Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5-FU/FA) were gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neuropathy). Overall, these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination than with 5-FU/FA alone.

Tabulated list of adverse reactions
The frequencies reported in the table below are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1,108 patients, respectively in the oxaliplatin + 5-FU/FA treatment arms) and from post-marketing experience.
Frequencies in this table are defined using the following convention: Very common ( 1/10), Common ( 1/100, < 1/10), Uncommon ( 1/1,000, < 1/100), Rare ( 1/10,000, < 1/1,000), Very rare (< 1/10,000), Not known (cannot be estimated from the available data).
Further details are given after the table.


MedDRA System            Very Common                  Common               Uncommon                  Rare Organ Class
Infections and        - Infection               - Rhinitis               - Sepsis++++ infestations*                                   - Upper respiratory tract infection
- Neutropenic sepsis
Blood and             - Anaemia                 - Febrile neutropenia                       - Immunoallergic lymphatic system      - Neutropenia                                                           thrombocytopenia disorders*            - Thrombocytopenia                                                    - Haemolytic anaemia - Leukopenia
- Lymphopenia

Immune system         - Allergy/allergic disorders*              reaction+


MedDRA System          Very Common                Common              Uncommon                Rare Organ Class
Metabolism and       - Anorexia              - Dehydration           - Metabolic nutrition            - Hyperglycaemia        - Hypocalcaemia           acidosis disorders            - Hypokalaemia
- Hypernatraemia
Psychiatric                                  - Depression           - Nervousness disorders                                    - Insomnia

Nervous system      - Peripheral sensory  - Dizziness                                - Dysarthria disorders*            neuropathy          - Motor neuritis                           - Reversible Posterior - Sensory disturbance - Meningism                                  Leukoencephalopathy - Dysgeusia                                                        syndrome (RPLS) - Headache

Eye disorders                                - Conjunctivitis                        - Visual acuity - Visual disturbance                      reduced transiently
- Visual field disturbances
- Optic neuritis
- Transient vision loss,
reversible following therapy discontinuation

Ear and                                                              - Ototoxicity   - Deafness labyrinth disorders
Vascular                                     - Haemorrhage disorders                                    - Flushing
- Deep vein thrombosis
- Hypertension
Respiratory,        - Dyspnoea               - Hiccups                               - Interstitial lung thoracic and        - Cough                  - Pulmonary                               disease, sometimes mediastinal         - Epistaxis                embolism                                fatal disorders                                                                            - Pulmonary fibrosis** 
Gastrointestinal   - Nausea                  - Dyspepsia             - Ileus         - Colitis including disorders*         - Diarrhoea               - Gastroesophageal      - Intestinal      Clostridium difficile - Vomiting                  reflux                  obstruction     diarrhoea - Stomatitis/ Mucositis   - Gastrointestinal                      - Pancreatitis - Abdominal pain            haemorrhage
- Constipation            - Rectal haemorrhage

Skin and            - Skin disorder          - Skin exfoliation subcutaneous        - Alopecia                 (i.e., hand-foot tissue disorders                               syndrome)
- Rash erythematous
- Rash
- Hyperhidrosis
- Nail disorder

MedDRA System            Very Common                Common               Uncommon                  Rare Organ Class
Musculoskeletal       - Back pain              - Arthralgia and connective                                 - Bone pain tissue disorders
Renal and                                      - Haematuria urinary                                        - Dysuria disorders                                      - Micturition frequency abnormal

General               - Fatigue disorders and         - Fever++ administration        - Asthenia site conditions       - Pain
- Injection site reaction+++

Investigations       - Hepatic enzyme      - Blood creatinine increase              increase
- Blood alkaline      - Weight decrease phosphatase increase (metastatic setting)
- Blood bilirubin increase
- Blood lactate dehydrogenase increase
- Weight increase
(adjuvant setting)
Injury, poisoning                           - Fall and procedural complications

* See detailed section below.
** See section 4.4.
+      Very common: frequent allergy /allergic reactions, occurring mainly during perfusion, sometimes fatal (frequent allergic reactions such as skin rash, in particular urticaria, conjunctivitis, rhinitis). Common anaphylactic reactions, including bronchospasm, angioedema, low blood pressure and anaphylactic shock. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the infusion.
++    Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism.
+++ Injection site reactions including local pain, redness, swelling and thrombosis have been reported.
Extravasation may also result in local pain and inflammation which may be severe and lead to complications including necrosis, especially when oxaliplatin is infused through a peripheral vein (see section 4.4).
++++ Common neutropenic sepsis, including fatal outcomes.


Description of selected adverse reactions

Infections and infestations

Table 1:
Incidence by patient (%)
Oxaliplatin and                 Metastatic Setting        Adjuvant Setting 5-FU/FA
85 mg/m²                            All grades                   All grades every 2 weeks
Sepsis (including sepsis
1.5                         1.7 and neutropenic sepsis)

Post-marketing experience with frequency not known
Septic shock, including fatal outcomes.

