Adverse reactions : תופעות לוואי

4.8 Undesirable effects

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.

The frequencies reported in the table below are derived from clinical trials in the metastatic and adjuvant setting (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 (≥1/1,000, <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 shown after the table.
MedDRA Organ          Very Common                 Common               Uncommon               Rare System Classes
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)
Blood and           - Anaemia                  - Febrile neutropenia                   - Immunoallergic lymphatic system    - Neutropenia                                                      thrombocytopenia disorders*          - Thrombocytopenia                                                 - Haemolytic anaemia - Leukopenia
- Lymphopenia
Nervous system      - Peripheral sensory       - Dizziness                             - Dysarthria disorders*          neuropathy                 - Motor neuritis                        - Reversible Posterior - Sensory disturbance      - Meningism                             Leukoencephalopathy - Dysgeusia                                                        syndrome (RPLS, or - Headache                                                         PRES)** (see section 4.4)
Eye disorders                                  - Conjunctivitis                        - Visual acuity - Visual disturbance                    reduced transiently
- Visual field disturbances
- Optic neuritis
- Transient vision loss,
reversible following therapy discontinuation
Ear and labyrinth                                                      - Ototoxicity   - Deafness disorders
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                - Gastro-esophageal - Intestinal        clostridium difficile - Vomiting                 reflux              obstruction         diarrhea - Stomatitis / Mucositis   - Gastrointestinal                      - Pancreatitis - Abdominal pain           hemorrhage
- Constipation             - Rectal haemorrhage
Renal and urinary                              - Haematuria disorders                                      - Dysuria
- Micturition frequency abnormal
Skin and            - Skin disorder          - Skin exfoliation
Subcutaneous tissue - Alopecia               (i.e. Hand & Foot disorders                                    syndrome)
- Rash erythematous
- Rash
- Hyperhidrosis
- Nail disorder
Musculoskeletal     - Back pain              - Arthralgia and connective                               - Bone pain tissue disorders
Metabolism and      - Anorexia               - Dehydration         - Metabolic nutrition disorders - Hyperglycemia          - Hypocalcemia        acidosis - Hypokalaemia
- Hypernatraemia
Infections and      - Infection              - Rhinitis            - Sepsis, infestations*                                - Upper respiratory including fatal tract infection       outcomes
- Neutropenic sepsis,
including fatal outcomes
Vascular disorders                           - Haemorrhage                          - Disseminated - Flushing                             intravascular
- Deep vein                            coagulation (DIC),
thrombosis                             including fatal
- Hypertension                         outcomes (see section
4.4)
General disorders - Fatigue and administration - Fever++ site conditions    - Asthenia
- Pain
- Injection site reaction+++

Immune system        - Allergy/allergic disorders*           reaction+

Psychiatric                                  - Depression          - Nervousness disorders                                    - Insomnia

* See detailed section below.
** See section 4.4.
+ Very common allergies/allergic reactions, occurring mainly during infusion, sometimes fatal.
Common allergic reactions include skin rash particularly urticaria, conjunctivitis and rhinitis.
Common anaphylactic or anaphylactoid reactions, include bronchospasm, sensation of chest pain, angioedema, hypotension and anaphylactic shock.
++ 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).
Post-marketing experience with frequency unknown

Infections and infestations

Septic shock, including fatal outcomes.
Blood and lymphatic system disorders

Incidence by patient (%) by grade

Oxaliplatin and                            Metastatic setting                  Adjuvant setting 5-FU/FA 85 mg/m2                      All                                 All every 2 weeks                                  Grade 3      Grade 4                Grade 3    Grade 4 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 Neutropenic sepsis                     1.1       0.7          0.4          1.1       0.6        0.4 
Post-marketing experience with frequency unknown

Hemolytic uremic syndrome
Immune system disorders

Incidence of allergic reactions by patient (%) by grade

Oxaliplatin and                                Metastatic setting               Adjuvant setting 5-FU/FA 85 mg/m2
All                                 All every 2 weeks                                       Grade 3    Grade 4              Grade 3    Grade 4 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 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 cumulated 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 paraesthesias of moderate intensity (2.3%) or with paraesthesias that may interfere with functional activities (0.5%).

Acute neurosensory manifestations have been reported (see section 5.3). They start within hours of administration and often occur on exposure to cold. They usually present as transient paresthesia, dysesthesia and hypoaesthesia. 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 with the above-mentioned events, 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 unknown

Convulsion
Gastrointestinal disorders

Incidence by patient (%) by grade

Oxaliplatin and                            Metastatic setting                   Adjuvant setting 5-FU/FA 85 mg/m2                      All                                  All every 2 weeks                                  Grade 3      Grade 4                 Grade 3    Grade 4 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 diarrhea/emesis particularly when combining oxaliplatin with 5-fluorouracil (5- FU) (see section 4.4).

Post-marketing experience with frequency unknown
• intestinal ischaemia, including fatal outcomes. (see section 4.4).
• duodenal ulcer, and complications, such as duodenal ulcer haemorrhage or perforation, which can be fatal. (see section 4.4).

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.

Renal and urinary disorders

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

Cardiac disorders

Post-marketing experience with frequency unknown
QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal. (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Post-marketing experience with frequency unknown
Laryngospasm

Musculoskeletal and connective tissue disorders

Post-marketing experience with frequency unknown
Rhabdomyolysis, including fatal outcomes. (see section 4.4).

Combined therapy of oxaliplatin with leucovorin, irinotecan and 5-fluorouracil (FOLFIRINOX) - Grade 3 and 4 adverse reactions:

- Blood and lymph system disorders
Very common
Neutropenia (45.7%)

Common
Thrombocytopenia (9.1%)
Anemia (7.8%)
Febrile neutropenia (5.4%)
- Vascular disorders
Common
Thromboembolism (6.6%)

- Metabolic and nutritional disorders
Very common
Fatigue (23.6%)

- Gastrointestinal disorders
Very common
Vomiting (14.5%)
Diarrhea (12.7%)
- Nervous system disorders
Common
Sensory neuropathy (9%)

- Hepatobiliary disorders
Common
Increased ALAT (7.3%)