Chemical formula: C₂₀H₂₈O₂ Molecular mass: 300.442 g/mol PubChem compound: 5538
Tretinoin interacts in the following cases:
Due to limited information on patients with hepatic and/or renal insufficiency, the dose will be decreased to 25 mg/m² as a precautionary measure.
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. Therefore, caution should be exercised when administering tretinoin concomitantly with these agents.
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.
Because hypercalcaemia may occur during therapy, serum calcium levels should be monitored.
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.
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.
If intracranial hypertension/pseudotumor cerebri occur, a reduction of tretinoin dose is recommended in addition to administration of diuretics (acetazolamide), corticosteroids and/or analgesics.
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 is teratogenic. 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.
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 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.
Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques.
Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietale incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied.
There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species.
In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic dose adjusted for total body surface area in both species).
With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of topical tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.
Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area).
There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Breast-feeding must be discontinued if therapy with oral tretinoin is initiated.
It is not known whether topical tretinoin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when it is administered to a nursing woman.
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 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 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.
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.
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.
The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin cream/gel. To date, all adverse effects have been reversible upon discontinuance of therapy.
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