Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: CHEPLAPHARM Arzneimittel GmbH, Bahnhofstr. 1a, 17498 Mesekenhagen, Germany
Hypersensitivity to tretinoin, retinoids, soya, peanut or to any of the excipients listed in section 6.1.
Tretinoin is teratogenic. It is contraindicated during breast-feeding (see section 4.6).
Combination with vitamin A, tetracyclines, retinoids (see section 4.5).
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 x109/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.
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 characterized 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. Retinoic acid syndrome 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.
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 × 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
Tretinoin may cause intracranial hypertension/pseudotumor cerebri. Pseudotumor cerebri is a benign intracranial hypertension with cerebral oedema and absence of a tumor, clinically characterized by headache, papilloedema, diplopia, and possibly an altered state of consciousness.
The concomitant use of other agents known to cause intracranial hypertension /pseudotumor cerebri might increase the risk of this condition (see section 4.5).
If intracranial hypertension/pseudotumor cerebri occur, a reduction of tretinoin dose is recommended in addition to administration of diuretics (acetazolamide), corticosteroids and/or analgesics.
Pseudotumor cerebri (see section 4.8) has a higher incidence in paediatric patients than in adults. Clinical trial data show a decreased incidence of pseudotumor 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 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 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 characterized by an increase in transaminases. The hepatic damage observed is reversible with the suspension of arsenic trioxide and/or tretinoin.
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 Vesanoid/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.
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 progesterone preparations (“minipill”) are an inadequate method of contraception during treatment with tretinoin (see section 4.6).
Vesanoid/Tretinoin capsules contain sorbitol; therefore patients with rare hereditary problems of fructose intolerance should not take Vesanoid/Tretinoin.
Contra-indicated combinations (see also section 4.3):
The effect of food on the bioavailability of tretinoin has not been characterised. Since the bioavailability of retinoids, as a class, is known to increase in the presence of food, it is recommended that tretinoin be administered with a meal or shortly thereafter.
As tretinoin is metabolised by the hepatic P450 system, there is the potential for alteration of pharmacokinetics parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and ciclosporin. There are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of tretinoin.
Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with tretinoin and antifibrinolytic agents such as tranexamic acid, aminocaproic acid and aprotinin (see section 4.4). Therefore, caution should be exercised when administering tretinoin concomitantly with these agents.
There are no data on a possible pharmacokinetic interaction between tretinoin and daunorubicin, idarubicin or AraC.
All the measures listed below should be considered in relationship to the severity of the disease and the urgency of the treatment.
There are no data available in humans.
Therapy with tretinoin should only be started in a female patient of childbearing age if each of the following conditions is met:
Tretinoin is teratogenic (see sections 4.3 and 5.3). Tretinoin is a retinoid and teratogenic effects have been seen in humans exposed to retinoid drugs.
In humans there is a limited amount of data from the use of tretinoin in pregnant women but there is a high risk of severe malformation of the foetus, particularly when tretinoin is given during the first trimester.
Vesanoid/Tretinoin must not be used during pregnancy, especially during the first trimester, nor in women of childbearing potential not using contraception, unless the clinical condition of the woman (severity of the patient’s condition, urgency of the treatment) requires treatment with tretinoin.
If Vesanoid/Tretinoin is administered in early pregnancy the patient must be warned of the teratogenic risk of Vesanoid/Tretinoin and of the risk of severe malformation of the foetus.
Breast-feeding must be discontinued if therapy with tretinoin is initiated (see section 4.3).
Vesanoid/Tretinoin has minor or moderate influence on the ability to drive and use machines, particularly if patients are experiencing dizziness or severe headache.
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).
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).
Not known: Necrotising fasciitis
Not known: Thrombocytosis, leukocytosis, basophilia (with or without symptomatic hyperhistaminemia)
Very common: Decreased appetite
Not known: Hypercalcaemia
Very common: Confusional state, anxiety, depression, insomnia
Very common: Headache, intracranial pressure increased, pseudotumor cerebri, dizziness, paraesthesia
Not known: Cerebrovascular accident
Very common: Visual disturbances, conjunctival disorders
Very common: Hearing impaired
Very common: Arrhythmia
Not known: Myocardial infarction
Very common: Flushing
Not known: Arterial thrombosis, venous thrombosis involving various sites (e.g. cerebrovascular accident, myocardial infarction, renal infarct), vasculitis
Very common: Respiratory failure, nasal dryness, asthma
Very common: Dry mouth, nausea, vomiting, abdominal pain, diarrhoea, constipation, pancreatitis, cheilitis
Very common: Erythema, rash, pruritus, alopecia, hyperhidrosis
Not known: Erythema nodosum, acute febrile neutrophilic dermatosis (Sweet’s syndrome)
Very common: Bone pain
Not known: Myositis
Not known: Renal infarct
Not known: Genital ulceration
Very common: Chest pain, chills, malaise
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.
Differentiation syndrome (formerly known as retinoic acid syndrome) may be fatal and is characterized by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, pleural and pericardial effusions, hypotension, oedema, weight gain, hepatic, renal and multi-organ failure. Retinoic acid syndrome is frequently associated with hyperleukocytosis. For prevention and treatment of retinoic acid 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 tretinoin/arsenic trioxide combination therapy compared to tretinoin/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.
See section 4.6.
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 pseudotumor cerebri (see section 4.4).
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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
