Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Tretinoin should be administered to patients with acute promyelocytic leukaemia only under the strict supervision of a physician who is experienced in the treatment of haematological/oncological diseases.

Supportive care appropriate for patients with acute promyelocytic leukaemia, for example prophylaxis for bleeding and prompt therapy for infection, should be maintained during therapy with tretinoin. The patient’s haematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently.

Supportive measures to counteract APL-associated coagulopathy include administration of platelets transfusion to maintain a platelet count > 30-50 x 109/L and fresh-frozen plasma or fibrinogen to maintain a fibrinogen level > 100-150 mg/dL.
These values should be monitored daily and supportive care should continue during the entire induction phase until disappearance of clinical and laboratory signs of coagulopathy.

Differentiation syndrome (formerly known as retinoic acid syndrome) 

During clinical trials hyperleukocytosis has been frequently observed, sometimes associated with the differentiation syndrome” (DS). DS has been reported in many acute promyelocytic leukaemia patients treated with tretinoin (about 26% in some clinical trials) or in association with arsenic trioxide and may be fatal.

DS is characterised by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, hypotension, pleural and pericardial effusions, peripheral oedema, weight gain; and may progress to pulmonary, hepatic, renal and multi-organ failure. Full- blown DS is a life-threatening condition. Early recognition and treatment of DS is therefore of paramount importance. DS is frequently associated with hyperleukocytosis (see 'Hyperleukocytosis').

An increased body mass index (BMI) has been identified as a predictor factor for DS.
Therefore, patients with increased BMI should be closely monitored during therapy especially in terms of respiratory functions, diuresis and creatinine levels.

Treatment with dexamethasone (10 mg intravenously every 12 hours for a minimum of 3 days or until resolution of the symptoms) must be initiated immediately for patients who present early clinical signs of the syndrome.

In cases of severe DS, temporary interruption of tretinoin therapy should be considered.

Hyperleukocytosis

Patients experiencing hyperleukocytosis should be treated with full-dose anthracycline-based chemotherapy. Immediate treatment of patients with a white blood cell (WBC) count of ≥ 5 x 109/L at diagnosis or at any time during therapy is recommended.

The use of hydroxyurea should be considered for treatment of leukocytosis in patients treated with combination therapy of tretinoin with arsenic trioxide, to keep WBC < 10,000/µL.

Pseudotumour cerebri

Tretinoin may cause intracranial hypertension/pseudotumour cerebri. Pseudotumour cerebri is a benign intracranial hypertension with cerebral oedema and absence of a tumour, clinically characterised by headache, papilloedema, diplopia, and possibly an altered state of consciousness.
The concomitant use of other agents known to cause intracranial hypertension /pseudotumour cerebri might increase the risk of this condition (see section 4.5).
If intracranial hypertension/pseudotumour cerebri occurs, a reduction of tretinoin dose is recommended in addition to administration of diuretics (acetazolamide), corticosteroids and/or analgesics.

Paediatric population

Pseudotumour cerebri (see section 4.8) has a higher incidence in paediatric patients than in adults. Clinical trial data show a decreased incidence of pseudotumour cerebri with the use of a lower tretinoin dose, without compromising the outcome results.
Therefore, a dose reduction to 25 mg/m2 should be considered for children with toxicity symptoms, such as intractable headache (see section 4.2).

QTc prolongation

QTc prolongations have been observed in connection with combination therapy of tretinoin and arsenic trioxide. This might lead to life-threatening torsade de pointes arrhythmias.
ECG monitoring prior to and during the course of therapy is recommended for management of QTc prolongation, especially for patients with existing risk factors.

Hepatotoxicity
Hepatotoxicity is increased with combination therapy of tretinoin and arsenic trioxide.
Liver toxicity has occurred predominantly during the first phase of therapy (induction therapy) and is mainly characterised by an increase in transaminases. The hepatic damage observed is reversible with the suspension of arsenic trioxide and/or tretinoin.

Psychiatric disorders

Depression, depression aggravated, anxiety, and mood alterations have been reported in patients treated with systemic retinoids, including tretinoin. Particular care should be taken in patients with a history of depression. Patients should be monitored for signs of depression and referred for appropriate treatment if necessary. Awareness by family or friends may be useful to detect mental health deterioration.

Others

Cases of Sweet’s syndrome or acute febrile neutrophilic dermatitis responded dramatically to corticosteroid treatment.

There is a risk of thrombosis (both venous and arterial) which may involve any organ system, during the first month of treatment (see section 4.8). Therefore, caution should be exercised when treating patients with the combination of tretinoin and antifibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin (see section 4.5).

Because hypercalcaemia may occur during therapy, serum calcium levels should be monitored.

Counselling for women of childbearing potential (see section 4.6) 
Tretinoin is a retinoid and teratogenic effects have been seen in humans exposed to retinoid drugs. Consequently, therapy with tretinoin should only be started in a female patient of childbearing age if she is informed of the risks concerning pregnancy during tretinoin treatment. The patient must use a reliable method of contraception and pregnancy tests must be performed before treatment and at monthly intervals during therapy.

Micro-dosed progestogen preparations (”minipill”) are an inadequate method of contraception during treatment with tretinoin (see section 4.6).

Sorbitol
This medicinal product contains 1.93 - 2.94 mg sorbitol in each soft capsule.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per soft capsule, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7   Effects on ability to drive and use machines

Vesanoid/Tretinoin has minor or moderate influence on the ability to drive and use machines, particularly if patients are experiencing dizziness or severe headache.