Tafinlar

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 

Tafinlar 50 mg hard capsules 

Tafinlar 75 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Tafinlar 50 mg hard capsules 

 

Each hard capsule contains dabrafenib mesilate equivalent to 50 mg of dabrafenib. 

 

Tafinlar 75 mg hard capsules 

 

Each hard capsule contains dabrafenib mesilate equivalent to 75 mg of dabrafenib. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Hard capsule (capsule). 

 

Tafinlar 50 mg hard capsules 

 

Opaque dark red capsules, approximately 18 mm long, with capsule shell imprinted with “GS TEW” 

and “50 mg”. 

 

Tafinlar 75 mg hard capsules 

 

Opaque dark pink capsules, approximately 19 mm long, with capsule shell imprinted with “GS LHF” 

and “75 mg”. 
 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Melanoma 

 

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). 

 

Adjuvant treatment of melanoma 

 

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. 

 

Non-small cell lung cancer (NSCLC) 

 

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. 

 

  



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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. 

 

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). 

 

Posology 

 

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. 

 

Duration of treatment 

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. 

 

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 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. 

 



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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 twice daily 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). 

 

Dose modification exceptions (where only one of the two therapies is dose reduced) for selected 

adverse reactions 

Pyrexia 

When dabrafenib is used alone and in combination with trametinib, therapy with dabrafenib should be 

interrupted if the patient’s temperature is ≥38.5oC (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. 

 



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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 SmPC (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 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. 

 

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 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. 

 

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. 

 



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Paediatric population 

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). 

 

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 SmPC for information on method of administration when given in 

combination with dabrafenib. 

 

4.3 Contraindications 
 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

When dabrafenib is given in combination with trametinib, the SmPC of trametinib must be consulted 

prior to intiation of combination treatment. For additional information on warnings and precautions 

associated with trametinib treatment, please refer to the trametinib SmPC. 

 

BRAF V600 testing 

 

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF 

melanoma or wild-type BRAF NSCLC therefore dabrafenib should not be used in patients with 

wild-type BRAF melanoma or wild-type BRAF NSCLC (see sections 4.2 and 5.1). 

 

Dabrafenib in combination with trametinib in patients with melanoma who have progressed on a 

BRAF inhibitor 

 

There are limited data in patients taking the combination of dabrafenib with trametinib who have 

progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be 

lower in these patients (see section 5.1). Therefore, other treatment options should be considered 

before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing 

of treatments following progression on a BRAF inhibitor therapy has not been established. 

 

  



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New malignancies 

 

New malignancies, cutaneous and non-cutaneous, can occur when dabrafenib is used as monotherapy 

or in combination with trametinib. 

 

Cutaneous malignancies 

Cutaneous squamous cell carcinoma (cuSCC) 

Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with dabrafenib 

alone and in combination with trametinib (see section 4.8). In the Phase III clinical trials MEK115306 

and MEK116513 in patients with unresectable or metastatic melanoma, cuSCC occurred in 10% 

(22/211) of patients receiving dabrafenib as a monotherapy and in 18% (63/349) of patients receiving 

vemurafenib as a monotherapy, respectively. In the integrated safety population of patients with 

melanoma and advanced NSCLC, cuSCC occurred in 2% (19/1076) of patients receiving dabrafenib in 

combination with trametinib. The median time to diagnosis of the first occurrence of cuSCC in study 

MEK115306 was 223 days (range 56 to 510 days) in the combination therapy arm and 60 days (range 

9 to 653 days) in the dabrafenib monotherapy arm. In the Phase III study BRF115532 (COMBI-AD) 

in the adjuvant treatment of melanoma, 1% (6/435) of patients receiving dabrafenib in combination 

with trametinib as compared to 1% (5/432) of patients receiving placebo developed cuSCC. The 
median time to onset of the first occurrence of cuSCC in the combination arm of the adjuvant 

treatment study was approximately 18 weeks and was 33 weeks in the placebo arm. 

 

It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib 

and monthly throughout treatment and for up to six months after treatment for cuSCC. Monitoring 

should continue for 6 months following discontinuation of dabrafenib or until initiation of another 

anti-neoplastic therapy. 

 

Cases of cuSCC should be managed by dermatological excision and dabrafenib treatment or, if taken 

in combination, dabrafenib and trametinib should be continued without any dose adjustment. Patients 

should be instructed to immediately inform their physician if new lesions develop. 

 

New primary melanoma 

New primary melanomas have been reported in clinical trials in patients treated with dabrafenib. In 

clinical trials in unresectable or metastatic melanoma,these cases were identified within the first 

5 months of dabrafenib as monotherapy. Cases of new primary melanoma can be managed with 

excision and do not require treatment modification. Monitoring for skin lesions should occur as 

described for cuSCC. 

 

Non-cutaneous malignancies 

In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase 

(MAP kinase) signalling in BRAF wild-type cells with RAS mutations when exposed to BRAF 

inhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure 

(see section 4.8) when RAS mutations are present. RAS-associated malignancies have been reported 

in clinical trials, both with another BRAF inhibitor (chronic myelomonocytic leukaemia and 

non-cutaneous SCC of the head and neck) as well as with dabrafenib monotherapy (pancreatic 

adenocarcinoma, bile duct adenocarcinoma) and with dabrafenib in combination with the MEK 

inhibitor, trametinib (colorectal cancer, pancreatic cancer). 

 

Prior to initiation of treatment patients should undergo a head and neck examination with minimally 

visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen computerised 

tomography (CT) scan. During treatment patients should be monitored as clinically appropriate which 

may include a head and neck examination every 3 months and a chest/abdomen CT scan every 

6 months. Anal examinations and pelvic examinations are recommended before and at the end of 

treatment or when considered clinically indicated. Complete blood cell counts and blood chemistry 

should be performed as clinically indicated. 

 



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The benefits and risks should be considered before administering dabrafenib in patients with a prior or 

concurrent cancer associated with RAS mutations. No dose modification of trametinib is required 

when taken in combination with dabrafenib. 

 

Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent 

malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. 

Abnormal findings should be managed according to clinical practices. 

 

Haemorrhage 

 

Haemorrhagic events, including major haemorrhagic and fatal haemorrhages, have occurred in 

patients taking the combination of dabrafenib with trametinib (see section 4.8). Please refer to the 

trametinib SmPC (see section 4.4) for additional information. 

 

Visual impairment 

 

In clinical trials ophthalmologic reactions, including uveitis, iridocyclitis and iritis, have been reported 

in patients treated with dabrafenib as monotherapy and in combination with trametinib. Patients should 

be routinely monitored for visual signs and symptoms (such as change in vision, photophobia and eye 

pain) while on therapy. 

 

No dose modifications are required 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. No dose modification of 

trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis. 

 

RPED and RVO may occur with dabrafenib in combination with trametinib. Please refer to the 

trametinib SmPC (see section 4.4). No dose modification of dabrafenib is required when taken in 

combination with trametinib following diagnosis of RVO or RPED. 

 

Pyrexia 

 

Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination with 

trametinib (see section 4.8). In 1% of patients in clinical trials with dabrafenib monotherapy, serious 

non-infectious febrile events were identified defined as fever accompanied by severe rigors, 

dehydration, hypotension and/or acute renal insufficiency of pre-renal origin in subjects with normal 

baseline renal function (see section 4.8). The onset of these serious non-infectious febrile events was 

typically within the first month of dabrafenib as monotherapy. Patients with serious non-infectious 

febrile events responded well to dose interruption and/or dose reduction and supportive care. 

 

The incidence and severity of pyrexia are increased with combination therapy. In the combination 

therapy arm of study MEK115306 in patients with unresectable or metastatic melanoma, pyrexia was 

reported in 57% (119/209) of patients with 7% Grade 3, as compared to the dabrafenib monotherapy 

arm with 33% (69/211) of patients reporting pyrexia, 2% Grade 3. In the Phase II study BRF113928 in 

patients with advanced NSCLC the incidence and severity of pyrexia were increased slightly when 

dabrafenib was used in combination with trametinib (48%, 3% Grade 3) as compared to dabrafenib 

monotherapy (39%, 2% Grade 3). In the Phase III study BRF115532 in the adjuvant treatment of 

melanoma, the incidence and severity of pyrexia were higher in the dabrafenib in combination with 

trametinib arm (67%; 6% Grade 3/4) as compared to the placebo arm (15%; <1% Grade 3). 

 

For patients with unresectable or metastatic melanoma who received dabrafenib in combination with 

trametinib and developed pyrexia, approximately half of the first occurrences of pyrexia happened 

within the first month of therapy and approximately one-third of the patients had 3 or more events. 

 



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Therapy with dabrafenib should be interrupted if the patient’s temperature is ≥38.5ºC (please refer to 

Table 2 for dose modification guidance). Patients should be evaluated for signs and symptoms of 

infection. Dabrafenib can be restarted once the fever resolves with appropriate prophylaxis using 

non-steroidal anti-inflammatory medicinal products or paracetamol. The use of oral corticosteroids 

should be considered in those instances in which anti-pyretics are insufficient. If fever is associated 

with other severe signs or symptoms, dabrafenib should be restarted at a reduced dose once fever 

resolves and as clinically appropriate (see section 4.2). No dose modification of trametinib is required 

when taken in combination with dabrafenib. 

 

LVEF reduction/Left ventricular dysfunction 

 

Dabrafenib in combination with trametinib has been reported to decrease LVEF (see section 4.8). 

Please refer to the trametinib SmPC for additional information (see section 4.4). No dose modification 

of dabrafenib is required when taken in combination with trametinib. 

 

Renal failure 

 

Renal failure has been identified in <1% of patients treated with dabrafenib alone and in ≤1% of 

patients treated with dabrafenib in combination with trametinib. Observed cases were generally 

associated with pyrexia and dehydration and responded well to dose interruption and general 

supportive measures. Granulomatous nephritis has been reported (see section 4.8). Patients should be 

routinely monitored for serum creatinine while on therapy. If creatinine increases, dabrafenib may 

need to be interrupted as clinically appropriate. Dabrafenib has not been studied in patients with renal 

insufficiency (defined as creatinine >1.5 x ULN) therefore caution should be used in this setting (see 

section 5.2). 

 

Hepatic events 

 

Hepatic adverse events have been reported in clinical trials with dabrafenib in combination with 

trametinib (see section 4.8). It is recommended that patients receiving treatment with dabrafenib in 

combination with trametinib have liver function monitored every four weeks for 6 months after 

treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically 

indicated. Please refer to the trametinib SmPC for additional information. 

 

Hypertension 

 

Elevations in blood pressure have been reported in association with dabrafenib in combination with 

trametinib, in patients with or without pre-existing hypertension (see section 4.8). Please refer to the 

trametinib SmPC for additional information. 

 

Interstitial lung disease (ILD)/Pneumonitis 

 

Cases of pneumonitis or ILD have been reported in clinical trials with dabrafenib in combination with 

trametinib. Please refer to the trametinib SmPC section 4.4 for additional information. If dabrafenib is 

being used in combination with trametinib then therapy with dabrafenib may be continued at the same 

dose. 

 

Rash 

 

Rash has been observed in about 24% of patients in clinical trials when dabrafenib is used in 

combination with trametinib (see section 4.8). The majority of these cases were Grade 1 or 2 and did 

not require any dose interruptions or dose reductions. Please refer to the trametinib SmPC section 4.4 

for additional information. 

 



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Rhabdomyolysis 

 

Rhabdomyolysis has been reported in patients taking dabrafenib in combination with trametinib (see 

section 4.8). Please refer to the trametinib SmPC section 4.4 for additional information. 

 

Pancreatitis 

 

Pancreatitis has been reported in <1% of patients treated with dabrafenib as monotherapy and in 

combination with trametinib in unresectable or metastatic melanoma clinical trials and about 4% of 

patients treated with dabrafenib in combination with trametinib in the NSCLC clinical trial. One of the 

events occurred on the first day of dabrafenib dosing of a metastatic melanoma patient and recurred 

following re-challenge at a reduced dose. In the adjuvant treatment of melanoma trial, pancreatitis was 

reported in <1% (1/435) of patients receiving dabrafenib in combination with trametinib, and no 

patients receiving placebo. Unexplained abdominal pain should be promptly investigated to include 

measurement of serum amylase and lipase. Patients should be closely monitored when re-starting 

dabrafenib after an episode of pancreatitis. 

 

Deep vein thrombosis/Pulmonary embolism 

 

Pulmonary embolism or deep vein thrombosis can occur when dabrafenib is used in combination with 

trametinib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as 

shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. 

Permanently discontinue trametinib and dabrafenib for life-threatening pulmonary embolism. 

 

Severe cutaneous adverse reactions 

 

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drug 

reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, 

have been reported during treatment with dabrafenib/trametinib combination therapy. Before initiating 

treatment, patients should be advised of the signs and symptoms and monitored closely for skin 

reactions. If signs and symptoms suggestive of SCARs appear, dabrafenib and trametinib should be 

withdrawn. 

 

Gastrointestinal disorders 

 

Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking 

dabrafenib in combination with trametinib (see section 4.8). Please refer to the trametinib SmPC for 

additional information (see section 4.4). 

 

Effects of other medicinal products on dabrafenib 

 

Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers of these enzymes should be 

avoided when possible as these agents may decrease the efficacy of dabrafenib (see section 4.5). 

 

Effects of dabrafenib on other medicinal products 

 

Dabrafenib is an inducer of metabolising enzymes which may lead to loss of efficacy of many 

commonly used medicinal products (see examples in section 4.5). A drug utilisation review (DUR) is 

therefore essential when initiating dabrafenib treatment. Concomitant use of dabrafenib with medicinal 

products that are sensitive substrates of certain metabolising enzymes or transporters (see section 4.5) 

should generally be avoided if monitoring for efficacy and dose adjustment is not possible. 

 

Concomitant administration of dabrafenib with warfarin results in decreased warfarin exposure. 

