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Spexotras is a brand name for Trametinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Low-grade glioma Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. High-grade glioma Spexotras in combination with dabrafenib is indicated for the treatment of…
Verbatim from this product's EMA label. Tap a section to expand.
Treatment with Spexotras should be initiated and supervised by a qualified physician experienced in the use of anti-cancer medicinal products. Before taking Spexotras, patients must have confirmation of BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose.
If the CE-marked IVD is not available, confirmation of BRAF V600E should be assessed by an alternative validated test. Spexotras is used in combination with dabrafenib dispersible tablets. See the summary of product characteristics (SmPC) for posology of dabrafenib dispersible tablets.
3 Posology The recommended once-daily dose of Spexotras is determined by body weight (Table 1). 60 mg ≥51 kg 40 ml 2 mg *Round body weight to the nearest kg, if necessary. The recommended dose for patients with a body weight less than 8 kg has not been established.
Please refer to the dabrafenib dispersible tablets SmPC, “Posology” and “Method of administration”, for dosing instructions for treatment with dabrafenib when used in combination with Spexotras. Duration of treatment Treatment with Spexotras should continue until disease progression or until the development of unacceptable toxicity.
There are limited data in patients older than 18 years of age with glioma, therefore continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician. Missed or delayed doses If a dose of Spexotras is missed, it should only be taken if it is more than 12 hours until the next scheduled dose.
If vomiting occurs after taking Spexotras, an additional dose should not be administered and the next dose should be taken at the next scheduled time. Dose modification The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation (see Tables 2 and 3).
If treatment-related toxicities occur, then both trametinib and dabrafenib should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dose modifications are necessary for only one of the two treatments are detailed below for uveitis, RAS mutation-positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lung disease (ILD)/pneumonitis (primarily related to trametinib).
Summary of the safety profile In clinical studies of paediatric patients treated with trametinib in combination with dabrafenib, the most common adverse reactions (reported at a frequency ≥20%) were: pyrexia (70%), rash (49%), headache (47%), vomiting (40%), fatigue (36%), dry skin (35%), diarrhoea (34%), haemorrhage (34%), nausea (29%), dermatitis acneiform (29%), abdominal pain (28%), neutropenia (26%), cough (24%) and transaminases increased (22%).
The most frequently reported severe (Grade 3/4) adverse reactions were: neutropenia (15%), pyrexia (11%), transaminases increased (6%) and weight increased 13 (5%). 3). The safety profile in paediatric patients was largely consistent with the safety profile previously established in adult patients.
The following additional adverse reactions have so far only been reported in adult patients treated with trametinib tablets and dabrafenib capsules: cutaneous squamous cell carcinoma, seborrhoeic keratosis, peripheral neuropathy (including sensory and motor neuropathy), lymphoedema, dry mouth, actinic keratosis, renal failure, potentiation of radiation toxicity (common), melanoma, acrochordon, sarcoidosis, chorioretinopathy, pneumonitis, acute renal failure, nephritis, cardiac failure, left ventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinal perforation, haemophagocytic lymphohistiocytosis (rare), tumour lysis syndrome, myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, tattoo-associated skin reactions (frequency not known).
Tabulated list of adverse reactions The safety of trametinib in combination with dabrafenib has been evaluated in a pooled safety set of 171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advanced solid tumours.
3%) patients were 12 to <18 years of age at enrolment. 3 years. Adverse reactions (Table 5) are listed below by MedDRA system organ class ranked by frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (1/1 000 to <1/100), rare (1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).
Spexotras is intended for use in combination with dabrafenib dispersible tablets as there are limited efficacy data for trametinib monotherapy and for dabrafenib monotherapy in BRAF V600 mutation- positive glioma. The dabrafenib dispersible tablets SmPC must be consulted prior to initiation of treatment.
For additional information on warnings and precautions associated with dabrafenib treatment, please refer to the dabrafenib dispersible tablets SmPC. 7 BRAF V600E testing The efficacy and safety of trametinib in combination with dabrafenib have not been evaluated in patients whose glioma tested negative for the BRAF V600E mutation.
New malignancies New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib. 8). It is recommended that skin examination be performed prior to initiation of therapy with trametinib and monthly throughout treatment and for up to six months after treatment.
Monitoring should continue for 6 months following discontinuation of trametinib or until initiation of another anti-neoplastic therapy. Suspicious skin lesions should be managed with dermatological excision and do not require treatment modifications.
Patients should be instructed to inform their physicians immediately if new skin lesions develop. Non-cutaneous malignancies Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present.
4). No dose modification of trametinib is required for RAS mutation-positive malignancies when taken in combination with dabrafenib. 8). Major haemorrhagic events and fatal haemorrhages have occurred in adult patients taking trametinib in combination with dabrafenib.
The potential for these events in patients with low platelet counts (<75 000/mm3) has not been established as such patients were excluded from clinical studies. The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy.
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Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Dose modifications or interruptions are not recommended for adverse reactions of cutaneous malignancies (see dabrafenib dispersible tablets SmPC for further details). 4 Table 2 Dose modification schedule based on the grade of any adverse reactions (excluding pyrexia) Grade (CTCAE)* Recommended trametinib dose modifications Grade 1 or Grade 2 (Tolerable) Continue treatment and monitor as clinically indicated.
Grade 2 (Intolerable) or Grade 3 Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one dose level when resuming therapy. Refer to Table 3 for dose level guidance. Grade 4 Discontinue permanently, or interrupt therapy until Grade 0 to 1 and reduce by one dose level when resuming therapy.
