Vesanoid Special Precautions

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 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/Retinoic acid syndrome: During clinical trials, hyperleukocytosis has been frequently observed, sometimes associated with the "retinoic acid syndrome" (RAS). RAS 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. RAS is now better defined as differentiation syndrome (DS).
DS is characterised by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, hypotension, pleural and pericardial effusions, peripheral oedema, weight gain, and may progress into 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. Differentiation syndrome is frequently associated with hyperleukocytosis (see "Hyperleukocytosis").
An increased body mass index (BMI) has been identified as 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 intravenous every 12 hours for a minimum of 3 days or until resolution of the symptoms) must be immediately initiated 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 white blood cell (WBC) count of ≥5 x 10⁹/L at diagnosis or during any time of therapy is recommended.
In terms of combination therapy of tretinoin with arsenic trioxide, the use of hydroxyurea should be considered for treatment of leukocytosis 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 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 Interactions).
If intracranial hypertension/pseudotumour cerebri occurs, dose reduction of tretinoin is recommended in addition to administration of diuretics (acetazolamide), corticosteroids and/or analgesics.
QTc prolongation: In connection with the combination therapy of tretinoin and arsenic trioxide, QTc prolongations were observed. This might lead to life-threatening torsade de pointes arrhythmias. For management of QTc prolongation an ECG monitoring prior and in the course of therapy, especially for patients with existing risk factors, is recommended.
Hepatotoxicity: Hepatotoxicity is increased with combination therapy of tretinoin and arsenic trioxide. The liver toxicity occurred predominantly during the first phase of therapy (induction therapy) and is mainly characterised by increase in transaminases. The observed hepatic damage 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 Adverse Reactions). 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 Interactions).
Because hypercalcaemia may occur during therapy, serum calcium levels should be monitored.
The ability to drive or operate machinery might be impaired in patients treated with tretinoin, particularly if they are experiencing dizziness or severe headache.
Counselling for women of childbearing potential (see Use in Pregnancy & Lactation): Tretinoin is a retinoid and teratogenic effects were seen in humans with 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 a treatment with tretinoin. The patient should use a reliable contraception method and pregnancy tests must be performed before treatment and at monthly intervals during therapy.
Micro-dosed progestagene preparations ("minipill") are an inadequate method of contraception during treatment with tretinoin.
Tretinoin (Vesanoid) contains sorbitol; therefore, patients with rare hereditary problems of fructose intolerance should not take Tretinoin (Vesanoid).
Use in Children: Pseudotumour cerebri (see Adverse Reactions) 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 Dosage & Administration).