Caution should be exercised and additional International Normalised Ratio (INR) monitoring is 

recommended when dabrafenib is used concomitantly with warfarin and at discontinuation of 

dabrafenib (see section 4.5). 

 



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Concomitant administration of dabrafenib with digoxin may result in decreased digoxin exposure. 

Caution should be exercised and additional monitoring of digoxin is recommended when digoxin (a 

transporter substrate) is used concomitantly with dabrafenib and at discontinuation of dabrafenib (see 

section 4.5). 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

Effect of other medicinal products on dabrafenib 

 

Dabrafenib is a substrate for the metabolising enzymes CYP2C8 and CYP3A4, while the active 

metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Medicinal 

products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are therefore likely to increase 

or decrease, respectively, dabrafenib concentrations. Alternative agents should be considered during 

administration with dabrafenib when possible. Use caution if strong inhibitors (e.g. ketoconazole, 

gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, 

voriconazole, posaconazole, atazanavir) are co-administered with dabrafenib. Avoid co-administration 

of dabrafenib with potent inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St 

John’s wort (Hypericum perforatum)) of CYP2C8 or CYP3A4. 

 

Administration of ketoconazole (a CYP3A4 inhibitor) 400 mg once daily, with dabrafenib 75 mg 

twice daily, resulted in a 71% increase in dabrafenib AUC and a 33% increase in dabrafenib Cmax 

relative to administration of dabrafenib 75 mg twice daily alone. Co-administration resulted in 

increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 82% and 68%, respectively). A 

decrease of 16% in AUC was noted for carboxy-dabrafenib. 

 

Administration of gemfibrozil (a CYP2C8 inhibitor) 600 mg twice daily, with dabrafenib 75 mg twice 

daily, resulted in a 47% increase in dabrafenib AUC but did not alter dabrafenib Cmax relative to 

administration of dabrafenib 75 mg twice daily alone. Gemfibrozil had no clinically relevant effect on 

the systemic exposure to dabrafenib metabolites (≤13%). 

 

Administration of rifampin (a CYP3A4/CYP2C8 inducer) 600 mg once daily with dabrafenib 150 mg 

twice daily resulted in a decrease in repeat dose dabrafenib Cmax (27%) and AUC (34%). No relevant 

change in AUC was noted for hydroxy-dabrafenib. There was an increase in AUC of 73% for 

carboxy-dabrafenib and a decrease in AUC of 30% for desmethyl-dabrafenib. 

 

Co-administration of repeat doses of dabrafenib 150 mg twice daily and the pH-elevating agent 

rabeprazole 40 mg once daily resulted in a 3% increase in AUC and a 12% decrease in dabrafenib 

Cmax. These changes in dabrafenib AUC and Cmax are considered not clinically meaningful. Medicinal 

products that alter the pH of the upper gastrointestinal (GI) tract (e.g. proton pump inhibitors, 

H2-receptor antagonists, antacids) are not expected to reduce the bioavailability of dabrafenib. 

 

Effect of dabrafenib on other medicinal products 

 

Dabrafenib is an enzyme inducer and increases the synthesis of drug-metabolising enzymes including 

CYP3A4, CYP2Cs and CYP2B6 and may increase the synthesis of transporters. This results in 

reduced plasma levels of medicinal products metabolised by these enzymes, and may affect some 

transported medicinal products. The reduction in plasma concentrations can lead to lost or reduced 

clinical effect of these medicinal products. There is also a risk of increased formation of active 

metabolites of these medicinal products. Enzymes that may be induced include CYP3A in the liver 

and gut, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGTs (glucuronide conjugating enzymes). The 

transport protein Pgp may also be induced as well as other transporters, e.g. MRP-2. Induction of 

OATP1B1/1B3 and BCRP is not likely based on the observations from a clinical study with 

rosuvastatin. 

 

In vitro, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4. In a clinical drug 

interaction study, Cmax and AUC of oral midazolam (a CYP3A4 substrate) decreased by 47% and 65%, 

respectively with co-administration of repeat-dose dabrafenib. 



12 

 

Administration of dabrafenib 150 mg twice daily and warfarin resulted in a decrease in AUC of S- and 

R- warfarin of 37% and 33%, respectively, compared to administration of warfarin alone. Cmax of 

S- and R-warfarin increased 18% and 19%. 

 

Interactions with many medicinal products eliminated through metabolism or active transport is 

expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not 

easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products 

are to be avoided or used with caution. The risk for liver injury after paracetamol administration is 

suspected to be higher in patients concomitantly treated with enzyme inducers. 

 

The number of affected medicinal products is expected to be large; although the magnitude of the 

interaction will vary. Groups of medicinal products that can be affected include, but are not limited to: 

 Analgesics (e.g. fentanyl, methadone) 

 Antibiotics (e.g. clarithromycin, doxycycline) 

 Anticancer agents (e.g. cabazitaxel) 

 Anticoagulants (e.g. acenocoumarol, warfarin, see section 4.4) 

 Antiepileptic (e.g. carbamazepine, phenytoin, primidone, valproic acid) 

 Antipsychotics (e.g. haloperidol) 

 Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil) 

 Cardiac glycosides (e.g. digoxin, see section 4.4) 

 Corticosteroids (e.g. dexamethasone, methylprednisolone) 

 HIV antivirals (e.g. amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, 
indinavir, lopinavir, nelfinavir, saquinavir, tipranavir) 

 Hormonal contraceptives (see section 4.6) 

 Hypnotics (e.g. diazepam, midazolam, zolpidem) 

 Immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus) 

 Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin) 
 

Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib. Upon 

discontinuation of dabrafenib offset of induction is gradual, concentrations of sensitive CYP3A4, 

CYP2B6, CYP2C8, CYP2C9 and CYP2C19, UDP glucuronosyl transferase (UGT) and transporter 

substrates (e.g. Pgp or MRP-2) may increase and patients should be monitored for toxicity and dose of 

these agents may need to be adjusted. 

 

In vitro, dabrafenib is a mechanism based inhibitor of CYP3A4. Therefore, transient inhibition of 

CYP3A4 may be observed during the first few days of treatment. 

 

Effects of dabrafenib on substance transport systems 

 

Dabrafenib is an in vitro inhibitor of human organic anion transporting polypeptide (OATP) 1B1 

(OATP1B1), OATP1B3 and BCRP. Following co-administration of a single dose of rosuvastatin 

(OATP1B1, OATP1B3 and BCRP substrate) with repeat-dose dabrafenib 150 mg twice daily in 

16 patients, Cmax of rosuvastatin increased 2.6-fold whereas the AUC was only minimally changed 

(7% increase). The increased Cmax of rosuvastatin is unlikely to have clinical relevance. 

 

Combination with trametinib 

 

Co-administration of repeat dosing of trametinib 2 mg once daily and dabrafenib 150 mg twice daily 

resulted in no clinically meaningful changes in trametinib or dabrafenib Cmax and AUC with increases 

of 16 and 23%, respectively, in dabrafenib Cmax and AUC. A small decrease in trametinib 

bioavailability, corresponding to a decrease in AUC of 12%, was estimated when trametinib is 

administered in combination with dabrafenib, a CYP3A4 inducer, using a population pharmacokinetic 

analysis. 

 



13 

When dabrafenib is used in combination with trametinib refer to the guidance for medicinal product 

interactions found in sections 4.4 and 4.5 of dabrafenib and trametinib SmPC. 

 

Effect of food on dabrafenib 

 

Patients should take dabrafenib as monotherapy or in combination with trametinib at least one hour 

prior to or two hours after a meal due to the effect of food on dabrafenib absorption (see section 5.2). 

 

Paediatric population 

 

Interaction studies have only been performed in adults. 

 

4.6 Fertility, pregnancy and lactation 
 

Women of childbearing potential/Contraception in females 

 

Women of childbearing potential must use effective methods of contraception during therapy and for 

2 weeks following discontinuation of dabrafenib and 16 weeks following the last dose of trametinib 

when given in combination with dabrafenib. Dabrafenib may decrease the efficacy of oral or any 

systemic hormonal contraceptives and an effective alternative method of contraception should be used 

(see section 4.5). 

 

Pregnancy 

 

There are no data from the use of dabrafenib in pregnant women. Animal studies have shown 

reproductive toxicity and embryo-foetal developmental toxicities, including teratogenic effects (see 

section 5.3). Dabrafenib should not be administered to pregnant women unless the potential benefit to 

the mother outweighs the possible risk to the foetus. If the patient becomes pregnant while taking 

dabrafenib, the patient should be informed of the potential hazard to the foetus. Please see trametinib 

SmPC (see section 4.6) when used in combination with trametinib. 

 

Breast-feeding 

 

It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are 

excreted in human milk, a risk to the breast-feeding child cannot be excluded. A decision should be 

made whether to discontinue breast-feeding or discontinue dabrafenib, taking into account the benefit 

of breast-feeding for the child and the benefit of therapy for the woman. 

 

Fertility 

 

There are no data in humans for dabrafenib as monotherapy or in combination with trametinib. 

Dabrafenib may impair male and female fertility as adverse effects on male and female reproductive 

organs have been seen in animals (see section 5.3). Male patients taking dabrafenib as monotherapy or 

in combination with trametinib should be informed of the potential risk for impaired spermatogenesis, 

which may be irreversible. Please see trametinib SmPC (see section 4.6) when used in combination 

with trametinib. 

 

4.7 Effects on ability to drive and use machines 
 

Dabrafenib has minor influence on the ability to drive and use machines. The clinical status of the 

patient and the adverse reaction profile of dabrafenib should be borne in mind when considering the 

patient's ability to perform tasks that require judgement, motor or cognitive skills. Patients should be 

made aware of the potential for fatigue and eye problems to affect these activities. 

 



14 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

The safety of dabrafenib monotherapy is based on the integrated safety population from five clinical 

trials, BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK-2), BRF113220, 

and BRF112680, which included 578 patients with BRAF V600 mutant unresectable or metastatic 

melanoma treated with dabrafenib 150 mg twice daily. The most common adverse reactions (incidence 

15%) reported with dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, 

papilloma, alopecia, rash, and vomiting. 

 

The safety of dabrafenib in combination with trametinib has been evaluated in the integrated safety 

population of 1076 patients with BRAF V600 mutant unresectable or metastatic melanoma, Stage III 

BRAF V600 mutant melanoma following complete resection (adjuvant treatment) and advanced 

NSCLC treated with dabrafenib 150 mg twice daily and trametinib 2 mg once daily. Of these patients, 

559 were treated with the combination for BRAF V600 mutant melanoma in two randomised Phase III 

clinical trials, MEK115306 (COMBI-d) and MEK116513 (COMBI-v), 435 were treated with the 

combination in the adjuvant treatment of Stage III BRAF V600 mutant melanoma after complete 

resection in a randomised Phase III study BRF115532 (COMBI-AD) and 82 were treated with the 

combination for BRAF V600 mutant NSCLC in a multi-cohort, non-randomised Phase II study 

BRF113928 (see section 5.1). 

 

The most common adverse reactions (incidence 20%) for dabrafenib in combination with trametinib 

were: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash. 

 

Tabulated list of adverse reactions 

 

Adverse drug reactions 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). Within each frequency grouping, adverse reactions are presented in order of 

decreasing seriousness. 

 

  



15 

Table 3 Adverse reactions reported in the integrated safety population of dabrafenib monotherapy 

in the studies BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 

(BREAK-2), BRF113220, and BRF112680 (n=578) 

 

System organ class Frequency (all grades) Adverse reactions 

Neoplasms benign, malignant 

and unspecified (including 

cysts and polyps) 

Very common Papilloma 

Common 

Cutaneous squamous cell carcinoma 

Seborrhoeic keratosis 

Acrochordon (skin tags) 

Basal cell carcinoma 

Uncommon New primary melanoma 

Immune system disorders Uncommon Hypersensitivity 

Metabolism and nutrition 

disorders 

Very common Decreased appetite 

Common 
Hypophosphataemia 

Hyperglycaemia 

Nervous system disorders Very common Headache 

Eye disorders Uncommon Uveitis 

Respiratory, thoracic and 

mediastinal disorders 
Very common Cough 

Gastrointestinal disorders 

Very common 

Nausea 

Vomiting 

Diarrhoea 

Common Constipation 

Uncommon Pancreatitis 

Skin and subcutaneous tissue 

disorders 

Very common 

Hyperkeratosis 

Alopecia 

Rash 

Palmar-plantar erythrodysaesthesia 

syndrome 

Common 

Dry skin 

Pruritus 

Actinic keratosis 

Skin lesion 

Erythema 

Photosensitivity 

Uncommon Panniculitis 

Musculoskeletal and 

connective tissue disorders 
Very common 

Arthralgia 

Myalgia 

Pain in extremity 

Renal and urinary disorders Uncommon 
Renal failure, acute renal failure 

Nephritis 

General disorders and 

administration site conditions 

Very common 

Pyrexia 

Fatigue 

Chills 

Asthenia 

Common Influenza-like illness 

 



16 

Table 4 Adverse reactions reported in the integrated safety population of dabrafenib in 

combination with trametinib in the studies MEK115306, MEK116513a, BRF113928, and 

BRF115532 (n=1076) 

 

System organ class Frequency (all grades) Adverse reactions 

Infections and infestations 

Very common Nasopharyngitis 

Common 

Urinary tract infection 

Cellulitis 

Folliculitis 

Paronychia 

Rash pustular 

Neoplasms benign, 

malignant and unspecified 

(incl cysts and polyps) 

Common 

Cutaneous squamous cell carcinomab 

Papillomac 

Seborrhoeic keratosis 

Uncommon 
New primary melanomad 

Acrochordon (skin tags) 

