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, <1/1000) very rare (<1/10,000), not known (cannot be estimated from the available data).



Further details are shown after the table

MedDRA               Very common              Common         Uncommon                 Rare Organ system classes
Investigations       -Hepatic enzyme         - Blood increase                creatinine
-Blood alkaline           increase phosphatase           - Weight increase                decrease
-Blood bilirubin        (metastatic increase setting)
-Blood lactate dehydrogenase increase
-Weight increase
(adjuvant setting)

Blood and        -Anaemia                - Febrile                         -Immunoallergic lymphatic        -Neutropenia            neutropenia                       thrombocytopenia 
 system          - Thrombocytopenia                                        -Haemolytic disorders*       -Leukopenia                                               anaemia -Lymphopenia

Nervous system      -Peripheral             - Dizziness                       - Dysarthria disorders*         sensory neuropathy             - Motor neuritis                  - Reversible - Sensory               - Meningism                         Posterior disturbance                                               Leukoen
- Dysgeusia cephalopathy
- Headache syndrome
(RPLS, or PRES)**
(see section 4.4)


Eye disorders                                -Conjunctivitis                   -Visual acuity -Visual                             reduced disturbance                         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                              - Pulmonary                       disease sometimes fatal - Cough
 mediastinal       - Epistaxis              emboilsm                         -Pulmonary disorders                                                                   fibrosis** Gastrointestinal     -Nausea                 -Dyspepsia         -Ileus         - Colitis including disorders*        - Diarrhoea              -Gastro              -Intestinal       clostridium difficile -Vomiting                 esophageal          obstruction       diarrhea -Stomatitis /Mucositis    reflux
- Abdominal pain         -Gastrointestinal                      - Pancreatitis -Constipation              hemorrhage
- Rectal haemorrhage
Renal and                                  -Haematuria urinary                                   - Dysuria disorders                                  - Micturition frequency abnormal
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                                     - Bone pain connective tissue disorders

Metabolism         - Anorexia               -Dehydration         -Metabolic and nutrition        - Hyperglycemia                               acidosis disorders         - Hypokalaemia
- Hypernatraemia



Infections and        -Infection               - Rhinitis infestations *                                 - Upper              Sepsis, respiratory tract    including fatal infection            outcomes
- Neutropenic sepsis,
including fatal outcomes


Vascular                                   - Haemorrhage disorders                                  - Flushing                             -Disseminated - Deep vein                            intravascular coagulation thrombosis                           (DIC), including fatal
- Hypertension                         outcomes.
(see Section 4.4)

General disorders     -Fatigue and             - Fever++ administration site   -Asthenia conditions         -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).


Postmarketing 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 every  2 All grades                   Grade 3        Grade 4    All grades     Grade 3            Grade 4 weeks
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 
Postmarketing 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 every             All               Grade 3       Grade 4      All grades      Grade 3         Grade 4 grades
2 weeks
Allergic reactions/
9.1             1.0            <1           10.3           2.3             0.6 allergy



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:”Special warnings and special precautions for use”).
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/m 2 (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:”Preclinical safety data”). 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:”Special warnings and special precautions for use”)
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.

Postmarketing experience with frequency unknown
Convulsion


Gastrointestinal disorders
Incidence by patient (%) by grade

Oxaliplatin and          Metastatic setting                                Adjuvant setting 2
5-FU/FA 85 mg/m every 2 weeks     All grades Grade 3 Grade 4                  All grades Grade 3            Grade 4 
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, hypokalmia, 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:”Special warnings and special precautions for use”).
Post marketing experience with frequency unknown

• Intestinal ischaemia, including fatal outcomes. (See section 4.4:”Special warnings and special precautions for use”). Duodenal ulcer, and complications, such as duodenal ulcer haemorrhage or perforation, which can be fatal. (See section 4.4:”Special warnings and special precautions for use”).

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:”Special warnings and special precautions for use”).

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:”Special warnings and special precautions for use”).


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%)

Reporting 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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il