Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1).
Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
Dabrafenib in combination with trametinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation.
Treatment with dabrafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products.
Before taking dabrafenib, patients must have confirmation of tumour BRAF V600 mutation using a validated test.
The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma or wild-type BRAF NSCLC. Dabrafenib should therefore not be used in patients with wild-type BRAF melanoma or wild-type BRAF NSCLC (see sections 4.4 and 5.1).
The recommended dose of dabrafenib, either used as monotherapy or in combination with trametinib, is 150 mg (two 75 mg capsules) twice daily (corresponding to a total daily dose of 300 mg). The recommended dose of trametinib, when used in combination with dabrafenib, is 2 mg once daily.
Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity (see Table 2). In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is disease recurrence or unacceptable toxicity.
If a dose of dabrafenib is missed, it should not be taken if it is less than 6 hours until the next scheduled dose.
If a dose of trametinib is missed, when dabrafenib is given in combination with trametinib, the dose of trametinib should only be taken if it is more than 12 hours until the next scheduled dose.
Two dabrafenib capsule strengths, 50 mg and 75 mg, are available to effectively manage dose modification requirements.
The management of adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation (see Tables 1 and 2).
Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see section 4.4).
Therapy should be interrupted if the patient’s temperature is ≥38.5oC. Patients should be evaluated for signs and symptoms of infection (see section 4.4).
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, withhold dabrafenib until resolution of ocular inflammation and then restart dabrafenib reduced by one dose level (see section 4.4).
Recommended dose level reductions and recommendations for dose modifications are provided in Tables 1 and 2, respectively.
Table 1. Recommended dose level reductions:
| Dose level | Dabrafenib dose Used as monotherapy or in combination with trametinib | Trametinib dose* Only when used in combination with dabrafenib |
|---|---|---|
| Starting dose 150 mg δύο φορές ημερησίως | 2 mg once daily | |
| 1st dose reduction | 100 mg twice daily | 1.5 mg once daily |
| 2nd dose reduction | 75 mg twice daily | 1 mg once daily |
| 3rd dose reduction | 50 mg twice daily | 1 mg once daily |
Dose adjustment for dabrafenib below 50 mg twice daily is not recommended, whether used as monotherapy or in combination with trametinib. Dose adjustment for trametinib below 1 mg once daily is not recommended, when used in combination with dabrafenib.
==*==For dosing instructions for treatment with trametinib monotherapy, see trametinib SmPC, Posology and Method of administration.
Table 2. Dose modification schedule based on the grade of any adverse events (AE):
| Grade (CTC-AE)* | Recommended dabrafenib dose modifications Used as monotherapy or in combination with trametinib |
|---|---|
| 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. |
| Grade 4 | Discontinue permanently, or interrupt therapy until Grade 0 to 1 and reduce by one dose level when resuming therapy. |
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events (CTC-AE) v4.0
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 dabrafenib dose should not exceed 150 mg twice daily.
If treatment-related toxicities occur when dabrafenib is used in combination with trametinib, then both treatments 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 pyrexia, 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).
When dabrafenib is used alone and in combination with trametinib, therapy with dabrafenib should be interrupted if the patient’s temperature is ≥38.5 o C (for dose modification guidance see Table 2). Trametinib should be continued at the same dose. 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).
Upon resolution of pyrexia dabrafenib should be restarted with appropriate anti-pyretic prophylaxis, either 1) at the same dose level, or 2) reduced by one dose level if the pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.
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 should 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.
If dabrafenib is being used in combination with trametinib and absolute decrease of >10% in LVEF compared to baseline and the ejection fraction is below the institution’s lower limit of normal (LLN), please refer to the trametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib.
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 dabrafenib and trametinib, please refer to the trametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib for confirmed cases of RVO or RPED.
In patients treated with dabrafenib in combination with trametinib 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, please refer to the trametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib for cases of ILD or pneumonitis.
No dose adjustment is required for patients with mild or moderate renal impairment. There are no clinical data in subjects with severe renal impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Dabrafenib should be used with caution in patients with severe renal impairment when administered as monotherapy or in combination with trametinib.
No dose adjustment is required for patients with mild hepatic impairment. There are no clinical data in subjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites and patients with moderate to severe hepatic impairment may have increased exposure. Dabrafenib should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with trametinib.
Limited safety and efficacy data have been collected on dabrafenib in non-Caucasian patients. The population pharmacokinetic analysis showed no significant differences in the pharmacokinetics of dabrafenib between Asian and Caucasian patients. No dabrafenib dose adjustment is needed in Asian patients.
No adjustment of the initial dose is required in patients >65 years of age.
The safety and efficacy of dabrafenib have not yet been established in children and adolescents (<18 years). No clinical data are available. Studies in juvenile animals have shown adverse effects of dabrafenib which had not been observed in adult animals (see section 5.3).
Tafinlar is for oral use. The capsules are to be swallowed whole with water. They should not be chewed or opened and should not be mixed with food or liquids due to chemical instability of dabrafenib.
It is recommended that the doses of dabrafenib be taken at similar times every day, leaving an interval of approximately 12 hours between doses. When dabrafenib and trametinib are taken in combination, the once-daily dose of trametinib should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib.
Dabrafenib should be taken at least one hour before, or at least 2 hours after a meal.
If a patient vomits after taking dabrafenib, the patient should not retake the dose and should take the next scheduled dose.
Please refer to trametinib SmPC for information on method of administration when given in combination with dabrafenib.
There is no specific treatment for an overdose of dabrafenib. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Shelf life: 3 years.
This medicinal product does not require any special storage conditions.
Opaque white high density polyethylene (HDPE) bottle with polypropylene screw cap and a silica gel desiccant.
Each bottle contains either 28 or 120 hard capsules.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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