Blood and lymphatic system 

disorders 
Common 

Neutropenia 

Anaemia 

Thrombocytopenia 

Leukopenia 

Immune system disorders Uncommon Hypersensitivitye 

Metabolism and nutrition 

disorders 

Very common Decreased appetite 

Common 

Dehydration 

Hyponatraemia 

Hypophosphataemia 

Hyperglycaemia 

Nervous system disorders Very common 
Headache 

Dizziness 

Eye disorders 

Common 

Vision blurred 

Visual impairment 

Uveitis 

Uncommon 

Chorioretinopathy 

Retinal detachment 

Periorbital oedema 

Cardiac disorders 

Common Ejection fraction decreased 

Uncommon Bradycardia 

Not known Myocarditis 

Vascular disorders 

Very common 
Hypertension 

Haemorrhagef 

Common 
Hypotension 

Lymphoedema 

Respiratory, thoracic and 

mediastinal disorders 

Very common Cough 

Common Dyspnoea 

Uncommon Pneumonitis 



17 

System organ class Frequency (all grades) Adverse reactions 

Gastrointestinal disorders 

Very common 

Abdominal paing 

Constipation 

Diarrhoea 

Nausea 

Vomiting 

Common 
Dry mouth 

Stomatitis 

Uncommon 
Pancreatitis 

Colitis 

Rare Gastrointestinal perforation 

Skin and subcutaneous 

disorders 

Very common 

Dry skin 

Pruritus 

Rash 

Erythemah 

Common 

Dermatitis acneiform 

Actinic keratosis 

Night sweats 

Hyperkeratosis 

Alopecia 

Palmar-plantar erythrodysaesthesia 

syndrome 

Skin lesion 

Hyperhidrosis 

Panniculitis 

Skin fissures 

Photosensitivity 

Not known 

Stevens-Johnson syndrome 

Drug reaction with eosinophilia and 

systemic symptoms 

Dermatitis exfoliative generalised 

Musculoskeletal and 

connective tissue disorders 
Very common 

Arthralgia 

Myalgia 

Pain in extremity 

Muscle spasmsi 

Renal and urinary disorders Uncommon 
Renal failure 

Nephritis 

General disorders and 

administration site 

conditions 

Very common 

Fatigue 

Chills 

Asthenia 

Oedema peripheral 

Pyrexia 

Influenza-like illness 

Common 
Mucosal inflammation 

Face oedema 



18 

System organ class Frequency (all grades) Adverse reactions 

Investigations 

Very common 
Alanine aminotransferase increased 

Aspartate aminotransferase increased 

Common 

Blood alkaline phosphatase increased 

Gamma-glutamyltransferase increased 

Blood creatine phosphokinase 

increased 
a The safety profile from MEK116513 is generally similar to that of MEK115306 with the following 

exceptions: 1) The following adverse reactions have a higher frequency category as compared to 

MEK115306: muscle spasm (very common); renal failure and lymphoedema (common); acute renal 

failure (uncommon); 2) The following adverse reactions have occurred in MEK116513 but not in 

MEK115306: cardiac failure, left ventricular dysfunction, interstitial lung disease (uncommon). 3) The 

following adverse reaction has occurred in MEK116513 and BRF115532 but not in MEK115306 and 

BRF113928: rhabdomyolysis (uncommon) 
b Cutaneous squamous cell carcinoma (cu SCC): SCC, SCC of the skin, SCC in situ (Bowen’s disease) 

and keratoacanthoma 
c Papilloma, skin papilloma 
d Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma stage III 
e Includes drug hypersensitivity 
f Bleeding from various sites, including intracranial bleeding and fatal bleeding 
g Abdominal pain upper and abdominal pain lower 
h Erythema, generalised erythema 
i Muscle spasms, musculoskeletal stiffness 

 

Description of selected adverse reactions 

 

Cutaneous squamous cell carcinoma 

For dabrafenib monotherapy in study MEK115306, cutaneous squamous cell carcinomas (including 

those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 10% of patients 

and approximately 70% of the events occurred within the first 12 weeks of treatment with a median 

time to onset of 8 weeks. In the integrated safety population for dabrafenib in combination with 

trametinib, 2% of patients developed cuSCC and the events occurred later than with dabrafenib 

monotherapy with a median time to onset of 18-31 weeks. All patients receiving dabrafenib as 

monotherapy or in combination with trametinib who developed cuSCC continued on treatment without 

dose modification. 

 

New primary melanoma 

New primary melanomas have been reported in clinical trials with dabrafenib as monotherapy and in 

combination with trametinib in melanoma studies. Cases were managed with excision and did not 

require treatment modification (see section 4.4). No new primary melanoma was reported from the 

Phase II NSCLC study (BRF113928). 

 

Non-cutaneous malignancy 

Activation of MAP-kinase signalling in BRAF wild type cells which are exposed to BRAF inhibitors 

may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (see 

section 4.4). Non-cutaneous malignancies were reported in 1% (6/586) of patients in the integrated 

safety population of dabrafenib monotherapy, and <1% (8/1076) of patients in the integrated safety 

population of dabrafenib in combination with trametinib. Cases of RAS-driven malignancies have 

been seen with dabrafenib as monotherapy and in combination with trametinib. Patients should be 

monitored as clinically appropriate. 

 

Haemorrhage 

Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, have occurred in 

patients taking dabrafenib in combination with trametinib. Please refer to the trametinib SmPC. 

 



19 

LVEF reduction/Left ventricular dysfunction 

Decreased LVEF has been reported in 6% (65/1076) of patients in the integrated safety population of 

dabrafenib in combination with trametinib. Most cases were asymptomatic and reversible. Patients 

with LVEF lower than the institutional lower limit of normal were not included in clinical trials with 

dabrafenib. Dabrafenib in combination with trametinib should be used with caution in patients with 

conditions that could impair left ventricular function. Please refer to the trametinib SmPC. 

 

Pyrexia 

Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination with 

trametinib; the incidence and severity of pyrexia are increased with the combination therapy (see 

section 4.4). For patients who received dabrafenib in combination with trametinib and developed 

pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of 

therapy and approximately one-third of the patients had 3 or more events. In 1% of patients receiving 

dabrafenib as monotherapy in the integrated safety population, serious non-infectious febrile events 

were identified as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal 

insufficiency or pre-renal origin in subjects with normal baseline renal function. The onset of these 

serious non-infectious febrile events was typically within the first month of therapy. Patients with 

serious non-infectious febrile events responded well to dose interruption and/or dose reduction and 

supportive care (see sections 4.2 and 4.4). 
 

Hepatic events 

Hepatic adverse events have been reported in clinical trials with dabrafenib in combination with 

trametinib. Please refer to the trametinib SmPC. 

 

Hypertension 

Elevations in blood pressure have been reported in association with dabrafenib in combination with 

trametinib, in patients with or without pre-existing hypertension. Blood pressure should be measured 

at baseline and monitored during treatment, with control of hypertension by standard therapy as 

appropriate. 

 

Arthralgia 

Arthralgia was reported very commonly in the integrated safety population of dabrafenib monotherapy 

(25%) and dabrafenib in combination with trametinib (25%) although these were mainly Grade 1 and 

2 in severity with Grade 3 occurring uncommonly (<1%) and no Grade 4 occurrences being reported. 

 

Hypophosphataemia 

Hypophosphataemia has been reported commonly in the integrated safety population of dabrafenib 

monotherapy (7%) and of dabrafenib in combination with trametinib (4%). It should be noted that 

approximately half of these occurrences with dabrafenib monotherapy (4%) and 1% with dabrafenib in 

combination with trametinib were Grade 3 in severity.  

 

Pancreatitis 

Pancreatitis has been reported in dabrafenib monotherapy and in combination with trametinib. 

Unexplained abdominal pain should be promptly investigated to include measurement of serum 

amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode 

of pancreatitis (see section 4.4). 

 

Renal failure 

Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was 

uncommon; however dabrafenib has not been studied in patients with renal insufficiency (defined as 

creatinine >1.5 x ULN). Caution should be used in this setting (see section 4.4). 

 



20 

Special populations 

 

Elderly 

Of the total number of patients in the integrated safety population of dabrafenib monotherapy (n=578), 

22% were 65 years of age and older, and 6% were 75 years of age and older. Compared with younger 

subjects (<65), more subjects 65 years old had adverse reactions that led to study drug dose 

reductions (22% versus 12%) or interruptions (39% versus 27%). In addition, older patients 

experienced more serious adverse reactions compared to younger patients (41% versus 22%). No 

overall differences in efficacy were observed between these subjects and younger subjects. 

 

In the integrated safety population of dabrafenib in combination with trametinib (n=1076), 

265 patients (25%) were ≥65 years of age, 62 patients (6%) were ≥75 years of age. The proportion of 

patients experiencing AEs was similar in those aged <65 years and those aged ≥65 years in all clinical 

trials. Patients ≥65 years were more likely to experience SAEs and AEs leading to permanent 

discontinuation of medicinal product, dose reduction and dose interruption than those <65 years. 

 

Dabrafenib in combination with trametinib in patients with brain metastases 

 

The safety and efficacy of the combination of dabrafenib and trametinib have been evaluated in a 

multi-cohort, open-label, Phase II study in patients with BRAF V600 mutant melanoma with brain 

metastases. The safety profile observed in these patients appears to be consistent with the integrated 

safety profile of the combination. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 
 

There is no specific treatment for an overdose of dabrafenib. If overdose occurs, the patient should be 

treated supportively with appropriate monitoring as necessary. 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE23 

 

Mechanism of action 

 

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive 

activation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a high 

frequency in specific cancers, including approximately 50% of melanoma. The most commonly 

observed BRAF mutation is V600E which accounts for approximately 90% of the BRAF mutations 

that are seen in melanoma. 
 

Preclinical data generated in biochemical assays demonstrated that dabrafenib inhibits BRAF kinases 

with activating codon 600 mutations (Table 5). 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


21 

Table 5 Kinase inhibitory activity of dabrafenib against RAF kinases 

 

Kinase Inhibitory concentration 50 (nM) 

BRAF V600E 0.65 

BRAF V600K 0.50 

BRAF V600D 1.8 

BRAF WT 3.2 

CRAF WT 5.0 

 

Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated 

ERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, in vitro and in animal 

models. 

 

In subjects with BRAF V600 mutation positive melanoma, administration of dabrafenib resulted in 

inhibition of tumour phosphorylated ERK relative to baseline. 

 

Combination with trametinib 

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular 

signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are 

components of the extracellular signal-related kinase (ERK) pathway. Thus, trametinib and dabrafenib 

inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides 

concomitant inhibition of the pathway. The combination of dabrafenib with trametinib has shown 

anti-tumour activity in BRAF V600 mutation positive melanoma cell lines in vitro and delays the 

emergence of resistance in vivo in BRAF V600 mutation positive melanoma xenografts. 

 

Determination of BRAF mutation status 

Before taking dabrafenib or combination with trametinib, patients must have BRAF V600 

mutation-positive tumour status confirmed by a validated test. In the Phase II and III clinical trials, 

screening for eligibility required central testing for BRAF V600 mutation using a BRAF mutation 

assay conducted on the most recent tumour sample available. Primary tumour or tumour from a 

metastatic site was tested with an investigational use only assay (IUO). The IUO is an allele-specific 

polymerase chain reaction (PCR) assay performed on DNA extracted from formalin-fixed 

paraffin-embedded (FFPE) tumour tissue. The assay was specifically designed to differentiate between 

the V600E and V600K mutations. Only subjects with BRAF V600E or V600K mutation positive 

tumours were eligible for study participation. 

 

Subsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validated 

assay, which has CE marking. The bMx THxID BRAF assay is an allele-specific PCR performed on 

DNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and 

V600K mutations with high sensitivity (down to 5% V600E and V600K sequence in a background of 

wild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical trials with 

retrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less 

common BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the 

specimens from the non-clinical and clinical trials (n=876) that were mutation positive by the THxID 

BRAF assay and subsequently were sequenced using the reference method, the specificity of the assay 

was 94%. 

 

  



22 

Clinical efficacy and safety 

 

Unresectable or metastatic melanoma 

 Dabrafenib in combination with trametinib 
Treatment-naïve patients 

The efficacy and safety of the recommended dose of trametinib (2 mg once daily) in combination with 

dabrafenib (150 mg twice daily) for the treatment of adult patients with unresectable or metastatic 

melanoma with a BRAF V600 mutation was studied in two Phase III trials and one supportive 

Phase I/II study. 

 

MEK115306 (COMBI-d): 

MEK115306 was a Phase III, randomised, double-blinded study comparing the combination of 

dabrafenib and trametinib to dabrafenib and placebo in first-line therapy for subjects with unresectable 

(Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The 

primary endpoint of the study was progression-free survival (PFS), with a key secondary endpoint of 

overall survival (OS). Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit 

of normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K). 

 

A total of 423 subjects were randomised 1:1 to either combination (N=211) or dabrafenib (N=212). 

Most subjects were Caucasian (>99%) and male (53%), with a median age of 56 years (28% were 

≥65 years). The majority of subjects had Stage IVM1c disease (67%). Most subjects had LDH ≤ULN 

(65%), Eastern Cooperative Oncology Group (ECOG) performance status of 0 (72%), and visceral 

disease (73%) at baseline. The majority of subjects had a BRAF V600E mutation (85%). Subjects with 

brain metastases were not included in the trial. 

 

Median OS and estimated 1-year, 2-year, 3-year, 4 year and 5-year survival rates are presented in 

Table 6. From an OS analysis at 5 years, the median OS for the combination arm was approximately 

7 months longer than for dabrafenib monotherapy (25.8 months versus 18.7 months) with 5-year 

survival rates of 32% for the combination versus 27% for dabrafenib monotherapy (Table 6, Figure 1). 

The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 1). The 5-year overall 

survival rate was 40% (95% CI: 31.2, 48.4) in the combination arm versus 33% (95% CI: 25.0, 41.0) 

in the dabrafenib monotherapy arm for patients who had a normal lactate dehydrogenase level at 

baseline, and 16% (95% CI: 8.4, 26.0) in the combination arm versus 14% (95% CI: 6.8, 23.1) in the 

dabrafenib monotherapy arm for patients with an elevated lactate dehydrogenase level at baseline. 

