Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: CHEPLAPHARM Arzneimittel GmbH, Bahnhofstr. 1a, 17498 Mesekenhagen, Germany
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).
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 harbor 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 characterized by high risk of early haemorrhagic death, current recommendations dictate that early 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 × 10^9^/L), intermediate risk (WBC≤10 × 109/L, platelet count ≤40 × 109/L), and low risk (WBC≤10x109/L, platelet count >40 × 109/L) - should be taken into consideration.
For all therapy phases a total daily dose of 45 mg/m² body surface divided in two equal doses is recommended for oral administration to adult and elderly APL patients. This is approximately 8 capsules per adult dose (one capsule contains 10 mg tretinoin).
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.
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 (see section 4.4) can receive additional chemotherapy at the very onset of induction treatment.
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.
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/pseudotumor cerebri (see section 4.4) occur, a reduction of tretinoin dose is recommended.
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.
Treatment 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 in 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.
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 tumor patients (maximal 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.
3 years.
Bottles:
Do not store above 30°C.
Keep the bottle tightly closed in order to protect from moisture.
Keep the bottle in the outer carton in order to protect from light.
Amber glass bottles of 100 capsules.
Use and handling: No special requirements.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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