Posology : מינונים

4.2      Posology and method of administration

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. In ATC and solid tumors, confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with dabrafenib and trametinib (see section 5.1).

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF solid tumors. Dabrafenib should therefore not be used in patients with wild type BRAF solid tumors (see sections 4.4 and 5.1).

Posology

The recommended dose of dabrafenib in adult patients, 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.
The recommended dosage for dabrafenib in pediatric patients who weigh at least 26 kg is based on body weight (Table 1). A recommended dose has not been established in patients who weigh less than 26 kg.
Table 1. Dosing in Pediatric Patients from 6 to 17 Years Old (Weight-Adjusted Dose)* Body Weight                          Recommended Dose
26 to 37 kg                               75 mg orally twice daily
38 to 50 kg                   100 mg (two 50 mg capsules) orally twice daily 51 kg or greater              150 mg (two 75 mg capsules) orally twice daily 
* Refer to the trametinib prescribing information for recommended trametinib dosing information.

Duration of treatment

Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity (see Table 4). In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is disease recurrence or unacceptable toxicity.
In ATC and Solid Tumors, the recommended duration of treatment is until disease progression or unacceptable toxicity.
Missed doses

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.

Dose modification

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 2, 3 and 4).

Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (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 2, 3 and 4, respectively.

Table 2 Recommended dose level reductions in adult patients

Dose level                   Dabrafenib dose                      Trametinib dose* Used as monotherapy or in         Only when used in combination with combination with trametinib                   dabrafenib
Starting dose               150 mg twice daily                   2 mg once daily 1st dose
100 mg twice daily reduction                                                       1.5 mg once daily 2nd dose
75 mg twice daily reduction                                                        1 mg once daily 3rd dose                      50 mg twice daily                  1 mg once daily reduction
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 Prescribing Information, Posology and Method of administration

Table 3 Recommended Dose Reductions for Dabrafenib for Adverse Reactions in Pediatric Patients (6 to 17 Years Old)
Action                                      Recommended Dosage (See table 1) 100 mg (two 50 mg capsules)      150 mg (two 75 mg capsules)
75 mg orally twice daily orally twice daily               orally twice daily
First Dose                                                                           100 mg (two 50 mg capsules) 50 mg orally twice daily       75 mg orally twice daily
Reduction                                                                                 orally twice daily Second Dose                       -
50 mg orally twice daily         75 mg orally twice daily
Reduction
Third Dose                        -                               -
50 mg orally twice daily
Reduction
Subsequent
Permanently discontinue if unable to tolerate dabrafenib 50 mg orally twice daily Modification

Table 4 Dose modification schedule based on the grade of any adverse events (AE) (excluding pyrexia)

Grade (CTC-AE)*           Recommended dabrafenib dose modifications
Used as monotherapy or in combination with trametinib
Grade 1 or Grade 2        Continue treatment and monitor as clinically indicated.
(Tolerable)
Grade 2 (Intolerable)     Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one or Grade 3                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.

Pyrexia
If a patient’s temperature is ≥38oC therapy should be interrupted (dabrafenib when used as monotherapy, and both dabrafenib and trametinib when used in combination). 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). Dabrafenib, or both dabrafenib and trametinib when used in combination, 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 the pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.
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, 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 modification exceptions (where only one of the two therapies is dose reduced) for selected adverse reactions

Uveitis
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).

RAS-mutation-positive non-cutaneous malignancies
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.

Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction 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 Prescribing Information (see section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib.

Retinal vein occlusion (RVO) and Retinal pigment epithelial detachment (RPED) 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 Prescribing Information (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.

Interstitial lung disease (ILD)/Pneumonitis
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 Prescribing Information (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.

Renal impairment
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.

Hepatic impairment
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.

Special populations
Non-Caucasian patients
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.


Elderly
No adjustment of the initial dose is required in patients >65 years of age.

Paediatric population

BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors
The safety and effectiveness of dabrafenib in combination with trametinib in pediatric patients 6 years of age and older that weigh at least 26 kg was established based on data in adults and data from a pediatric study X2101. In study X2101, Parts C and D enrolled a total of 48 patients (ages 1 to 17) with the following tumor types: LGG (n = 34), HGG (n = 2), LCH (n = 11), and juvenile xanthogranulomatosis (n = 1) (see sections 4.8, 5.1 and 5.2).
The safety and effectiveness of dabrafenib in combination with trametinib in pediatric patients younger than 6 years old have not been established.
The safety and effectiveness of dabrafenib as a single agent in pediatric patients have not been established.

Studies in juvenile animals have shown adverse effects of dabrafenib which had not been observed in adult animals (see section 5.3).

Method of administration

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 Prescribing Information for information on method of administration when given in combination with dabrafenib.