 

  



23 

Table 6 Overall Survival results for Study MEK115306 (COMBI-d) 

 

 
OS analysis 

(data cut-off: 12-Jan-2015) 

5-year OS analysis 

(data cut-off: 10-Dec-2018) 

 

Dabrafenib + 

Trametinib 

(n=211) 

Dabrafenib + 

Placebo 

(n=212) 

Dabrafenib + 

Trametinib 

(n=211) 

Dabrafenib + 

Placebo 

(n=212) 

Number of patients 

Died (event), n 

(%) 
99 (47) 123 (58) 135 (64) 151 (71) 

Estimates of OS (months) 

Median (95% CI) 
25.1 

(19.2, NR) 

18.7 

(15.2, 23.7) 

25.8 

(19.2, 38.2) 

18.7 

(15.2, 23.1) 

Hazard ratio 

(95% CI) 

0.71 

(0.55, 0.92) 

0.80 

(0.63, 1.01) 

p-value 0.011 NA 

Overall survival 

estimate, % (95% 

CI) 

Dabrafenib + Trametinib 

(n=211) 

Dabrafenib + Placebo 

(n=212) 

At 1 year 74 (66.8, 79.0) 68 (60.8, 73.5) 

At 2 years 52 (44.7, 58.6) 42 (35.4, 48.9) 

At 3 years 43 (36.2, 50.1) 31 (25.1, 37.9) 

At 4 years 35 (28.2, 41.8) 29 (22.7, 35.2) 

At 5 years 32 (25.1, 38.3) 27 (20.7, 33.0) 

NR = Not reached, NA = Not applicable 

 

Figure 1 Kaplan-Meier overall survival curves for Study MEK115306 (ITT population) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

E
s
ti

m
a
te

d
 S

u
rv

iv
a
l 
F

u
n

c
ti

o
n

 

0.0 

0.2 

0.4 

0.6 

0.8 

1.0 

Time since Randomisation (Months) 

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6 7 2 78 

Subjects at Risk: 
211 188 145 113 98 86 79 71 63 60 57 54 12 0 
212 175 137 104 84 69 60 56 54 51 50 46 10 0 

Dabrafenib + Placebo 
Dabrafenib + Trametinib 

Dabrafenib + Placebo 
Dabrafenib + Trametinib 



24 

Improvements for the primary endpoint of PFS were sustained over a 5 year timeframe in the 

combination arm compared to dabrafenib monotherapy. Improvements were also observed for overall 

response rate (ORR) and a longer duration of response (DoR) was observed in the combination arm 

compared to dabrafenib monotherapy (Table 7). 

 

Table 7 Efficacy results for Study MEK115306 (COMBI-d) 

 
 Primary analysis (data 

cut-off: 26-Aug-2013) 

Updated analysis (data 

cut-off: 12-Jan-2015) 

5-year analysis (data cut-

off: 10-Dec-2018) 

Endpoint Dabrafenib 

+ 

Trametinib 

(n=211) 

Dabrafenib 

+ 

Placebo 

(n=212) 

Dabrafenib 

+ 

Trametinib 

(n=211) 

Dabrafenib 

+ 

Placebo 

(n=212) 

Dabrafenib 

+ 

Trametinib 

(n=211) 

Dabrafenib 

+ 

Placebo 

(n=212) 

PFSa 

Progressive 

disease or death, n 

(%) 

102 (48) 109 (51) 139 (66) 162 (76) 160 (76) 166 (78) 

Median PFS 

(months) (95% 

CI) 

9.3 

(7.7, 11.1) 

8.8 

(5.9, 10.9) 

11.0 

(8.0, 13.9) 

8.8 

(5.9, 9.3) 

10.2 

(8.1, 12.8) 

8.8 

(5.9, 9.3) 

Hazard Ratio 

(95% CI) 

0.75 

(0.57, 0.99) 

0.67 

(0.53, 0.84) 

0.73 

(0.59, 0.91) 

 P value 0.035 <0.001f NA 

ORRb 

% (95% CI) 

67 

(59.9, 73.0) 

51 

(44.5, 58.4) 

69 

(61.8, 74.8) 

53 

(46.3, 60.2) 

69 

(62.5, 75.4) 

54 

(46.8, 60.6) 

ORR difference 

(95% CI) 

15e 

(5.9, 24.5) 

15e 

(6.0, 24.5) 

NA 

 P value 0.0015 0.0014f NA 

DoRc (months) 

Median 

(95% CI) 

 

9.2d 

(7.4, NR) 

 

10.2d 

(7.5, NR) 

 

12.9 

(9.4,19.5) 

 

10.6 

(9.1, 13.8) 

 

12.9 

(9.3, 18.4) 

 

10.2 

(8.3, 13.8) 

a – Progression-free survival (investigator assessed) 

b – Overall Response Rate = Complete Response + Partial Response 

c – Duration of response 

d – At the time of the reporting the majority (≥59%) of investigator-assessed responses were still ongoing 

e – ORR difference calculated based on the ORR result not rounded 

f – Updated analysis was not pre-planned and the p-value was not adjusted for multiple testing 

NR = Not reached 

NA = Not applicable 

 

MEK116513 (COMBI-v): 

Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing dabrafenib and 

trametinib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive 

unresectable or metastatic melanoma. The primary endpoint of the study was OS with a key secondary 

endpoint of PFS. Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of 

normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K). 

 

A total of 704 subjects were randomised 1:1 to either combination or vemurafenib. Most subjects were 

Caucasian (>96%) and male (55%), with a median age of 55 years (24% were ≥65 years). The 

majority of subjects had Stage IV M1c disease (61% overall). Most subjects had LDH ≤ULN (67%), 

ECOG performance status of 0 (70%), and visceral disease (78%) at Baseline. Overall, 54% of 

subjects had <3 disease sites at baseline. The majority of subjects had BRAF V600E mutation-positive 

melanoma (89%). Subjects with brain metastases were not included in the trial. 

 

Median OS and estimated 1-year, 2-year, 3-year, 4 year and 5-year survival rates are presented in 

Table 8. From an OS analysis at 5 years, the median OS for the combination arm was approximately 

8 months longer than the median OS for vemurafenib monotherapy (26.0 months versus 17.8 months) 

with 5-year survival rates of 36% for the combination versus 23% for vemurafenib monotherapy 

(Table 8, Figure 2). The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 2). 

The 5-year overall survival rate was 46% (95% CI: 38.8, 52.0) in the combination arm versus 28% 



25 

(95% CI: 22.5, 34.6) in the vemurafenib monotherapy arm for patients who had a normal lactate 

dehydrogenase level at baseline, and 16% (95% CI: 9.3, 23.3) in the combination arm versus 10% 

(95% CI: 5.1, 17.4) in the vemurafenib monotherapy arm for patients with an elevated lactate 

dehydrogenase level at baseline. 

 

Table 8 Overall Survival results for Study MEK116513 (COMBI-v) 

 

 OS analysis 

data cut-off: 13-Mar-2015) 

5-year OS analysis 

(data cut-off: 08-Oct-2018) 

 Dabrafenib + 

Trametinib 

(n=352) 

Vemurafenib 

(n=352) 

Dabrafenib + 

Trametinib 

(n=352) 

Vemurafenib 

(n=352) 

Number of patients 

Died (event), n 

(%) 
155 (44) 194 (55) 216 (61) 246 (70) 

Estimates of OS (months) 

Median (95% CI) 
25.6 

(22.6, NR) 

18.0 

(15.6, 20.7) 

26.0 

(22.1, 33.8) 

17.8 

(15.6, 20.7) 

Adjusted hazard 

ratio (95% CI) 
0.66 

(0.53, 0.81) 

0.70 

(0.58, 0.84) 

p-value <0.001 NA 

Overall survival 

estimate, % (95% 

CI)  

Dabrafenib + Trametinib 

(n=352) 

Vemurafenib 

(n=352) 

At 1 year 72 (67, 77) 65 (59, 70) 

At 2 years 53 (47.1, 57.8) 39 (33.8, 44.5) 

At 3 years 44 (38.8, 49.4) 31 (25.9, 36.2) 

At 4 years 39 (33.4, 44.0) 26 (21.3, 31.0) 

At 5 years 36 (30.5, 40.9) 23 (18.1, 27.4) 

NR = Not reached, NA = Not applicable 

 

Figure 2 Kaplan-Meier overall survival curves for Study MEK116513 

 

 
 

Dabrafenib + Trametinib 

0.0 

0.2 

0.4 

0.6 

0.8 

1.0 

Time since Randomisation (Months) 

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6 7 2 78 

Subjects at Risk: 

Vemurafenib 
352 311 246 201 171 151 140 130 118 109 104 49 4 0 
352 287 201 154 120 104 94 86 78 72 65 30 1 0 

E
s
ti

m
a
te

d
 S

u
rv

iv
a
l 
F

u
n

c
ti

o
n

 

Vemurafenib 

Dabrafenib + Trametinib 



26 

Improvements for the secondary endpoint of PFS were sustained over a 5 year timeframe in the 

combination arm compared to vemurafenib monotherapy. Improvements were also observed for ORR 

and a longer DoR was observed in the combination arm compared to vemurafenib monotherapy 

(Table 9). 

 

 

Table 9 Efficacy results for Study MEK116513 (COMBI-v) 

 

 Primary analysis (Data cut-off: 17-

Apr-2014) 

5-year analysis (Data cut-off: 08-

Oct-2018) 

Endpoint Dabrafenib + 

Trametinib 

(n=352) 

Vemurafenib 

(n=352) 

Dabrafenib + 

Trametinib 

(n=352) 

Vemurafenib 

(n=352) 

PFSa 

Progressive 

disease or death, 

n (%) 

166 (47) 217 (62) 257 (73) 259 (74) 

Median PFS 

(months) 

(95% CI) 

11.4 

(9.9, 14.9) 

7.3 

(5.8, 7.8) 
12.1 

(9.7, 14.7) 

7.3 

(6.0, 8.1) 

Hazard Ratio 

(95% CI) 

0.56 

(0.46, 0.69) 

0.62 

(0.52, 0.74) 

 P value <0.001 NA 

ORRb 

% (95% CI) 

64 

(59.1, 69.4) 

51 

(46.1, 56.8) 

67 

(62.2, 72.2) 

53 

(47.2, 57.9) 

ORR difference 

(95% CI) 

13 

(5.7, 20.2) 

NA 

 P value 0.0005 NA 

DoRc (months) 

Median 

(95% CI) 

 

13.8d 

(11.0, NR) 

 

7.5d 

(7.3, 9.3) 

 

13.8 

(11.3, 18.6) 

 

8.5 

(7.4, 9.3) 

a – Progression-free survival (investigator assessed) 

b – Overall Response Rate = Complete Response + Partial Response 

c – Duration of response 

d – At the time of the reporting the majority (59% of dabrafenib+trametinib and 42% of vemurafenib) 

of investigator-assessed responses were still ongoing 

NR = Not reached 

NA = Not applicable 

 

Prior BRAF inhibitor therapy 

There are limited data in patients taking the combination of dabrafenib with trametinib who have 

progressed on a prior BRAF inhibitor. 

 

Part B of study BRF113220 included a cohort of 26 patients that had progressed on a BRAF inhibitor. 

The trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination demonstrated limited 

clinical activity in patients who had progressed on a BRAF inhibitor. The investigator-assessed 

confirmed response rate was 15% (95% CI: 4.4, 34.9) and the median PFS was 3.6 months (95% CI: 

1.9, 5.2). Similar results were seen in the 45 patients who crossed over from dabrafenib monotherapy 

to the trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination in Part C of this 

study. In these patients a 13% (95 CI: 5.0, 27.0) confirmed response rate was observed with a median 

PFS of 3.6 months (95% CI: 2, 4). 

 



27 

Patients with brain metastases 

The efficacy and safety of dabrafenib in combination with trametinib in patients with BRAF 

mutant-positive melanoma that has metastasised to the brain was studied in a non-randomised, 

open-label, multicentre, Phase II study (COMBI-MB study). A total of 125 patients were enrolled into 

four cohorts: 

 Cohort A: patients with BRAFV600E mutant melanoma with asymptomatic brain metastases 
without prior local brain-directed therapy and ECOG performance status of 0 or 1. 

 Cohort B: patients with BRAFV600E mutant melanoma with asymptomatic brain metastases 
with prior local brain-directed therapy and ECOG performance status of 0 or1. 

 Cohort C: patients with BRAFV600D/K/R mutant melanoma with asymptomatic brain 
metastases, with or without prior local brain-directed therapy and ECOG performance status of 

0 or 1. 

 Cohort D: patients with BRAFV600D/E/K/R mutant melanoma with symptomatic brain 
metastases, with or without prior local brain-directed therapy and ECOG performance status of 

0 or 1 or 2. 

 

The primary endpoint of the study was intracranial response in Cohort A, defined as the percentage of 

patients with a confirmed intracranial response assessed by the investigator using modified Response 

Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Intracranial response assessed by the 

investigator in Cohorts B, C and D were secondary endpoints of the study. Due to small sample size 

reflected by wide 95% CIs, the results in Cohorts B, C, and D should be interpreted with caution. 

Efficacy results are summarised in Table 10. 

 

Table 10 Efficacy data by investigator assessment from COMBI-MB study 

 

 All treated patients population 

Endpoints/ 

assessment 

Cohort A 

N=76 

Cohort B 

N=16 

Cohort C 

N=16 

Cohort D 

N=17 

Intracranial response rate, % (95 % CI) 

 59% 

(47.3, 70.4) 

56% 

(29.9, 80.2) 

44% 

(19.8, 70.1) 

59% 

(32.9, 81.6) 

Duration of intracranial response, median, months (95% CI) 

 6.5 

(4.9, 8.6) 

7.3 

(3.6, 12.6) 

8.3 

(1.3, 15.0) 

4.5 

(2.8, 5.9) 

Overall response rate, % (95% CI) 

 59% 

(47.3, 70.4) 

56% 

(29.9, 80.2) 

44% 

(19.8, 70.1) 

65% 

(38.3, 85.8) 

Progression-free survival, median, months (95% CI) 

 5.7 

(5.3, 7.3) 

7.2 

(4.7, 14.6) 

3.7 

(1.7, 6.5) 

5.5 

(3.7, 11.6) 

Overall survival, median, months (95% CI) 

 10.8 

(8.7, 17.9) 

24.3 

(7.9, NR) 

10.1 

(4.6, 17.6) 

11.5 

(6.8, 22.4) 

CI = Confidence Interval 

NR = Not reached 

 

  



28 

 Dabrafenib monotherapy 
The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation positive 

unresectable or metastatic melanoma has been evaluated in 3  clinical trials (BRF113683 [BREAK-3], 

BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600E 

and/or V600K mutations. 

