4.1. Therapeutic indications

Vesanoid/Tretinoin is indicated in combination with arsenic trioxide or chemotherapy for the treatment of patients with acute promyelocytic leukaemia (APL) which is newly diagnosed, relapsed or refractory to chemotherapy (see sections 4.2 and 5.1).

Treatment regimens

Combination of tretinoin with chemotherapy or arsenic trioxide is known to be effective and to induce very high rates of haematologic remission in patients with genetically confirmed APL, i.e. patients whose blasts harbour the t(15;17) by karyotyping or FISH or the PML-RARa fusion as detected by PCR. Thus, genetic confirmation of diagnosis is mandatory. Combination treatment with arsenic trioxide has been shown an effective treatment option in patients with newly diagnosed low-to-intermediate risk APL. However, because APL is characterised by high risk of early haemorrhagic death, current recommendations dictate that treatment with tretinoin is started as soon as possible upon morphologic suspicion only.

For the selection of treatment strategy the relapse risk - indicated by pre-therapeutic white blood cell count (WBC) and platelet count (Sanz score) with high-risk (WBC > 10 x 109/L), intermediate risk (WBC ≤ 10 x 109/L, platelet count ≤ 40 x 109/L), and low risk (WBC ≤ 10 x 109/L, platelet count > 40 x 109/L) - should be taken into consideration.

4.2. Posology and method of administration

Posology

For all therapy phases a total daily dose of 45 mg/m2 body surface divided into two equal doses is recommended for oral administration to adult and elderly APL patients. This is approximately 8 capsules per patient per day (one capsule contains 10 mg tretinoin).

Paediatric population

There is limited safety and efficacy information on the use of tretinoin in children. For children the same treatment regimen as for adults is applicable.

The optimal paediatric dose of tretinoin has not yet been established. In an attempt to reduce tretinoin related toxicity, the daily dose administered to children can be reduced to 25 mg/m2. Dose reduction should be particularly considered for children with toxicity symptoms, such as intractable headache.

High risk patients

A treatment option for patients at high risk of disease relapse according to Sanz score (see section 4.1) is the triple combination of tretinoin, arsenic trioxide and chemotherapy (anthracyclines) for induction, followed by consolidation with tretinoin and arsenic trioxide.

Patients with hyperleukocytosis

Patients with hyperleukocytosis (see section 4.4) can receive additional chemotherapy at the very onset of induction treatment.

Patients with hepatic and/or renal impairment

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.

Dose delay, modification and re-initiation

In cases of severe differentiation syndrome (DS, see section 4.4) temporary interruption of tretinoin therapy should be considered. Treatment with tretinoin may need to be withheld during the initial acute symptomatic period, but may be resumed when symptoms resolve.

If intracranial hypertension/pseudotumour cerebri (see section 4.4) occur, a reduction of tretinoin dose is recommended.

Method of administration

The capsules should be swallowed whole with water. They should not be chewed. It is recommended to take the capsules with a meal or shortly thereafter.

Induction therapy should be continued until complete remission has been achieved or up to a maximum of 90 days.

After completion of induction, consolidation therapy should be initiated with a tretinoin/arsenic trioxide combination or with a tretinoin/anthracycline-based chemotherapy regimen. The recommended tretinoin dose during consolidation is the same as for induction therapy, i.e. 45 mg/m2 body surface divided into two equal doses, administered orally. Several cycles of consolidation therapy with tretinoin should be given. Current guidelines recommend that tretinoin-free intervals are included after remission and during consolidation cycles.

If maintenance therapy is given, tretinoin should be used at the same dose as for induction/consolidation therapy. The treatment regimen for maintenance therapy should include tretinoin-free intervals (“pulsed therapy”), as for consolidation therapy.

As clinical practice may vary across the EU or within national centres, national/local practice guidelines/protocols should be considered.

4.3. Contraindications

Hypersensitivity to tretinoin, other retinoids, soya, peanut or to any of the excipients listed in section 6.1.

Tretinoin is teratogenic. It is contraindicated during breastfeeding (see section 4.6).

Combination with vitamin A, tetracyclines, retinoids (see section 4.5).

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'.

4.5. Interaction with other medicinal products and other forms of interaction

Contra-indicated combinations (see also section 4.3):

+ Other retinoids: risk of symptoms suggestive of hypervitaminosis A.

+ Vitamin A: risk of symptoms suggestive of hypervitaminosis A for daily doses greater than 10,000 IU.

+ Tetracyclines: risk of intracranial hypertension (pseudotumour cerebri).

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 Vesanoid/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 pharmacokinetic 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. Increased toxicity of tretinoin (e.g. pseudotumour cerebri, hypercalcaemia) was reported when azole antifungals (e.g. fluconazole, voriconazole, posaconazole) were administered. This appears to be the result of a pharmacokinetic interaction mainly involving CYP3A4. Combination with other strong CYP3A4 inhibitors (protease inhibitors or macrolides, e.g. clarithromycin), may also trigger tretinoin toxicity. A dose reduction of tretinoin should be considered if necessary.

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 cytarabine.

4.6. Fertility, pregnancy and lactation

All the measures listed below should be considered in relationship to the severity of the disease and the urgency of the treatment.

Fertility

There are no data available in humans.

Women of childbearing potential / Contraception in females

Therapy with tretinoin should only be started in a female patient of childbearing age if each of the following conditions is met:

• The patient is informed by the physician of the risks concerning pregnancy during and for one month after treatment with tretinoin.

• The patient is willing to comply with the mandatory contraception measures. It is absolutely essential that every woman of childbearing potential who is to undergo treatment with tretinoin uses a reliable contraception method without interruption during and for one month after discontinuation of treatment with tretinoin (see section 4.4).

• Pregnancy tests must be performed at monthly intervals during therapy.

Pregnancy

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, or 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.

Breastfeeding

Breastfeeding must be discontinued if therapy with tretinoin is initiated (see section 4.3).

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.

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 system disorders

Not known

Thrombocytosis, leukocytosis, basophilia (with or without symptomatic hyperhistaminaemia)

Metabolism and nutrition disorders

Very common

Decreased appetite

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 disorders

Very common

Hearing impaired

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 mediastinal disorders

Very common

Respiratory failure, nasal dryness, asthma

Gastrointestinal disorders

Very common

Dry mouth, nausea, vomiting, abdominal pain, diarrhoea, constipation, pancreatitis, cheilitis

Skin and subcutaneous tissue disorders

Very common

Erythema, rash, pruritus, alopecia, hyperhidrosis

Not known

Erythema nodosum, acute febrile neutrophilic dermatosis (Sweet's syndrome)

Musculoskeletal and connective tissue disorders

Very common

Bone pain

Not known

Myositis

Renal and urinary disorders

Not known

Renal infarct

Reproductive system and breast disorders

Not known

Genital ulceration

General disorders and administration site conditions

Very common

Chest pain, chills, malaise

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 of 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In case of overdose with tretinoin, reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear.

The recommended dose in acute promyelocytic leukaemia is one quarter of the maximum tolerated dose in solid tumour patients (maximum dose: 195 mg/m2/day) and below the maximum tolerated dose in children (60 mg/m2/day).

There is no specific treatment in the case of an overdose, however, it is important that the patient be treated in a special haematological unit.