Bevacizumab to bolus Irinotecan/5FU/FA.
In addition, there was a small increase in the grade 3/4 chemotherapy adverse events of diarrhoea and leukopenia with this regimen compared to patients receiving bolus Irinotecan/5FU/FA alone. For other information on adverse reactions in combination with Bevacizumab, refer to the Bevacizumab summary of product characteristics.
Irinotecan has been studied in combination with 5FU and FA for metastatic colorectal cancer. Safety data of adverse reactions from clinical studies demonstrate very commonly observed NCI Grade 3 or 4 possibly or probably related adverse events in the blood and the lymphatic system disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders MedDRA System Organ Classes.
The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan have been reported from 145 patients treated by Irinotecan in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m². (See Table 2.)

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Description of selected adverse reactions (combination therapy): Severe diarrhoea was observed in 13.1 % of patients who followed recommendations for the management of diarrhoea. Of the evaluable cycles, 3.9 % had severe diarrhoea. A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients respectively). Constipation relative to Irinotecan and Loperamide has been observed in 3.4 % of patients.
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 78 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.
Severe transient acute cholinergic syndrome was observed in 1.4 % of patients treated in combination therapy.
Asthenia was severe 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 6.2 % of patients treated in combination therapy.
Laboratory tests: Transient increases in serum levels (Grades 1 and 2) of 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 increases were observed in 0 %, 0%, 0 % and 1 % of the patients, respectively. No Grade 4 elevation was observed.
Increases of amylase and/or lipase have been very rarely reported. Rare cases of hypokalaemia and hyponatraemia mostly related with diarrhoea and vomiting have been reported.