 

Included in these clinical trials were in total 402 subjects with BRAF V600E and 49 subjects with 

BRAF V600K mutation. Patients with melanoma driven by BRAF mutations other than V600E were 

excluded from the confirmatory trial and with respect to patients with the V600K mutation in single 

arm clinical trials the activity appears lower than in V600E tumours. 

 

No data is available in patients with melanoma harbouring BRAF V600 mutations others than V600E 

and V600K. Efficacy of dabrafenib in subjects previously treated with a protein kinase inhibitor has 

not been investigated. 

 

Previously untreated patients (results from the Phase III study [BREAK-3]) 

The efficacy and safety of dabrafenib were evaluated in a Phase III randomised, open-label study 

[BREAK 3] comparing dabrafenib to dacarbazine (DTIC) in previously untreated patients with BRAF 

V600E mutation positive advanced (unresectable Stage III) or metastatic (Stage IV) melanoma. 

Patients with melanoma driven by BRAF mutations other than V600E were excluded. 

 

The primary objective for this study was to evaluate the efficacy of dabrafenib compared to DTIC with 

respect to PFS per investigator assessment. Patients on the DTIC arm were allowed to cross over to 

dabrafenib after independent radiographic confirmation of initial progression. Baseline characteristics 

were balanced between treatment groups. Sixty percent of patients were male and 99.6% were 

Caucasian; the median age was 52 years with 21% of patients being ≥65 years, 98.4% had ECOG 

status of 0 or 1, and 97% of patients had metastatic disease. 

 

At the pre-specified analysis with a 19 December 2011 data cut, a significant improvement in the 

primary endpoint of PFS (HR=0.30; 95% Cl 0.18, 0.51; p < 0.0001) was achieved. Efficacy results 

from the primary analysis and a post-hoc analysis with 6-months additional follow up are summarised 

in Table 11. OS data from a further post-hoc analysis based on a 18 December 2012 data cut are 

shown in Figure 3. 

 

Table 11 Efficacy in previously untreated patients (BREAK-3 Study, 25 June 2012) 

  
Data as of 

December 19, 2011 

Data as of 

June 25, 2012  
Dabrafenib 

N=187 

DTIC 

N=63 

Dabrafenib 

N=187 

DTIC 

N=63 

Progression-free survival   

Median, months 

(95% CI)  

5.1 (4.9, 6.9) 2.7 (1.5, 3.2) 6.9 (5.2,9.0) 2.7 (1.5,3.2) 

HR (95% CI) 

 

0.30 (0.18, 0.51) 

P < 0.0001 

0.37 (0.24, 0.58) 

P < 0.0001 

Overall responsea   

% (95% CI) 53 (45.5, 60.3) 19 (10.2, 30.9) 59 (51.4, 66.0) 24 (14, 36.2) 

Duration of response  

Median, months 

(95% CI)  
N=99 

5.6 (4.8, NR) 

N=12 

NR (5.0, NR) 

N=110 

 8.0 (6.6, 11.5) 

N=15 

 7.6 (5.0, 9.7) 

Abbreviations: CI: confidence interval; DTIC: dacarbazine; HR: hazard ratio; NR: not reached 
a Defined as confirmed complete + partial response. 

 

As of 25 June 2012 cut-off, thirty five subjects (55.6%) of the 63 randomised to DTIC had crossed 

over to dabrafenib and 63% of subjects randomised to dabrafenib and 79% of subjects randomised to 

DTIC had progressed or died. Median PFS after cross-over was 4.4 months. 

 



29 

Table 12 Survival data from the primary analysis and post-hoc analyses 

 

Cut-off date Treatment Number of 

deaths (%) 

Hazard ratio (95% CI) 

December 19, 2011 DTIC 9 (14%) 0.61 (0.25, 1.48) (a) 
dabrafenib 21 (11%) 

June 25, 2012 DTIC 21 (33%) 
0.75 (0.44, 1.29) 

(a) 
dabrafenib 55 (29%)  

December 18, 2012 DTIC 28 (44%) 
0.76 (0.48, 1.21) 

(a) 
dabrafenib 78 (42%) 

(a) Patients were not censored at the time of cross-over 

 

OS data from a further post-hoc analysis based on the 18 December 2012 data cut demonstrated a 

12-month OS rate of 63% and 70% for DTIC and dabrafenib treatments, respectively. 

 

Figure 3 Kaplan-Meier curves of overall survival (BREAK-3) (18 December 2012) 

 

 

Patients with brain metastases (results from the Phase II study (BREAK-MB) 

BREAK-MB was a multicentre, open-label, two-cohort, Phase II study designed to evaluate the 

intracranial response of dabrafenib in subjects with histologically confirmed (Stage IV) 

BRAF-mutation positive (V600E or V600K) melanoma metastatic to the brain. Subjects were enrolled 

into Cohort A (subjects with no prior local therapy for brain metastasis) or Cohort B (subjects who 

received prior local therapy for brain metastasis). 

 

The primary endpoint of the study was overall intracranial response rate (OIRR) in the V600E patient 

population, as assessed by investigators. The confirmed OIRR and other efficacy results per 

investigator assessment are presented in Table 13. 

 



30 

Table 13 Efficacy data in patients with brain metastases (BREAK-MB Study) 

 

 All Treated Subjects Population 

 BRAF V600E (Primary) BRAF V600K  
Cohort A 

N=74 

Cohort B 

N=65 

Cohort A 

N=15 

Cohort B 

N=18 

Overall intracranial response rate,% (95% CI)a  

 39% (28.0, 51.2) 

P < 0.001b 

31% (19.9, 43.4) 

P < 0.001b 

7% (0.2, 31.9) 22% (6.4, 47.6) 

Duration of intracranial response, median, months (95% CI) 

 N=29 

4.6 (2.8, NR) 

N=20 

6.5 (4.6, 6.5) 

N=1 

2.9 (NR, NR) 

N=4 

3.8 (NR, NR) 

Overall response,% (95% CI)a 

 38% (26.8, 49.9) 31% (19.9, 43.4) 0 (0, 21.8) 28% (9.7, 53.5) 

Duration of response, median, months (95% CI) 

 N=28 

5.1 (3.7, NR) 

N=20 

4.6 (4.6, 6.5) 

NA N=5 

3.1 (2.8, NR) 

Progression-free survival, median, months (95% CI) 

 3.7 (3.6, 5.0) 3.8 (3.6, 5.5) 1.9 (0.7, 3.7) 3.6 (1.8, 5.2) 

Overall survival, median, months (95% CI) 

Median, months  7.6 (5.9, NR) 7.2 (5.9, NR) 3.7 (1.6, 5.2) 5.0 (3.5, NR) 

Abbreviations: CI: confidence interval; NR: not reached; NA: not applicable 

a Confirmed response. 

b This study was designed to support or reject the null hypothesis of OIRR ≤10% (based on 

historical results) in favour of the alternative hypothesis of OIRR ≥ 30% in BRAF V600E 

mutation positive subjects. 

 

Patients who were previously untreated or failed at least one prior systemic therapy (results from the 

Phase II [BREAK-2]) 

BRF113710 (BREAK-2) was a multicentre, single-arm study that enrolled 92 subjects with metastatic 

melanoma (Stage IV) with confirmed BRAF V600E or V600K mutation-positive melanoma. 

 

The investigator assessed confirmed response rate in patients with BRAF V600E metastatic melanoma 

(n=76) was 59% (95% CI: 48.2, 70.3) and the median DoR was 5.2 months (95% CI: 3.9, not 

calculable) based on a median follow-up time of 6.5 months. In patients with BRAF V600K mutation 

positive metastatic melanoma (n=16) the response rate was 13% (95% CI: 0.0, 28.7) with a median 

DoR of 5.3 months (95% CI: 3.7, 6.8). Although limited by the low number of patients, median OS 

appeared consistent with data in patients with BRAF V600E positive tumours. 

 
Adjuvant treatment of Stage III melanoma 

 

BRF115532 (COMBI-AD) 

The efficacy and safety of dabrafenib in combination with trametinib were studied in a Phase III, 

multicentre, randomised, double-blind, placebo-controlled study in patients with Stage III (Stage IIIA 

[lymph node metastasis >1 mm], IIIB, or IIIC) cutaneous melanoma with a BRAF V600 E/K 

mutation, following complete resection. 

 

Patients were randomised 1:1 to receive either combination therapy (dabrafenib 150 mg twice daily 

and trametinib 2 mg once daily) or two placebos for a period of 12 months. Enrollment required 

complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to 

randomisation. Any prior systemic anti-cancer treatment, including radiotherapy, was not allowed. 

Patients with a history of prior malignancy, if disease-free for at least 5 years, were eligible. Patients 

presenting with malignancies with confirmed activating RAS mutations were not eligible. Patients 

were stratified by BRAF mutation status (V600E versus V600K) and stage of disease prior to surgery 

using the American Joint Committee on Cancer (AJCC) 7th edition Melanoma Staging System (by 
Stage III sub-stage, indicating different levels of lymph node involvement and primary tumour size 



31 

and ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), defined 

as the time from randomisation to disease recurrence or death from any cause. Radiological tumour 

assessment was conducted every 3 months for the first two years and every 6 months thereafter, until 

first relapse was observed. Secondary endpoints include overall survival (OS; key secondary 

endpoint), freedom from relapse (FFR) and distant metastasis-free survival (DMFS). 

 

A total of 870 patients were randomised to the combination therapy (n=438) and placebo (n=432) 

arms. Most patients were Caucasian (99%) and male (55%), with a median age of 51 years (18% were 

≥65 years). The study included patients with all sub-stages of Stage III disease prior to resection; 18% 

of these patients had lymph node involvement only identifiable by microscope and no primary tumour 

ulceration. The majority of patients had a BRAF V600E mutation (91%). The median duration of 

follow-up (time from randomisation to last contact or death) was 2.83 years in the dabrafenib and 

trametinib combination arm and 2.75 years in the placebo arm. 

 

Results for the primary analysis of RFS are presented in Table 14. The study showed a statistically 

significant difference for the primary outcome of RFS between treatment arms, with a median RFS of 

16.6 months for the placebo arm and not yet reached for the combination arm (HR: 0.47; 95% 

confidence interval: (0.39, 0.58); p=1.53×10-14). The observed RFS benefit was consistently 

demonstrated across subgroups of patients including age, sex and race. Results were also consistent 

across stratification factors for disease stage and BRAF V600 mutation type. 

 
Table 14 Investigator-assessed RFS results for Study BRF115532 (COMBI-AD) 

 

 Dabrafenib + Trametinib Placebo 

RFS parameter N=438 N=432 

Number of events, n (%) 

Recurrence 

Relapsed with distant metastasis 

Death 

166 (38%) 

163 (37%) 

103 (24%) 

3 (<1%) 

248 (57%) 

247 (57%) 

133 (31%) 

1 (<1%) 

Median (months) 

(95% CI) 

NE 

(44.5, NE) 

16.6 

(12.7, 22.1) 

Hazard ratio[1] 

(95% CI) 

p-value[2] 

0.47 

(0.39, 0.58) 

1.53×10-14 

1-year rate (95% CI) 0.88 (0.85, 0.91) 0.56 (0.51, 0.61) 

2-year rate (95% CI) 0.67 (0.63, 0.72) 0.44 (0.40, 0.49) 

3-year rate (95% CI) 0.58 (0.54, 0.64) 0.39 (0.35, 0.44) 
[1] Hazard ratio is obtained from the stratified Pike model. 
[2] P-value is obtained from the two-sided stratified logrank test (stratification factors were disease 

stage – IIIA vs. IIIB vs. IIIC – and BRAF V600 mutation type – V600E vs. V600K) 

NE = not estimable 

 
  



32 

N       Events      Median, months (95% CI) 

438     177             NA (46.9, NA) 

432     254             16.6 (12.7, 22.1) 

HR for recurrence = 0.49 

95% CI (0.40, 0.59) 

Based on updated data with an additional 10 months of follow-up compared to the primary analysis 

(minimum follow-up of 40 months), the RFS benefit was maintained with an estimated HR of 0.49 

[95% CI: (0.40, 0.59)] (Figure 4). 

 

Figure 4 Kaplan-Meier RFS curves for Study BRF115532 (ITT population, updated results) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                      0      4       8      12     16     20     24     28    32     36     40     44    48     52     56    60    64 

 
Time from randomisation (months) 

Subjects at Risk 

Dabrafenib         438      405 
+ Trametinib  

381 354 324 281 262      249 236  227  183      148   92  47 13  2 0 

Placebo              432      322 263 219 198 178 168     164 157  147    128      107   63  27 4  1 0 

 

Based on 153 events (60 [14%] in the combination arm and 93 [22%] in the placebo arm) 

corresponding to a 26% information fraction of the total target of 597 OS events, the estimated hazard 

ratio for OS was 0.57 (95% CI: 0.42, 0.79; p=0.0006). These results did not meet the pre-specified 

boundary to claim statistical significance at this first OS interim analysis (HR=0.50; p=0.000019). 

Survival estimates at 1 and 2 years from randomisation were 97% and 91% in the combination arm 

and 94% and 83% in the placebo arm, respectively). 

