Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of safety profile
In patients treated with the recommended daily doses of tretinoin the most frequent undesirable effects are consistent with the signs and symptoms of the hypervitaminosis A syndrome (as for other retinoids).

Tabulated list of adverse reactions

The adverse reactions listed in the table below have been reported in pivotal clinical studies and during the post-marketing period.

Adverse reactions are presented by MedDRA System Organ Class and frequency (very common (≥ 1/10)). Adverse reactions reported during the post-marketing period are also included in the table under the frequency category “not known” (cannot be estimated from the available data).

System Organ Class            Frequency       Adverse Reaction(s) Infections and infestations   Not known       Necrotising fasciitis Blood and lymphatic           Not known       Thrombocytosis, leukocytosis, system disorders                              basophilia (with or without symptomatic hyperhistaminaemia)
Metabolism and nutrition      Very common     Decreased appetite disorders                    Not known        Hypercalcaemia Psychiatric disorders        Very common      Confusional state, anxiety, depression, insomnia
Nervous system disorders     Very common      Headache, intracranial pressure increased, pseudotumour cerebri,
dizziness, paraesthesia
Not known        Cerebrovascular accident
Eye disorders                Very common      Visual disturbances, conjunctival disorders
Ear and labyrinth            Very common      Hearing impaired disorders
Cardiac disorders            Very common      Arrhythmia
Not known        Myocardial infarction, myocarditis,
pericarditis
Vascular disorders           Very common      Flushing
Not known        Arterial thrombosis, venous thrombosis involving various sites (e.g.
cerebrovascular accident, myocardial infarction, renal infarct), vasculitis
Respiratory, thoracic and    Very common      Respiratory failure, nasal dryness, mediastinal disorders                         asthma
Gastrointestinal disorders   Very common      Dry mouth, nausea, vomiting, abdominal pain, diarrhoea, constipation,
pancreatitis, cheilitis
Skin and subcutaneous        Very common      Erythema, rash, pruritus, alopecia, tissue disorders                              hyperhidrosis
Not known        Erythema nodosum, acute febrile neutrophilic dermatosis (Sweet’s syndrome)
Musculoskeletal and          Very common      Bone pain connective tissue            Not known        Myositis disorders
Renal and urinary            Not known        Renal infarct disorders
Reproductive system and      Not known        Genital ulceration breast disorders
General disorders and        Very common      Chest pain, chills, malaise administration site conditions
Investigations               Very common      Blood triglyceride increased, blood creatinine increased, blood cholesterol increased, transaminases increased
Not known        Histamine level increased

The decision to interrupt or continue therapy should be based on an evaluation of the benefit of the treatment versus the severity of the side-effects.

Description of selected adverse reactions

Differentiation syndrome (formerly known as retinoic acid syndrome) may be fatal and is characterised by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, pleural and pericardial effusions, hypotension, oedema, weight gain, hepatic, renal and multi-organ failure. Differentiation syndrome is frequently associated with hyperleukocytosis. For prevention and treatment of differentiation syndrome see section 4.4.

Leukocytosis/hyperleukocytosis are frequent adverse effects associated with tretinoin therapy of APL and may be accompanied by differentiation syndrome. However, most cases of leukocytosis/hyperleukocytosis are not associated with differentiation syndrome.

In clinical trials, increased frequencies of hyperleukocytosis, QTc prolongation and hepatotoxic effects have been observed with combination therapy of tretinoin with arsenic trioxide compared to combination therapy of tretinoin with chemotherapy. Liver toxicity occurred predominantly during the first phase of therapy (induction therapy) and is mainly characterised by increase in transaminases. For the characteristics, prevention, and treatment of hyperleukocytosis, QTc prolongation and hepatotoxic effects see section 4.4.

Teratogenicity: See section 4.6.

Paediatric population
There is limited safety information on the use of tretinoin in children. There have been some reports of increased toxicity in children treated with tretinoin, particularly increased pseudotumour cerebri (see section 4.4).

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 https://sideeffects.health.gov.il/