Adverse reactions : תופעות לוואי

4.8.    Undesirable effects

CLINICAL STUDIES
Adverse reaction data have been extensively collected from studies in metastatic colorectal cancer; the frequencies are presented below. The adverse reactions for other indications are expected to be similar to those for colorectal cancer.

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 whatever the use 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 (see section 4.4).

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).
Adverse Reactions Reported with Irinotecan in Monotherapy (350 mg/m2 every-3-weeks schedule) MedDRA System Organ Class                 Frequency Category Preferred Term Infections and infestations               Common             Infection Blood and lymphatic system disorders      Very common        Neutropenia Very common        Anaemia
Common             Thrombocytopenia
Common             Febrile neutropenia
Metabolism and nutrition disorders        Very common        Decreased appetite Nervous system disorders                  Very common        Cholinergic syndrome Gastrointestinal disorders                Very common        Diarrhoea Very common        Vomiting
Very common        Nausea
Very common        Abdominal pain
Common             Constipation
Skin and subcutaneous tissue disorders    Very common        Alopecia (reversible) General disorders and administration site Very common        Mucosal inflammation conditions                                Very common        Pyrexia
Very common        Asthenia
Investigations                            Common             Blood creatinine increased Common             Transaminases (ALT and AST) increased
Common             Blood bilirubin increased
Common             Blood alkaline phosphatase increased

Description of selected adverse reactions (monotherapy)

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.
Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.
Constipation has been 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.
Febrile neutropenia was reported in 6.2% of patients and in 1.7% of cycles.
Infections 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 platelet count ≤ 50,000 cells/mm3 and 0.2% of cycles.
Nearly all the patients showed a recovery by day 22.
Acute cholinergic syndrome
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.



Page 11 of 21
Pyrexia 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.

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.

Adverse Reactions Reported with Irinotecan in Combination Therapy (180 mg/m2 every-2- weeks schedule)
MedDRA System Organ Class Frequency Category                  Preferred Term Infections and infestations    Common                         Infection Blood and lymphatic system     Very common                    Thrombocytopenia disorders                      Very common                    Neutropenia Very common                    Anaemia
Common                         Febrile neutropenia
Metabolism and nutrition       Very common                    Decreased appetite disorders
Nervous system disorders       Very common                    Cholinergic syndrome Gastrointestinal disorders     Very common                    Diarrhoea Very common                    Vomiting
Very common                    Nausea
Common                         Abdominal pain
Common                         Constipation
Skin and subcutaneous tissue   Very common                    Alopecia (reversible) disorders
General disorders and          Very common                    Mucosal inflammation administration site conditions Very common                    Asthenia Common                         Pyrexia
Investigations                 Very common                    Transaminases (ALT and AST) increased
Very common                    Blood bilirubin increased
Very common                    Blood alkaline phosphatase increased

Description of selected adverse reactions (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.
A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients, respectively).
Constipation relative to Irinotecan and/or loperamide has been observed in 3.4 % of patients.


Page 12 of 21
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.
Febrile neutropenia was reported in 3.4% of patients and in 0.9% of cycles.
Infections 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.
Acute cholinergic syndrome
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. Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 6.2 % of patients treated in combination therapy.
Laboratory tests
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 were 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 hypokalaemia and hyponatremia mostly related with diarrhoea and vomiting have been reported.

OTHER ADVERSE EVENTS REPORTED IN CLINICAL STUDIES WITH THE WEEKLY
REGIMEN FOR IRINOTECAN

The following additional drug-related events have been reported in clinical studies with irinotecan: pain, sepsis, anorectal disorder, GI candida infection, hypomagnesamia, rash, skin signs, gait disturbance, confusion, headache, syncope, flushing, bradycardia, urinary tract infection, breast pain, increased gamma-glutamyltransferase, extravasation, and tumour lysis syndrome, cardiovascular disorders (angina pectoris,cardiac arrest, myocardial infarction, myocardial ischaemia, peripheral vascular disorder, vascular disorder), and thromboembolic events (arterial thrombosis, cerebral infarction, cerebrovascular accident, deep vein thrombosis, peripheral embolism , pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section 4.4).



Page 13 of 21
POST-MARKETING SURVEILLANCE

Frequencies from post-marketing surveillance are not known (cannot be estimated from available data).

MedDRA System Organ Class            Preferred Term
Infections and infestations          • Pseudomembranous colitis one of which has been documented bacteriologically (Clostridium difficile)
• Sepsis
• Fungal infections*
• Viral infections†
Blood and lymphatic system           • Thrombocytopenia with antiplatelet antibodies disorders
Immune system disorders              •   Hypersensitivity
•   Anaphylactic reaction
Metabolism and nutrition disorders   •   Dehydration (due to diarrhoea and vomiting) •   Hypovolaemia
Nervous system disorders             •   Speech disorder generally transient in nature, in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan
•   Paraesthesia
•   Muscular contractions involuntary
Cardiac disorders                    •   Hypertension (during or after infusion) •   Cardio circulatory failure*
Vascular disorders                   •   Hypotension*
Respiratory, thoracic and            •   Interstitial lung disease presenting as lung infiltration is mediastinal disorders                    uncommon during irinotecan therapy; early effects such as dyspnoea have been reported (see section 4.4)
•   Dyspnoea (see section 4.4)
•   Hiccups
Gastrointestinal disorders           •   Intestinal obstruction
•   Ileus: cases of ileus without preceding colitis have also been reported
•   Megacolon
•   Gastrointestinal haemorrhage
•   Colitis; in some cases, colitis was complicated by ulceration, bleeding, ileus, or infection.
•   Typhlitis
•   Colitis ischaemic
•   Colitis ulcerative
•   Symptomatic or asymptomatic pancreatic enzymes incraesed
•   Intestinal perforation
Hepatobiliary disorders              •   Steatohepatitis
•   Hepatic steatosis
Skin and subcutaneous tissue         •   Skin reaction disorders
Musculoskeletal and connective       •   Cramps tissue disorders


Page 14 of 21
Renal and urinary disorders                •    Renal impairment and acute renal failure generally in patients who become infected and/or volume depleted from severe gastrointestinal toxicities.*
•    Renal insufficiency*
General disorders and                      •    Infusion site reaction administration site conditions
Investigations                             •     Amylase increased
•    Lipase increased
•    Hypokalaemia
•    Hyponatraemia mostly related with diarrhoea and vomiting
•     Transaminases increased(i.e., AST and ALT) in the absence of progressive liver metastasis have been very rarely reported
* e.g. Pneumocystis jirovecii pneumonia, bronchopulmonary aspergillosis, systemic candida.
† e.g. Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.
* 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, or sepsis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse event should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il