 

  

0 

0.1 

0.2 

0.3 

0.4 

0.5 

0.7 

0.8 

0.9 

1.0 

P
ro

p
o

rt
io

n
 a

li
v

e 
an

d
 r

el
ap

se
 f

re
e
 

Group 

Dabrafenib + trametinib 

Placebo 

0.6 



33 

Non-small cell lung cancer 

Study BRF113928 
The efficacy and safety of dabrafenib in combination with trametinib was studied in a Phase II, 

three-cohort, multicentre, non-randomised and open-label study in which patients with stage IV BRAF 

V600E mutant NSCLC were enrolled. The primary endpoint was ORR using the RECIST 1.1 assessed 

by the investigator. Secondary endpoints included DoR, PFS, OS, safety and population 

pharmacokinetics. ORR, DoR and PFS were also assessed by an Independent Review Committee 

(IRC) as a sensitivity analysis. 

 

Cohorts were enrolled sequentially: 

 Cohort A: Monotherapy (dabrafenib 150 mg twice daily), 84 patients enrolled. 78 patients had 
previous systemic treatment for their metastatic disease. 

 Cohort B: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once 
daily), 59 patients enrolled. 57 patients had 1-3 lines of previous systemic treatment for their 

metastatic disease. 2 patients had no previous systemic treatment and were included in the 

analysis for patients enrolled in Cohort C. 

 Cohort C: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once 
daily), 34 patients. All patients received study medicinal product as first-line treatment for 

metastatic disease. 

 

Among the total of 93 patients who were enrolled in the combination therapy cohorts B and C, most 

patients were Caucasian (>90%), and similar female versus male (54% versus 46%), with a median 

age of 64 years in second line or higher patients and 68 years in the first line patients. Most patients 

(94%) enrolled in the combination therapy treated cohorts had an ECOG performance status of 0 or 1. 

26 (28%) had never smoked. The majority of patients had a non-squamous histology. In the previously 

treated population, 38 patients (67%) had one line of systemic anti-cancer therapy for metastatic 

disease. 

 

For the primary endpoint of investigator-assessed ORR, the ORR in the first line population was 

61.1% (95% CI, 43.5%, 76.9%) and in the previously treated population was 66.7% (95% CI, 52.9%, 

78.6%). These met the statistical significance to reject the null hypothesis that the ORR of dabrafenib 

in combination with trametinib for this NSCLC population was less than or equal to 30%. The ORR 

results assessed by IRC were consistent with the investigator assessment. The response was durable 

with median DoR in the previously treated population reaching 9.8 months (95% CI, 6.9, 16.0) by 

investigator assessment. In the first line population, 68% of patients had not progressed after 9 months. 

The median DoR and PFS were not yet estimable (Table 15). The efficacy of the combination with 

trametinib was superior when indirectly compared to dabrafenib monotherapy in Cohort A. 

 



34 

Table 15 Summary of efficacy in the combination treatment cohorts based on investigator and 

independent radiology review 

 

Endpoint Analysis Combination 1st line 

N=361 

Combination 2nd line plus 

N=571 

Overall confirmed 

response n (%) 

(95% CI) 

By Investigator 

 

By IRC 

22 (61.1%) 

(43.5, 76.9) 

22 (61.1%) 

(43.5, 76.9) 

38 (66.7%) 

(52.9, 78.6) 

36 (63.2%) 

(49.3, 75.6) 

Median DoR 

Months (95% CI) 

By Investigator 

By IRC 

NE2 (8.3, NE) 

NE (6.9, NE) 

9.8 (6.9, 16.0) 

12.6 (5.8, NE) 

Median PFS 

Months (95% CI) 

By Investigator 

By IRC 

-3 

-3 

10.2 (6.9, 16.7) 

8.6 (5.2, 16.8) 

Median OS 

Months (95% CI) 

- 24.6 (11.7, NE)4 18.2 (14.3, NE) 

1 Data cut-off: 8th August 2016 
2 NE: Not Evaluable 
3 Median PFS currently not estimable 
4 Event rate for OS calculation was 28% and hence the defined median value still needs to mature 

 

QT prolongation 

 

Worst-case QTc prolongation of >60 millisecond (msec) was observed in 3% of dabrafenib-treated 

subjects (one >500 msec in the integrated safety population). In the Phase III study MEK115306 no 

patients treated with trametinib in combination with dabrafenib had worst-case QTcB prolongation to 

>500 msec; QTcB was increased more than 60 msec from baseline in 1% (3/209) of patients. In the 

Phase III study MEK116513 four patients (1%) treated with trametinib in combination with dabrafenib 

had a QTcB Grade 3 increase (>500 msec). Two of these patients had a QTcB Grade 3 increase 

(>500 msec) that was also an increase >60 msec from baseline. 

 

The potential effect of dabrafenib on QT prolongation was assessed in a dedicated multiple dose QT 

study. A supratherapeutic dose of 300 mg dabrafenib twice daily was administered in 32 subjects with 

BRAF V600 mutation-positive tumours. No clinically relevant effect of dabrafenib or its metabolites 

on the QTc interval was observed. 
 

Paediatric population 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

dabrafenib in one or more subsets of the paediatric population in melanoma and solid malignant 

tumours (see section 4.2 for information on paediatric use). 

 

  



35 

5.2 Pharmacokinetic properties 
 

Absorption 

 

Dabrafenib is absorbed orally with median time to achieve peak plasma concentration of 2 hours 

post-dose. Mean absolute bioavailability of oral dabrafenib is 95% (90% CI: 81, 110%). Dabrafenib 

exposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following 

single-dose administration, but the increase was less than dose-proportional after repeat twice daily 

dosing. A decrease in exposure was observed with repeat dosing, likely due to induction of its own 

metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of 

150 mg twice daily, geometric mean Cmax, AUC(0-) and predose concentration (C) were 1478 ng/ml, 

4341 ng*hr/ml and 26 ng/ml, respectively. 

 

Administration of dabrafenib with food reduced the bioavailability (Cmax and AUC decreased by 51% 

and 31% respectively) and delayed absorption of dabrafenib capsules when compared to the fasted 

state. 

 

Distribution 

 

Dabrafenib binds to human plasma protein and is 99.7% bound. The steady-state volume of 

distribution following intravenous microdose administration is 46 L. 

 

Biotransformation 

 

The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form 

hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib. 

Carboxy-dabrafenib can be decarboxylated via a non-enzymatic process to form 

desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may 

also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to 

oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 

10 hrs while the carboxy- and desmethyl-metabolites exhibited longer half-lives (21-22 hours). Mean 

metabolite to parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for 

hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and 

pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the 

clinical activity of dabrafenib while the activity of carboxy-dabrafenib is not likely to be significant. 

 

In vitro evaluation of drug-drug interaction potential 

 

Dabrafenib is a substrate of human P-glycoprotein (Pgp) and human BCRP in vitro. However, these 

transporters have minimal impact on dabrafenib oral bioavailability and elimination and the risk for 

clinically relevant drug-drug interactions with inhibitors of Pgp or BCRP is low. Neither dabrafenib 

nor its 3 main metabolites were demonstrated to be inhibitors of Pgp in vitro. 

 

Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and 

desmethyl-dabrafenib, were inhibitors of human organic anion transporter (OAT) 1 and OAT3 

in vitro, and dabrafenib and its desmethyl metabolite were found to be inhibitors of organic cation 

transporter 2 (OCT2) in vitro, the risk of a drug-drug interaction at these transporters is minimal based 

on clinical exposure of dabrafenib and its metabolites. 

 

  



36 

Elimination 

 

Terminal half-life of dabrafenib following an intravenous single microdose is 2.6 hours. Dabrafenib 

terminal half-life after a single oral dose is 8 hours due to absorption-limited elimination after oral 

administration (flip-flop pharmacokinetics). IV plasma clearance is 12 l/hr. 

 

After an oral dose, the major route of elimination of dabrafenib is metabolism, mediated via CYP3A4 

and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71% of an oral dose 

recovered in faeces; 23% of the dose was recovered in urine in the form of metabolites only. 

 

Special patient populations 

 

Hepatic impairment 

A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels 

(based on National Cancer Institute [NCI] classification) do not significantly affect dabrafenib oral 

clearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have a 

significant effect on dabrafenib metabolite plasma concentrations. No data are available in patients 

with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are the 

primary routes of elimination of dabrafenib and its metabolites, administration of dabrafenib should be 

undertaken with caution in patients with moderate to severe hepatic impairment (see section 4.2). 

 

Renal impairment 

A population pharmacokinetic analysis suggests that mild renal impairment does not affect oral 

clearance of dabrafenib. Although data in moderate renal impairment are limited these data may 

indicate no clinically relevant effect. No data are available in subjects with severe renal impairment 

(see section 4.2). 

 

Elderly 

Based on the population pharmacokinetic analysis, age had no significant effect on dabrafenib 

pharmacokinetics. Age greater than 75 years was a significant predictor of carboxy- and 

desmethyl-dabrafenib plasma concentrations with a 40% greater exposure in subjects ≥75 years of age, 

relative to subjects <75 years old. 

 

Body weight and gender 

Based on the population pharmacokinetic analysis, gender and weight were found to influence 

dabrafenib oral clearance; weight also impacted oral volume of distribution and distributional 

clearance. These pharmacokinetic differences were not considered clinically relevant. 

 

Race 

The population pharmacokinetic analysis showed no significant differences in the pharmacokinetics of 

dabrafenib between Asian and Caucasian patients. There are insufficient data to evaluate the potential 

effect of other races on dabrafenib pharmacokinetics. 

 

Paediatric population 

No studies have been conducted to investigate the pharmacokinetics of dabrafenib in paediatric 

patients. 

 

  



37 

5.3 Preclinical safety data 
 

Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib was not mutagenic or 

clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent 

micronucleus assay. 

 

In combined female fertility, early embryonic and embryo-foetal development studies in rats numbers 

of ovarian corpora lutea were reduced in pregnant females at 300 mg/kg/day (approximately 3 times 

human clinical exposure based on AUC), but there were no effects on oestrous cycle, mating or 

fertility indices. Developmental toxicity including embryo-lethality and ventricular septal defects and 

variation in thymic shape were seen at 300 mg/kg/day, and delayed skeletal development and reduced 

foetal body weight at ≥20 mg/kg/day (≥0.5 times human clinical exposure based on AUC). 

 

Male fertility studies with dabrafenib have not been conducted. However, in repeat dose studies, 

testicular degeneration/depletion was seen in rats and dogs (≥0.2 times the human clinical exposure 

based on AUC). Testicular changes in rat and dog were still present following a 4-week recovery 

period (see section 4.6). 

 

Cardiovascular effects, including coronary arterial degeneration/necrosis and/or haemorrhage, cardiac 

atrioventricular valve hypertrophy/haemorrhage and atrial fibrovascular proliferation were seen in 

dogs (≥2 times clinical exposure based on AUC). Focal arterial/perivascular inflammation in various 

tissues was observed in mice and an increased incidence of hepatic arterial degeneration and 

spontaneous cardiomyocyte degeneration with inflammation (spontaneous cardiomyopathy) was 

observed in rats (≥0.5 and 0.6 times clinical exposure for rats and mice respectively). Hepatic effects, 

including hepatocellular necrosis and inflammation, were observed in mice (≥0.6 times clinical 

exposure). Bronchoalveolar inflammation of the lungs was observed in several dogs at ≥20 mg/kg/day 

(≥9 times human clinical exposure based on AUC) and was associated with shallow and/or laboured 

breathing. 

 

Reversible haematological effects have been observed in dogs and rats given dabrafenib. In studies of 

up to 13 weeks, decreases in reticulocyte counts and/or red cell mass were observed in dogs and rats 

(≥10 and 1.4 times clinical exposure, respectively). 

 

In juvenile toxicity studies in rats, effects on growth (shorter long bone length), renal toxicity (tubular 

deposits, increased incidence of cortical cysts and tubular basophilia and reversible increases in urea 

and/or creatinine concentrations) and testicular toxicity (degeneration and tubular dilation) were 

observed (≥0.2 times adult human clinical exposure based on AUC). 

 

Dabrafenib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay and 

in vivo at doses ≥100 mg/kg (>44 times clinical exposure based on Cmax) in an oral phototoxicity study 

in hairless mice. 

 

Combination with trametinib 

 

In a study in dogs in which trametinib and dabrafenib were given in combination for 4 weeks, signs of 

gastrointestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lower 

exposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as in 

comparable monotherapy studies. 

 

 



38 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Capsule content 

 

Microcrystalline cellulose 

Magnesium stearate 

Colloidal silicone dioxide 

 

Capsule shell 

 

Red iron oxide (E172) 

Titanium dioxide (E171) 

Hypromellose (E464) 

 

Printing ink 

 

Black iron oxide (E172) 

Shellac 

Propylene glycol 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 

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. 

 

6.6 Special precautions for disposal 
 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 



39 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Tafinlar 50 mg hard capsules 

 

EU/1/13/865/001 

EU/1/13/865/002 

 

Tafinlar 75 mg hard capsules 

 

EU/1/13/865/003 

EU/1/13/865/004 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 26 August 2013 

Date of latest renewal: 08 May 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

  



40 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



41 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

 

GLAXO WELLCOME, S.A. 