Blood and lymphatic system disorders
Table 2:
Incidence by patient (%), by grade
Oxaliplatin and 5-FU/FA           Metastatic Setting                Adjuvant Setting 85 mg/m2                      All      Grade 3     Grade 4      All     Grade 3    Grade 4 every 2 weeks               grades                            grades
Anaemia                      82.2         3          <1        75.6       0.7         0.1 Neutropenia                  71.4        28          14        78.9      28.8        12.3 Thrombocytopenia             71.6         4          <1        77.4       1.5         0.2 Febrile neutropenia           5.0        3.6         1.4        0.7       0.7         0.0 
Rare (≥1/10,000, <1/1,000):
Disseminated intravascular coagulation (DIC), including fatal outcomes (see section 4.4).

Post-marketing experience with frequency not known
Haemolytic uremic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukaemia.
Immune system disorders
Table 3:
Incidence of allergic reactions by patient (%), by grade
Oxaliplatin and 5-FU/FA              Metastatic Setting                   Adjuvant Setting 85 mg/m2                         All       Grade 3     Grade 4       All      Grade 3    Grade 4 every 2 weeks                  grades                              grades Allergic reactions/allergy       9.1         1.0         <1          10.3       2.3        0.6 
Nervous system disorders
The dose-limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy, characterised by dysaesthesia and/or paraesthesia of the extremities with or without cramps, often triggered by the cold. These symptoms occur in up to 95% of patients treated. The duration of these symptoms, which usually regress between courses of treatment, increases with the number of treatment cycles.
The onset of pain and/or a functional disorder are indications, depending on the duration of the symptoms, for dose adjustment, or even treatment discontinuation (see section 4.4).
This functional disorder includes difficulties in executing delicate movements and is a possible consequence of sensory impairment. The risk of occurrence of persistent symptoms for a cumulative dose of 850 mg/m2 (10 cycles) is approximately 10% and 20% for a cumulative dose of 1,020 mg/m2 (12 cycles).
In the majority of the cases, the neurological signs and symptoms improve or totally recover when treatment is discontinued.
In the adjuvant setting of colon cancer, 6 months after treatment cessation, 87% of patients had no or mild symptoms. After up to 3 years of follow-up, about 3% of patients presented either with persisting localised paraesthesias of moderate intensity (2.3%) or with paraesthesias that may interfere with functional activities (0.5%).

Acute neurosensory manifestations (see section 5.3) have been reported. They start within hours of administration and often occur on exposure to cold. They usually present as transient paraesthesia, dysesthesia and hypoesthesia. An acute syndrome of pharyngolaryngeal dysesthesia occurs in 1% - 2% of patients and is characterised by subjective sensations of dysphagia or dyspnoea/feeling of suffocation, without any objective evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or bronchospasm (no stridor or wheezing). Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible even in the absence of treatment. Prolongation of the infusion helps to reduce the incidence of this syndrome (see section 4.4).
Occasionally, other symptoms that have been observed include jaw spasm/muscle spasms/muscle contractions-involuntary/muscle twitching/myoclonus, coordination abnormal/gait abnormal/ataxia/balance disorders, throat or chest tightness/pressure/discomfort/pain. In addition, cranial nerve dysfunctions may be associated, or also occur as an isolated event such as ptosis, diplopia, aphonia/dysphonia/hoarseness, sometimes described as vocal cord paralysis, abnormal tongue sensation or dysarthria, sometimes described as aphasia, trigeminal neuralgia/facial pain/eye pain, decrease in visual acuity, visual field disorders.
Other neurological symptoms, such as dysarthria, loss of deep tendon reflex and Lhermitte’s sign, were reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.

Post-marketing experience with frequency not known
Convulsion, ischemic and haemorrhagic cerebrovascular disorder.

Cardiac disorders
Post-marketing experience with frequency not known
QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal (see section 4.4).
Acute coronary syndrome, including myocardial infarction and coronary arteriospasm and angina pectoris in patients treated with oxaliplatin in combination with 5-FU and bevacizumab.

Respiratory, thoracic and mediastinal disorders
Post-marketing experience with frequency not known
Laryngospasm. Pneumonia and bronchopneumonia, including fatal outcomes.

Gastrointestinal disorders
Table 4:
Incidence by patient (%), by grade
Oxaliplatin and 5-FU/FA                Metastatic Setting               Adjuvant Setting 85 mg/m2                          All                               All Grade 3      Grade 4             Grade 3    Grade 4 every 2 weeks                    grades                           grades Nausea                            69.9         8          <1       73.7       4.8        0.3 Diarrhoea                         60.8         9           2       56.3       8.3        2.5 Vomiting                          49.0         6           1       47.2       5.3        0.5 Mucositis/Stomatitis              39.9         4          <1       42.1       2.8        0.1 
Prophylaxis and/or treatment with potent antiemetic agents is indicated.
Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil (5-FU) (see section 4.4).

Post-marketing experience with frequency not known
Intestinal ischemia, including fatal outcomes (see section 4.4). Gastrointestinal ulcer and perforation, which can be fatal (see section 4.4). Oesophagitis.

Hepato-biliary disorders
Very rare (<1/10,000):


Liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of liver, or pathological manifestations related to such liver disorder, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases.

Post- marketing experience with frequency not known
Focal nodular hyperplasia.

Skin and subcutaneous tissue disorders
Post-marketing experience with frequency not known
Hypersensitivity vasculitis.
Musculoskeletal and connective tissue disorders
Post-marketing experience with frequency not known
Rhabdomyolysis, including fatal outcomes (see section 4.4).

Renal and urinary disorders
Very rare (<1/10,000):
Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

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 events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il.