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 neurophathy).
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 1108 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 (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), 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                        - Immunoallergic lymphatic system - Neutropenia               neutropenia                      thrombocytopenia disorders*       - Thrombocytopenia                                           - Haemolytic anaemia - Leukopenia
- Lymphopenia
Immune system    - Allergy / allergic
disorders*       reaction+
Metabolism and - Anorexia                    - Dehydration       - Metabolic nutrition        - Hyperglycaemia            - Hypocalcaemia     acidosis disorders        - Hypokalaemia
- Hypernatraemia
Psychiatric                                  - Depression        -
disorders                                    - Insomnia          Nervousness 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 reduced - Visual                            transiently
disturbance                         - 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
Musculoskeletal     - Back pain             - Arthralgia
and connective                              - Bone pain
tissue disorders
Renal and                                   - Haematuria
urinary disorders                           - Dysuria
- 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
phosphatise 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 particularly urticaria, conjunctivitis, rhinitis). Common anaphylactic reactions, including bronchospasm, angioeodema, 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
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 and
1.5                              1.7
neutropenic sepsis)


Postmarketing experience with frequency not known
Septic shock, including fatal outcomes
Blood and lymphatic system disorders

Incidence by patient (%), by grade
Oxaliplatin and 5-FU/FA                 Metastatic Setting                Adjuvant Setting 85 mg/m2                           All        Gr 3         Gr 4       All      Gr 3        Gr 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).

Postmarketing experience with frequency not known
Haemolytic uremic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukaemia 
Immune system disorders

Incidence of allergic reactions by patient (%), by grade
Oxaliplatin and 5-FU/FA                 Metastatic Setting                  Adjuvant Setting 85 mg/m2                           All          Gr 3       Gr 4        All        Gr 3       Gr 4 every 2 weeks                    grades                               grades Allergic reactions / Allergy       9.1           1          <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 1020 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 paresthesias of moderate intensity (2.3 %) or with paresthesias 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 paresthesia, 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.

Postmarketing experience with frequency not known
Convulsion, ischaemic 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

Incidence by patient (%), by grade
Oxaliplatin and 5-FU/FA                 Metastatic Setting                Adjuvant Setting 85 mg/m2                           All        Gr 3         Gr 4       All      Gr 3        Gr 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.

Skin and subcutaneous tissue disorders

Postmarketing 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/ In addition, you may report suspected adverse reactions by sending an e-mail message to safety@tzamal-medical.co.il