Avda. Extremadura, 3, Pol. Ind. Allendeduero 

09400, Aranda de Duero (Burgos) 

Spain 

 

Novartis Pharmaceuticals UK Limited 

Frimley Business Park 

Frimley 

Camberley, Surrey GU16 7SR 

United Kingdom 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

  



42 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



43 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

  



44 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tafinlar 50 mg hard capsules 

dabrafenib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains dabrafenib mesilate equivalent to 50 mg dabrafenib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

28 capsules 

120 capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Contains desiccant, do not remove or eat. 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



45 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/865/001  28 capsules 

EU/1/13/865/002  120 capsules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

tafinlar 50 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



46 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tafinlar 50 mg capsules 

dabrafenib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains dabrafenib mesilate equivalent to 50 mg dabrafenib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

28 capsules 

120 capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



47 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/865/001  28 capsules 

EU/1/13/865/002  120 capsules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

  



48 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tafinlar 75 mg hard capsules 

dabrafenib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains dabrafenib mesilate equivalent to 75 mg dabrafenib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

28 capsules 

120 capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Contains desiccant, do not remove or eat. 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



49 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/865/003  28 capsules 

EU/1/13/865/004  120 capsules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

tafinlar 75 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



50 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Tafinlar 75 mg capsules 

dabrafenib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains dabrafenib mesilate equivalent to 75 mg dabrafenib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

28 capsules 

120 capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



51 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/865/003  28 capsules 

EU/1/13/865/004  120 capsules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

  



52 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



53 

Package leaflet: Information for the patient 
 

Tafinlar 50 mg hard capsules 

Tafinlar 75 mg hard capsules 
dabrafenib 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
 

1. What Tafinlar is and what it is used for 

2. What you need to know before you take Tafinlar 

3. How to take Tafinlar 

4. Possible side effects 

5. How to store Tafinlar 

6. Contents of the pack and other information 

 

 

1. What Tafinlar is and what it is used for 

 

Tafinlar is a medicine that contains the active substance dabrafenib. It is used either on its own or in 

combination with another medicine containing trametinib in adults to treat a type of skin cancer called 

melanoma that has spread to other parts of the body, or cannot be removed by surgery. 

 

Tafinlar in combination with trametinib is also used to prevent melanoma from coming back after it 

has been removed by surgery. 

 

Tafinlar in combination with trametinib is also used to treat a type of lung cancer called non-small cell 

lung cancer (NSCLC). 

 

Both cancers have a particular change (mutation) in a gene called BRAF at the V600 position. This 

mutation in the gene may have caused the cancer to develop. Your medicine targets proteins made 

from this mutated gene and slows down or stops the development of your cancer. 

 

 

2. What you need to know before you take Tafinlar 

 

Tafinlar should only be used to treat melanomas and NSCLC with the BRAF mutation. Therefore 

before starting treatment your doctor will test for this mutation. 

 

If your doctor decides that you will receive treatment with the combination of Tafinlar and trametinib, 

read the trametinib leaflet carefully as well as this leaflet. 
 

If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist. 

 

Do not take Tafinlar: 

 if you are allergic to dabrafenib or any of the other ingredients of this medicine (listed in 
section 6). 

Check with your doctor if you think this applies to you. 

 



54 

Warnings and precautions 

Talk to your doctor, before taking Tafinlar. Your doctor needs to know if you: 

 have any liver problems. 

 have or have ever had any kidney problems. 
Your doctor may take blood samples to monitor your liver and kidney function while you are 

taking Tafinlar. 

 have had a different type of cancer other than melanoma or NSCLC, as you may be at 
greater risk of developing other skin and non-skin cancers when taking Tafinlar. 

 

Before you take Tafinlar in combination with trametinib your doctor also needs to know if you: 

 have heart problems such as heart failure or problems with the way your heart beats. 

 have eye problems including blockage of the vein draining the eye (retinal vein occlusion) or 
swelling in the eye which may be caused by fluid leakage (chorioretinopathy). 

 have any lung or breathing problems, including difficulty in breathing often accompanied by a 
dry cough, shortness of breath and fatigue. 

 have or have had any gastrointestinal problems such as diverticulitis (inflamed pouches in the 
colon) or metastases to the gastrointestinal tract. 

 

Check with your doctor if you think any of these may apply to you. 

 

Conditions you may need to look out for 

Some people taking Tafinlar develop other conditions, which can be serious. You need to know about 

important signs and symptoms to look out for while you’re taking this medicine. Some of these 

symptoms (bleeding, fever, changes to your skin and eye problems) are briefly mentioned in this 

section, but more detailed information is found in section 4, “Possible side effects”. 

 

Bleeding 

Taking Tafinlar in combination with trametinib can cause serious bleeding including in your brain, the 

digestive system (such as stomach, rectum or intestine), lungs, and other organs, and can lead to death. 

Symptoms may include: 

 headaches, dizziness, or feeling weak 

 passing blood in the stools or passing black stools 

 passing blood in the urine 

 stomach pain 

 coughing / vomiting up blood 
 

Tell your doctor as soon as possible if you get any of these symptoms. 

 

Fever 

Taking Tafinlar or the combination of Tafinlar and trametinib may cause fever, although it is more 

likely if you are taking the combination treatment (see also section 4). In some cases, people with 

fever may develop low blood pressure, dizziness or other symptoms. 

 

Tell your doctor immediately if you get a temperature above 38.5ºC while you are taking this 

medicine. 

 

Heart disorder 

Tafinlar can cause heart problems, or make existing heart problems worse (see also “Heart conditions” 

in section 4), in people taking Tafinlar in combination with trametinib. 

 

Tell your doctor if you have a heart disorder. Your doctor will run tests to check that your heart is 

working properly before and during your treatment with Tafinlar in combination with trametinib. Tell 

your doctor immediately if it feels like your heart is pounding, racing, or beating irregularly, or if you 

experience dizziness, tiredness, light-headedness, shortness of breath or swelling in the legs. If 

necessary, your doctor may decide to interrupt your treatment or to stop it altogether. 

 



55 

Changes in your skin which may indicate new skin cancer 
Your doctor will check your skin before you start taking this medicine and regularly while you are 

taking it. Tell your doctor immediately if you notice any changes to your skin while taking this 

medicine or after treatment (see also section 4). 

 

Eye problems 

You should have your eyes examined by your doctor while you are taking this medicine. 

Tell your doctor immediately if you get eye redness and irritation, blurred vision, eye pain or other 

vision changes during your treatment (see also section 4). 

Tafinlar when given in combination with trametinib can cause eye problems including blindness. 

Trametinib is not recommended if you have ever had blockage of the vein draining the eye (retinal 

vein occlusion). Tell your doctor immediately if you get the following symptoms of eye problems: 

blurred vision, loss of vision or other vision changes, coloured dots in your vision or halos (seeing 

blurred outline around objects) during your treatment. If necessary, your doctor may decide to 

interrupt your treatment or to stop it altogether. 

 

 Read the information about fever, changes in your skin and eye problems in section 4 of 
this leaflet. Tell your doctor, pharmacist or nurse if you get any of the signs and symptoms 

listed. 

 

Liver problems 
Tafinlar in combination with trametinib can cause problems with your liver which may develop into 

serious conditions such as hepatitis and liver failure, which may be fatal. Your doctor will monitor you 

periodically. Signs that your liver may not be working properly may include: 

- loss of appetite 
- feeling sick (nausea) 
- being sick (vomiting) 
- pain in your stomach (abdomen) 
- yellowing of your skin or the whites of your eyes (jaundice) 
- dark-coloured urine 
- itching of your skin 
 

Tell your doctor as soon as possible if you get any of these symptoms 

 

Muscle pain 

Tafinlar in combination with trametinib can result in the breakdown of muscle (rhabdomyolysis). Tell 

your doctor as soon as possible if you get any of these symptoms. 

 muscle pain 

 dark urine due to kidney damage 
 

If necessary, your doctor may decide to interrupt your treatment or to stop it altogether. 

 

Hole in the stomach or intestine (perforation) 
Taking the combination of Tafinlar and trametinib may increase the risk of developing holes in the gut 

wall. Tell your doctor as soon as possible if you have severe abdominal pain. 

 

Serious skin reactions 

Serious skin reactions have been reported in people taking Tafinlar in combination with trametinib. 

Tell your doctor immediately if you notice any changes to your skin (see section 4 for symptoms to be 

aware of). 

 

Children and adolescents 

Tafinlar is not recommended for children and adolescents. The effects of Tafinlar in people younger 

than 18 years old are not known. 

 



56 

Other medicines and Tafinlar 
Before starting treatment, tell your doctor, pharmacist or nurse if you are taking, have recently taken 

or might take any other medicines. This includes medicines obtained without a prescription. 

 

Some medicines may affect how Tafinlar works, or make it more likely that you will have side effects. 

Tafinlar can also affect how some other medicines work. These include: 

 birth control medicines (contraceptives) containing hormones, such as pills, injections, or 
patches 

 warfarin and acenocoumarol, medicines used to thin the blood 

 digoxin, used to treat heart conditions 

 medicines to treat fungal infections, such as ketoconazole, itraconazole, voriconazole and 
posaconazole 

 some calcium channel blockers, used to treat high blood pressure, such as diltiazem, 
felodipine, nicardipine, nifedipine or verapamil 

 medicines to treat cancer, such as cabazitaxel 

 some medicines to lower fat (lipids) in the blood stream, such as gemfibrozil 

 some medicines used to treat certain psychiatric conditions, such as haloperidol 

 some antibiotics, such as clarithromycin, doxycyline and telithromycin 

 some medicines for tuberculosis (TB), such as rifampicin 

 some medicines that reduce cholesterol levels, such as atorvastatin and simvastatin 

 some immunosuppressants, such as cyclosporin, tacrolimus and sirolimus 

 some anti-inflammatory medicines, such as dexamethasone and methylprednisolone 

 some medicines to treat HIV, such as ritonavir, amprenavir, indinavir, darunavir, delavirdine, 
efavirenz, fosamprenavir, lopinavir, nelfinavir, tipranavir, saquinavir and atazanavir 

 some medicines used for pain relief, such as fentanyl and methadone 

 medicines to treat seizures (epilepsy), such as phenytoin, phenobarbital, primidone, valproic 
acid or carbamazepine 

 antidepressant medicines such as nefazodone and the herbal medicine St John’s wort 
(Hypericum perforatum) 

 

 Tell your doctor, pharmacist or nurse if you are taking any of these (or if you are not sure). 
Your doctor may decide to adjust your dose. 

 

Keep a list of the medicines you take, so you can show it to your doctor, pharmacist or nurse. 

 

Pregnancy, breast-feeding and fertility 

Tafinlar is not recommended during pregnancy. 

 If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, 
pharmacist or nurse for advice before taking this medicine. Tafinlar is not recommended during 

pregnancy, since it may potentially harm an unborn baby. 

 If you are a woman who could become pregnant you must use a reliable birth control method 
while you are taking Tafinlar and for at least 2 weeks after you stop taking it and for at least 

16 weeks following the last dose of trametinib when given in combination with Tafinlar. 

 Birth control medicines containing hormones (such as pills, injections or patches) may not work 
as well while you are taking Tafinlar or combination treatment (Tafinlar as well as trametinib). 

You need to use another effective method of birth control so you do not become pregnant while 

you are taking this medicine. Ask your doctor, pharmacist or nurse for advice. 

 If you do become pregnant while you are taking this medicine, tell your doctor immediately. 
 

Tafinlar is not recommended while breast-feeding. 

It is not known whether the ingredients of this medicine can pass into breast milk. 

If you are breast-feeding, or planning to breast-feed, you must tell your doctor. You and your doctor 

will decide if you will take this medicine or breast-feed. 

 



57 

Fertility – both men and women 

Animal studies have shown that the active substance dabrafenib may permanently reduce male 

fertility. In addition, men who are taking Tafinlar may have a reduced sperm count and their sperm 

count may not return to normal levels after they stop taking this medicine. 

 

Prior to starting treatment with Tafinlar, talk to your doctor about options to improve your chances to 

have children in the future. 

 

Taking Tafinlar with trametinib: trametinib may impair fertility in both men and women. 

 

If you have any further questions on the effect of this medicine on sperm count, ask your doctor, 

pharmacist or nurse. 

 

Driving and using machines 

Tafinlar can have side effects that may affect your ability to drive or use machines. 

Avoid driving or using machines if you have problems with your vision or if you feel tired or weak, or 

if your energy levels are low. 

Descriptions of these effects can be found in sections 2 and 4. 

Discuss with your doctor, pharmacist or nurse if you are unsure about anything. Even your disease, 

symptoms and treatment situation may affect your ability to drive or use machines. 

 

 

3. How to take Tafinlar 

 

Always take Tafinlar exactly as your doctor, pharmacist or nurse has told you to. Check with your 

doctor, pharmacist or nurse if you are not sure. 

 

How much to take 

The usual dose of Tafinlar either used alone or in combination with trametinib is two 75 mg capsules 

twice a day (corresponding to a daily dose of 300 mg). The recommended dose of trametinib, when 

used in combination with Tafinlar, is 2 mg once a day. 

 

Your doctor may decide that you should take a lower dose if you get side effects. 

 

Tafinlar are also available as 50 mg capsules if a dose reduction is recommended. 

 

Don’t take more Tafinlar than your doctor has recommended, since this may increase the risk of 

side effects. 

 

How to take it 

Swallow the capsules whole with water, one after the other. 

 

Don’t chew or crush the capsules, since they will otherwise lose their effect. 

 

Take Tafinlar twice a day, on an empty stomach. This means that 

 after taking Tafinlar, you must wait at least 1 hour before eating, or 

 after eating, you must wait at least 2 hours before taking Tafinlar. 
 

Take Tafinlar in the morning and evening, about 12 hours apart. Take your morning and evening doses 

of Tafinlar at the same times every day. This will increase the chance of remembering to take the 

capsules. 

 

Don’t take the morning and evening doses of Tafinlar at the same time. 

 

If you take more Tafinlar than you should 

If you take too many capsules of Tafinlar, contact your doctor, pharmacist or nurse for advice. If 

possible, show them the Tafinlar pack with this leaflet. 



58 

 

If you forget to take Tafinlar 

If the missed dose is less than 6 hours late, take it as soon as you remember. 

If the missed dose is more than 6 hours late, skip that dose and take your next dose at the usual time. 

Then carry on taking your capsules at regular times as usual. 

Do not take a double dose to make up for a missed dose. 

 

If you stop taking Tafinlar 

Take Tafinlar for as long as your doctor recommends. Do not stop unless your doctor, pharmacist or 

nurse advises you to. 

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

How should you take Tafinlar in combination with trametinib 

 Take Tafinlar in combination with trametinib exactly as your doctor, nurse or pharmacist tells 
you. Do not change your dose or stop Tafinlar or trametinib unless your doctor, nurse or 

pharmacist tells you to. 

