Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
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.
Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment.
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.
The recommended once-daily dose of Spexotras is determined by body weight (Table 1).
Table 1. Dosing regimen by body weight:
| Body weight* | Recommended dose | |
|---|---|---|
| Volume of oral solution (ml) once daily | corresponding to mg trametinib | |
| 8 kg | 6 ml | 0.30 mg |
| 9 to 10 kg | 7 ml | 0.35 mg |
| 11 kg | 8 ml | 0.40 mg |
| 12 to 13 kg | 9 ml | 0.45 mg |
| 14 to 17 kg | 11 ml | 0.55 mg |
| 18 to 21 kg | 14 ml | 0.70 mg |
| 22 to 25 kg | 17 ml | 0.85 mg |
| 26 to 29 kg | 18 ml | 0.90 mg |
| 30 to 33 kg | 20 ml | 1 mg |
| 34 to 37 kg | 23 ml | 1.15 mg |
| 38 to 41 kg | 25 ml | 1.25 mg |
| 42 to 45 kg | 28 ml | 1.40 mg |
| 46 to 50 kg | 32 ml | 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.
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.
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.
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).
Dose modifications or interruptions are not recommended for adverse reactions of cutaneous malignancies (see dabrafenib dispersible tablets SmPC for further details).
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.
Table 3. Recommended dose reduction levels for adverse reactions:
| Body weight | Recommended dose | Reduced dose | |
|---|---|---|---|
| ml solution (mg trametinib) (once daily) | Dose after the first reduction (once daily) | Dose after the second reduction (once daily) | |
| 8 kg | 6 ml (0.30 mg) | 5 ml | 3 ml |
| 9 to 10 kg | 7 ml (0.35 mg) | 5 ml | 4 ml |
| 11 kg | 8 ml (0.40 mg) | 6 ml | 4 ml |
| 12 to 13 kg | 9 ml (0.45 mg) | 7 ml | 5 ml |
| 14 to 17 kg | 11 ml (0.55 mg) | 8 ml | 6 ml |
| 18 to 21 kg | 14 ml (0.70 mg) | 11 ml | 7 ml |
| 22 to 25 kg | 17 ml (0.85 mg) | 13 ml | 9 ml |
| 26 to 29 kg | 18 ml (0.90 mg) | 14 ml | 9 ml |
| 30 to 33 kg | 20 ml (1 mg) | 15 ml | 10 ml |
| 34 to 37 kg | 23 ml (1.15 mg) | 17 ml | 12 ml |
| 38 to 41 kg | 25 ml (1.25 mg) | 19 ml | 13 ml |
| 42 to 45 kg | 28 ml (1.40 mg) | 21 ml | 14 ml |
| 46 to 50 kg | 32 ml (1.60 mg) | 24 ml | 16 ml |
| ≥51 kg v40 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.
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. Patients should be evaluated for signs and symptoms of infection and, if necessary, treated in line with local practice (see section 4.4). 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.
Trametinib should be interrupted in patients who have an absolute decrease of >10% in LVEF compared to baseline and the ejection fraction is below the institution’s lower limit of normal (LLN) (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib. If the LVEF recovers, treatment with trametinib may be restarted, but the dose should be reduced by one dose level with careful monitoring (see section 4.4).
Trametinib should be permanently discontinued in patients with Grade 3 or 4 left ventricular dysfunction or clinically significant LVEF reduction which does not recover within 4 weeks (see section 4.4).
If patients report new visual disturbances such as diminished central vision, blurred vision or loss of vision at any time while on combination therapy with trametinib and dabrafenib, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatment with trametinib should be permanently discontinued. If RPED is diagnosed, follow the dose modification schedule in Table 4 below for trametinib (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib for confirmed cases of RVO or RPED.
Table 4. Recommended dose modifications for trametinib for RPED:
| Grade 1 RPED | Continue treatment with retinal evaluation monthly until resolution. If RPED worsens follow instructions below and withhold trametinib for up to 3 weeks. |
| Grade 2 or 3 RPED | Withhold trametinib for up to 3 weeks. |
| Grade 2 or 3 RPED that improves to Grade 0 or 1 within 3 weeks | Resume trametinib at a lower dose level (see Table 3) or discontinue trametinib in patients on the lowest dose level. |
| Grade 2 or 3 RPED that does not improve to at least Grade 1 within 3 weeks | Permanently discontinue trametinib. |
Trametinib must be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion or infiltrates, pending clinical investigations. Trametinib must be permanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis. No dose modification of dabrafenib is required when taken in combination with trametinib for cases of ILD or pneumonitis.
No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld until resolution of ocular inflammation, and then dabrafenib should be restarted reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib (see section 4.4).
The benefits and risks must be considered before continuing treatment with dabrafenib in patients with a non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is required when taken in combination with dabrafenib (see section 4.4).
No dose adjustment is required in patients with mild hepatic impairment. Available data from a clinical pharmacology study indicate a limited impact of moderate to severe hepatic impairment on trametinib exposure (see section 5.2). Trametinib should be used with caution in patients with moderate or severe hepatic impairment.
No dose adjustment is required in patients with mild or moderate renal impairment. There are no data with trametinib in patients with severe renal impairment; therefore, the potential need for dose adjustment cannot be determined (see section 5.2). Trametinib should be used with caution in patients with severe renal impairment.
The safety and efficacy of combination therapy with trametinib and dabrafenib in children below 1 year of age have not been established. No data are available. Studies in juvenile animals have shown effects of trametinib which were not observed in adult animals (see section 5.3). Longer-term safety data in paediatric patients are currently limited.
Spexotras is for oral use.
Spexotras powder must be reconstituted to the oral solution by the pharmacist prior to being dispensed. It is recommended that a healthcare professional discusses how to administer the prescribed daily dose of the oral solution with the patient or caregiver prior to administration of the first dose.
Spexotras should be taken without food, at least one hour prior to or two hours after a meal (see section 5.2). Breast-feeding and/or baby formula may be given on demand if a patient is unable to tolerate the fasting conditions.
It is recommended that the dose of Spexotras is taken at a similar time every day, using the re-usable oral syringe provided. The once-daily dose of Spexotras should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib.
If the patient is unable to swallow and has a nasogastric tube in situ, the Spexotras oral solution can be administered via the tube.
Instructions for preparation are provided in section 6.6.
No acute overdose symptoms have been reported in paediatric patients who received trametinib in combination with dabrafenib in clinical studies. Persistent overdosing of trametinib could result in increased rash, decreased LVEF, or retinal abnormalities. There is no specific treatment for overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Powder for oral solution:
3 years.
Reconstituted oral solution:
Store below 25ºC.
Do not freeze.
Discard any unused solution 35 days after reconstitution.
Store in a refrigerator (2°C–8°C).
Store in the original package in order to protect from light and moisture.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
Amber glass bottle of 180 ml with a child-resistant screw cap closure, containing 12 g of powder.
Each carton contains one bottle, one press-in bottle adapter and one 20 ml re-usable oral dosing syringe with 0.5 ml graduation marks.
Spexotras powder must be reconstituted to the oral solution by the pharmacist prior to being dispensed.
Reconstitution instructions (for the pharmacist only):
1. Wash and dry your hands.
2. Check the powder expiry date on the bottle.
3. Tap the bottle to loosen the powder.
4. Remove the cap and add 90 ml distilled or purified water to the powder in the bottle.
5. Attach the cap and invert the bottle repeatedly for up to 5 minutes, until fully dissolved. You may also gently shake.
6. Separate the bottle adapter from the oral syringe. Remove the bottle cap and insert the bottle adapter into the bottle neck. Push hard until the bottle adapter is fully inserted. The bottle adapter should be fully flush with the bottle neck.
7. Write the date of preparation on the carton. The solution expires 35 days after preparation.
8. Inform the recipient of the dose and the date the solution was prepared on.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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