Refer to Table 3 for dose level guidance. * The intensity of clinical adverse reactions graded by the Common Terminology Criteria for Adverse Events (CTCAE) The recommended dose reductions to approximately 75% of the recommended dose (first dose reduction level) and to approximately 50% of the recommended dose (second dose reduction level) are shown in Table 3.
60 mg) 24 ml 16 ml ≥51 kg 40 ml (2 mg) 30 ml 20 ml Dose adjustment for Spexotras below 50% of the recommended dose is not recommended. When an individual’s adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered.
The trametinib dose should not exceed the recommended dose indicated in Table 1. Dose modifications for selected adverse reactions Pyrexia If a patient’s temperature is ≥38°C, therapy with trametinib and dabrafenib should be interrupted.
In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient.
4). Therapy should be restarted if the patient is symptom-free for at least 24 hours either (1) at the same dose level, or (2) reduced by one dose level if pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.
5 Dose modification exceptions (where only one of the two therapies is dose reduced) for […]
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 5 Adverse reactions with trametinib in combination with dabrafenib Infections and infestations Very common Paronychia, nasopharyngitis*1 Common Urinary tract infection, cellulitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Very common Skin papilloma Blood and lymphatic system disorders Very common Neutropenia*2, anaemia, leukopenia* Common Thrombocytopenia* Immune system disorders Common Hypersensitivity Metabolism and nutrition disorders Common Dehydration, decreased appetite Nervous system disorders Very common Headache, dizziness*3 Eye disorders Common Vision blurred, visual impairment, uveitis*4 Uncommon Retinal detachment, periorbital oedema Cardiac disorders Common Ejection fraction decreased, bradycardia* Uncommon Atrioventricular block5 Vascular disorders Very common Haemorrhage*6 Common Hypertension, hypotension Respiratory, thoracic and mediastinal disorders Very common Cough* Common Dyspnoea 14 Gastrointestinal disorders Very common Abdominal pain*, constipation, diarrhoea, nausea, vomiting Common Pancreatitis, stomatitis Uncommon Colitis* Skin and subcutaneous tissue disorders Very common Dermatitis acneiform*7, dry skin*8, pruritus, rash*9, erythema Common Dermatitis exfoliative generalised*10, alopecia, palmar-plantar erythrodysaesthesia syndrome, folliculitis, skin lesion, panniculitis, hyperkeratosis, photosensitivity*11 Uncommon Acute febrile neutrophilic dermatosis, skin fissures, night sweats, hyperhidrosis Musculoskeletal and connective tissue disorders Very common Arthralgia, pain in extremity Common Myalgia*, muscle spasms*12 General disorders and administration site conditions Very common Pyrexia*, fatigue*13, weight increased Common Mucosal inflammation, face oedema*, chills, oedema peripheral, influenza-like illness Investigations Very common Transaminases increased*14 Common Hyponatraemia, hypophosphataemia, hyperglycaemia, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatine phosphokinase increased *Denotes grouped term of two or more MedDRA preferred terms that were considered clinically similar.
1 nasopharyngitis includes pharyngitis 2 neutropenia includes neutrophil count decreased and febrile neutropenia 3 dizziness includes vertigo 4 uveitis includes iridocyclitis 5 atrioventricular block includes atrioventricular block first degree 6 haemorrhage includes epistaxis, haematuria, contusion, haematoma, international normalised ratio increased, anal haemorrhage, catheter site haemorrhage, cerebral haemorrhage, ecchymosis, extradural haematoma, gastrointestinal haemorrhage, haematochezia, petechiae, post-procedural haemorrhage, rectal haemorrhage, red blood cell count decreased, upper gastrointestinal haemorrhage, uterine haemorrhage, heavy menstrual bleeding and purpura 7 dermatitis acneiform includes acne and acne pustular 8 dry skin includes xerosis and xeroderma 9 rash includes rash maculo-papular, rash pustular, rash erythematous, rash papular, rash macular 10 dermatitis exfoliative generalised includes skin exfoliation and dermatitis exfoliative 11 photosensitivity includes photosensitivity reaction and sunburn 12 muscle spasms include musculoskeletal stiffness 13 fatigue includes malaise and asthenia 14 transaminases increased includes aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased and […]
If haemorrhage occurs, patients should be treated as clinically indicated. 8). In clinical studies in paediatric patients, the median time to onset of the first occurrence of LVEF decrease was around one month. In clinical studies in adult patients, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 and 5 months.
Trametinib should be used with caution in patients with impaired left ventricular function. Patients with left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acute coronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, and uncontrolled hypertension were excluded from clinical studies; safety of use in this population is therefore unknown.
2 regarding dose modification). In patients receiving trametinib in combination with dabrafenib, there have been occasional reports of acute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed when 8 stopping treatment.
Physicians should be alert to the possibility of myocarditis in patients who develop new or worsening cardiac signs or symptoms. 8). 4). In patients receiving trametinib in combination with dabrafenib, pyrexia may be accompanied by severe rigors, dehydration and hypotension which in some cases can lead to acute renal insufficiency.
5 months. 1). In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient.
Patients should be evaluated for signs and symptoms of infection. Therapy can be restarted once the fever resolves. 2). 8). Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate.
4% (5/211) of patients treated with trametinib monotherapy developed ILD or pneumonitis; all five patients required hospitalisation. The median time to onset of the first presentation of ILD or pneumonitis was 160 days […]