 Take Tafinlar twice daily and take trametinib once daily. It may be good for you to get into 
the habit of taking both medicines at the same times each day. The Tafinlar doses should be 

about 12 hours apart. Trametinib when given in combination with Tafinlar should be taken with 

either the morning dose of Tafinlar or the evening dose of Tafinlar. 

 Take Tafinlar and trametinib on an empty stomach, at least one hour before or two hours after a 
meal. Take whole with a full glass of water. 

 If you miss a dose of Tafinlar or trametinib, take it as soon as you remember. Do not make up 
for missed doses and just take your next dose at your regular time: 

o If it is less than 6 hours to your next scheduled dose of Tafinlar, which is taken twice 
daily. 

o If it is less than 12 hours to your next scheduled dose of trametinib, which is taken once 
daily. 

 If you take too much Tafinlar or trametinib, immediately contact your doctor, nurse or 
pharmacist. Take Tafinlar capsules and trametinib tablets with you when possible. If possible, 

show them the Tafinlar and trametinib pack with each leaflet. 

 If you get side effects your doctor may decide that you should take lower doses of Tafinlar and / 
or trametinib. Take the doses of Tafinlar and trametinib exactly as your doctor, nurse or 

pharmacist tells you. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Possible side effects in patients taking Tafinlar alone 

 

Possible serious side effects 

Bleeding problems 

Tafinlar can cause serious bleeding problems, especially in your brain when taken in combination with 

trametinib. Call your doctor or nurse and get medical help right away if you have any unusual signs of 

bleeding, including: 

 headaches, dizziness, or weakness 

 coughing up of blood or blood clots 

 vomit containing blood or that looks like “coffee grounds” 

 red or black stools that look like tar 
 



59 

Fever 

Taking Tafinlar may cause fever in more than 1 in 10 people. Tell your doctor, pharmacist or nurse 

immediately if you get a fever (temperature 38.5ºC or above) while you are taking this medicine. 

They will carry out tests to find out if there are other causes for the fever and treat the problem. 

 

In some cases, people with fever may develop low blood pressure and dizziness. If the fever is severe, 

your doctor may recommend that you stop taking Tafinlar while they treat the fever with other 

medicines. Once the fever is controlled, your doctor may recommend that you start taking Tafinlar 

again. 

 

Heart conditions 

Tafinlar can affect how well your heart pumps blood when taken in combination with trametinib. It is 

more likely to affect people who have an existing heart problem. You will be checked for any heart 

problems while you are taking Tafinlar in combination with trametinib. Signs and symptoms of heart 

problems include: 

 feeling like your heart is pounding, racing, or beating irregularly 

 dizziness 

 tiredness 

 feeling lightheaded 

 shortness of breath 

 swelling in the legs 
 

Tell your doctor as soon as possible if you get any of these symptoms, either for the first time or if 

they get worse. 

 

Changes in your skin 

Serious skin reactions have been reported in people taking Tafinlar in combination with trametinib 

(frequency not known). If you notice any of the following: 

 reddish patches on the trunk that are circular or target-shaped, with central blisters. Skin 
peeling. Ulcers of mouth, throat, nose, genitals and eyes. These serious skin rashes can be 

preceded by fever and flu-like symptoms (Stevens-Johnson syndrome). 

 widespread rash, fever, and enlarged lymph nodes (DRESS-syndrome or drug hypersensitivity 
syndrome). 

 stop using the medicine and seek medical attention immediately. 
 

Patients taking Tafinlar may commonly (may affect up to 1 in 10 people) develop a different type of 

skin cancer called cutaneous squamous cell carcinoma (cuSCC). Others may develop a type of skin 

cancer called basal cell carcinoma (BCC). Usually, these skin changes remain local and can be 

removed with surgery and treatment with Tafinlar can be continued without interruption. 

 

Some people taking Tafinlar may also notice that new melanomas have appeared. These melanomas 

are usually removed by surgery and treatment with Tafinlar can be continued without interruption. 

 

Your doctor will check your skin before you start taking Tafinlar, then check it again every month 

while you are taking this medicine and for 6 months after you stop taking it. This is to look for any 

new skin cancers. 

 

Your doctor will also check your head, your neck, your mouth, your lymph glands and you will have 

scans of your chest and stomach area (called CT scans) regularly. You may also have blood tests. 

These checks are to detect if any other cancer, including squamous cell carcinoma, develops inside 

your body. Pelvic examinations (for women) and anal examinations are also recommended before and 

at the end of your treatment. 

 

  



60 

Check your skin regularly whilst taking Tafinlar 

If you notice any of the following: 

 new wart 

 skin sore or reddish bump that bleeds or does not heal 

 change of a mole in size or colour 

 Tell your doctor, pharmacist or nurse as soon as possible if you get any of these 
symptoms - either for the first time or if they get worse. 

 

Skin reactions (rash) can happen while taking Tafinlar in combination with trametinib. Talk to your 

doctor if you get a skin rash while taking Tafinlar in combination with trametinib. 

 

Eye problems 

Patients taking Tafinlar alone can uncommonly (may affect up to 1 in 100 people) develop an eye 

problem called uveitis, which could damage your vision if it is not treated. This may occur commonly 

(may affect up to 1 in 10 people) in patients taking Tafinlar in combination with trametinib. 

 

Uveitis may develop rapidly and the symptoms include: 

 eye redness and irritation 

 blurred vision 

 eye pain 

 increased sensitivity to light 

 floating spots before the eyes 

 Contact your doctor, pharmacist or nurse immediately if you get these symptoms. 
 

Tafinlar can cause eye problems when taken in combination with trametinib. Trametinib is not 

recommended if you have ever had a blockage of the vein draining the eye (retinal vein occlusion). 

Your doctor may advise an eye examination before you take Tafinlar in combination with trametinib 

and while you are taking it. Your doctor may ask you to stop taking trametinib or refer you to a 

specialist, if you develop signs and symptoms in your vision that include: 

 loss of vision 

 eye redness and irritation 

 coloured dots in your vision 

 halo (seeing a blurred outline around objects) 

 blurred vision 

 Contact your doctor, pharmacist or nurse immediately if you get these symptoms. 
 

It is very important to tell your doctor, pharmacist or nurse immediately if you develop these 

symptoms, especially if you have a painful, red eye that does not clear up quickly. They may arrange 

for you to see a specialist eye doctor for a complete eye examination. 

 

  

http://www.medicinenet.com/script/main/art.asp?articlekey=99346
http://www.medicinenet.com/script/main/art.asp?articlekey=26384


61 

The other side effects that you may see when you take Tafinlar alone are as follows: 

 

Very common side effects (may affect more than 1 in 10 people) 

 Papilloma (a type of skin tumour which is usually not harmful) 

 Decreased appetite 

 Headache 

 Cough 

 Feeling sick (nausea), being sick (vomiting) 

 Diarrhoea 

 Thickening of the outer layers of the skin 

 Unusual hair loss or thinning 

 Rash 

 Reddening and swelling of the palms, fingers and soles of the feet (see “Changes in your skin” 
earlier in section 4) 

 Joint pain, muscle pain, or pain in the hands or feet 

 Fever (see “Fever” earlier in section 4) 

 Lack of energy 

 Chills 

 Feeling weak 
 

Common side effects (may affect up to 1 in 10 people) 

 Skin effects including cutaneous squamous cell carcinoma (a type of skin cancer), wart-like 
growths, skin tags, uncontrolled skin growths or lesions (basal cell carcinoma), dry skin, itching 

or redness of skin, patches of thick, scaly, or crusty skin (actinic keratosis), skin lesions, skin 

reddening, increased sensitivity of the skin to sun 

 Constipation 

 Flu-like illness 
 

Common side effects that may show up in your blood tests 

 Low levels of phosphate (hypophosphataemia) in the blood 

 Increase in blood sugar level (hyperglycaemia) 
 

Uncommon side effects (may affect up to 1 in 100 people) 

 New melanoma 

 Allergic reaction (hypersensitivity) 

 Inflammation of the eye (uveitis, see “Eye problems” earlier in section 4)) 

 Inflammation of the pancreas (causing strong abdominal pain) 

 Inflammation of the fatty layer under the skin (panniculitis) 

 Kidney problems, kidney failure 

 Inflammation of kidneys 
 

Possible side effects when Tafinlar and trametinib are taken together 

 

When you take Tafinlar and trametinib together you may get any of the side effects given in the lists 

above, although the frequency may change (increase or decrease). 

 

You may also get additional side effects due to taking trametinib at the same time as Tafinlar. 

 

Tell your doctor as soon as possible if you get any of these symptoms, either for the first time or if 

they get worse. 

 

Please also read the trametinib package leaflet for details of the side effects you may get with 

trametinib. 

 

  



62 

The side effects that you may see when you take Tafinlar in combination with trametinib are as 

follows: 

 

Very common side effects (may affect more than 1 in 10 people) 

 Nasal and throat inflammation 

 Decreased appetite 

 Headache 

 Dizziness 

 High blood pressure (hypertension) 

 Bleeding, at various sites in the body, which may be mild or serious (haemorrhage) 

 Cough 

 Stomach ache 

 Constipation 

 Diarrhoea 

 Feeling sick (nausea), being sick (vomiting) 

 Rash, dry skin, itching, skin reddening 

 Joint pain, muscle pain, or pain in the hands or feet 

 Muscle spasms 

 Lack of energy, feeling weak 

 Chills 

 Swelling of the hands or feet (oedema peripheral) 

 Fever 

 Flu-like illness 
 

Very common side effects that may show up in your blood tests 

 Abnormal blood test results related to the liver 
 

Common side effects (may affect up to 1 in 10 people) 

 Infection of the urinary system 

 Skin effects including infection of the skin (cellulitis), inflammation of hair follicles in the skin, 
nail disorders such as nail bed changes, nail pain, infection and swelling of the cuticles, skin 

rash with pus-filled blisters, cutaneous squamous cell carcinoma (a type of skin cancer), 

papilloma (a type of skin tumour which is usually not harmful), wart-like growths, increased 

sensitivity of the skin to sun (see also “Changes in your skin” earlier in section 4) 

 Dehydration (low levels of water or fluid) 

 Blurred vision, eyesight problems, inflammation of the eye (uveitis) 

 Heart pumping less efficiently 

 Low blood pressure (hypotension) 

 Localised tissue swelling 

 Shortness of breath 

 Dry mouth 

 Sore mouth or mouth ulcers, inflammation of mucous membranes 

 Acne-like problems 

 Thickening of the outer layer of the skin (hyperkeratosis), patches of thick, scaly, or crusty skin 
(actinic keratosis), chapping or cracking of the skin 

 Increased sweating, night sweats 

 Unusual hair loss or thinning 

 Red, painful hands and feet 

 Inflammation of the fatty layer under the skin (panniculitis) 

 Inflammation of the mucosa 

 Swelling of the face 
 

  



63 

Common side effects that may show up in your blood tests 

 Low levels of white blood cells 

 Decrease in number of red blood cells (anaemia), blood platelets (cells that help blood to clot), 
and a type of white blood cells (leukopenia) 

 Low levels of sodium (hyponatraemia) or phosphate (hypophosphataemia) in the blood 

 Increase in blood sugar level 

 Increase in creatine phosphokinase, an enzyme found mainly in heart, brain, and skeletal muscle 

 Increase in some substances (enzymes) produced by the liver 
 

Uncommon side effects (may affect up to 1 in 100 people) 

 Appearance of new skin cancer (melanoma) 

 Skin tags 

 Allergic reactions (hypersensitivity) 

 Eye changes including swelling in the eye caused by fluid leakage (chorioretinopathy), 
separation of the light-sensitive membrane in the back of the eye (the retina) from its supporting 

layers (retinal detachment) and swelling around the eyes 

 Heart rate that is lower than the normal range and/or a decrease in heart rate 

 Inflammation of the lung (pneumonitis) 

 Inflammation of pancreas 

 Inflammation of the intestines (colitis) 

 Kidney failure 

 Inflammation of the kidneys 
 

Rare side effects (may affect up to 1 in 1000 people) 

 A hole (perforation) in the stomach or intestines 
 

Not known (frequency cannot be estimated from the available data) 

 Inflammation of the heart muscle (myocarditis) which can result in breathlessness, fever, 
palpitations and chest pain 

 Inflamed, flaky skin (exfoliative dermatitis) 
 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Tafinlar 

 

Keep this medicine out of the sight and reach of children. 

 

Do not take Tafinlar after the expiry date (EXP) which is stated on the bottle label and the carton. The 

expiry date refers to the last day of that month. 

 

This medicine does not require any special storage conditions. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


64 

6. Contents of the pack and other information 

 

What Tafinlar contains 

- The active substance is dabrafenib. Each hard capsule contains dabrafenib mesilate equivalent 
to 50 mg or 75 mg of dabrafenib. 

- The other ingredients are: microcrystalline cellulose, magnesium stearate, colloidal silicone 
dioxide, red iron oxide (E172), titanium dioxide (E171), and hypromellose (E464). Further, the 

capsules are printed with black ink that contains black iron oxide (E172) shellac and propylene 

glycol. 

 

What Tafinlar looks like and contents of the pack 

Tafinlar 50 mg hard capsules are opaque dark red and imprinted with “GS TEW” and “50 mg”. 

Tafinlar 75 mg hard capsules are opaque dark pink and imprinted with “GS LHF” and “75 mg”. 

 

The bottles are opaque white plastic with threaded plastic closures. 

 

The bottles also include a silica gel desiccant in a small cylinder shaped container. The desiccant must 

be kept inside the bottle and must not be eaten. 

 

Tafinlar 50 mg and 75 mg hard capsules are available in packs containing 28 or 120 capsules. Not all 

pack sizes may be marketed in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Glaxo Wellcome, S.A., Avda. Extremadura, 3, 09400 Aranda De Duero, Burgos, Spain 

Novartis Pharmaceuticals UK Limited, Frimley Business Park, Frimley, Camberley, Surrey GU16 

7SR, United Kingdom 

Novartis Pharma GmbH, Roonstraße 25, D-90429 Nuremberg, Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 



65 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in  
 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu. 

 

This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET