Mekinist

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 

Mekinist 0.5 mg film-coated tablets 

Mekinist 2 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Mekinist 0.5 mg film-coated tablets 

Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib. 

 

Mekinist 2 mg film-coated tablets 

Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Film-coated tablet (tablet) 

 

Mekinist 0.5 mg film-coated tablets 

Yellow, modified oval, biconvex, film-coated tablets, approximately 4.8 x 8.9 mm, with “GS” 

debossed on one face and “TFC” on the opposing face. 

 

Mekinist 2 mg film-coated tablets 

Pink, round, biconvex, film-coated tablets, approximately 7.5 mm, with “GS” debossed on one face 

and “HMJ” on the opposing face. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Melanoma 

 

Trametinib as monotherapy or in combination with dabrafenib 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). 

 

Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a 

prior BRAF inhibitor therapy (see section 5.1). 

 

Adjuvant treatment of melanoma 

 

Trametinib in combination with dabrafenib 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) 

 

Trametinib in combination with dabrafenib 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 trametinib should only be initiated and supervised by a physician experienced in the 

administration of anti-cancer medicinal products. 

 

Before taking trametinib, patients must have confirmation of BRAF V600 mutation using a validated 

test. 

 

Posology 

 

The recommended dose of trametinib, either used as monotherapy or in combination with dabrafenib, 

is 2 mg once daily. The recommended dose of dabrafenib, when used in combination with trametinib, 

is 150 mg twice daily. 

 

Duration of treatment 

 

It is recommended that patients continue treatment with trametinib until patients no longer derive 

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 trametinib is missed, it should only be taken if it is more than 12 hours until the next 

scheduled dose. 

 

If a dose of dabrafenib is missed, when trametinib is given in combination with dabrafenib, the dose of 

dabrafenib should only be taken if it is more than 6 hours until the next scheduled dose. 

 

Dose modification 

 

The management of adverse reactions may require dose reduction, treatment interruption or treatment 

discontinuation (see Tables 1 and 2). 

 

Dose modifications are not recommended for adverse reactions of cutaneous squamous cell carcinoma 

(cuSCC) or new primary melanoma (see dabrafenib SmPC for further details). 

 

Table 1 Recommended dose level reductions 

 

Dose level Trametinib dose 

Used as monotherapy or in 

combination with dabrafenib 

Dabrafenib dose* 

Only when used in combination with 

trametinib 

Starting dose 2 mg once daily 150 mg twice daily 

1st dose reduction 1.5 mg once daily 100 mg twice daily 

2nd dose reduction 1 mg once daily 75 mg twice daily 

3rd dose reduction 

(combination only) 

1 mg once daily 50 mg twice daily 

Dose adjustment for trametinib below 1 mg once daily is not recommended, whether used as 

monotherapy or in combination with dabrafenib. Dose adjustment for dabrafenib below 50 mg 

twice daily is not recommended when used in combination with trametinib. 
*Please refer to the dabrafenib SmPC, Posology and method of administration, for dosing instructions for 

treatment with dabrafenib monotherapy. 

 



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Table 2 Dose modification schedule based on the grade of any adverse reactions 

 

Grade (CTC-AE)* Recommended trametinib dose modifications 

Used as monotherapy or in combination with dabrafenib 

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 reactions graded by the Common Terminology Criteria for Adverse 

Events v4.0 (CTC-AE) 

 

When an individual’s adverse reactions are under effective management, dose re-escalation following 

the same dosing steps as de-escalation may be considered. The trametinib dose should not exceed 

2 mg once daily. 

 

If treatment-related toxicities occur when trametinib is used in combination with dabrafenib, 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 trametinib is used in combination with dabrafenib and the patient’s temperature is ≥38.5oC 

please refer to the dabrafenib SmPC (section 4.2) for dose modifications for dabrafenib. No dose 

modification of trametinib is required when taken in combination with dabrafenib. 

 

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 must be considered before continuing treatment with dabrafenib in patients with 

a non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is required 

when taken in combination with dabrafenib. 

 

Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction 

Trametinib should be interrupted in patients who have an asymptomatic, absolute decrease of >10% in 

LVEF compared to baseline and the ejection fraction is below the institution’s lower limit of normal 

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

combination with dabrafenib. If the LVEF recovers, treatment with trametinib may be restarted, but 

the dose should be reduced by one dose level with careful monitoring (see section 4.4). 

 

Trametinib should be permanently discontinued in patients with Grade 3 or 4 left ventricular cardiac 

dysfunction or clinically significant LVEF reduction which does not recover within 4 weeks (see 

section 4.4). 

 



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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 trametinib therapy, a prompt ophthalmological assessment is 

recommended. In patients who are diagnosed with RVO, treatment with trametinib, whether given as 

monotherapy or in combination with dabrafenib, should be permanently discontinued. No dose 

modification of dabrafenib is required when trametinib is taken in combination with dabrafenib. If 

RPED is diagnosed, follow the dose modification schedule in Table 3 below for trametinib (see 

section 4.4). 

 

Table 3 Recommended dose modifications for trametinib for RPED 

 

Grade 1 RPED Continue treatment with retinal evaluation monthly until 

resolution. If RPED worsens follow instructions below 

and withhold trametinib for up to 3 weeks. 

Grade 2-3 RPED Withhold trametinib for up to 3 weeks. 

Grade 2-3 RPED that improves to 

Grade 0-1 within 3 weeks 

Resume trametinib at a lower dose (reduced by 0.5 mg) 

or discontinue trametinib in patients taking trametinib 

1 mg daily. 

Grade 2-3 RPED that does not improve 

to at least Grade 1 within 3 weeks 

Permanently discontinue trametinib. 

 

Interstitial lung disease (ILD)/Pneumonitis 

Trametinib must be withheld in patients with suspected ILD or pneumonitis, including patients 

presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, 

hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Trametinib must be 

permanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis. No dose 

modification of dabrafenib is required when trametinib is taken in combination with dabrafenib for 

cases of ILD or pneumonitis. 

 

Renal impairment 

No dosage adjustment is required in patients with mild or moderate renal impairment (see section 5.2). 

There are no data with trametinib in patients with severe renal impairment; therefore, the potential 

need for starting dose adjustment cannot be determined. Trametinib should be used with caution in 

patients with severe renal impairment when administered as monotherapy or in combination with 

dabrafenib. 

 

Hepatic impairment 

No dosage adjustment is required in patients with mild hepatic impairment (see section 5.2). There are 

no clinical data in patients with moderate or severe hepatic impairment; therefore, the potential need 

for starting dose adjustment cannot be determined. Trametinib should be used with caution in patients 

with moderate or severe hepatic impairment when administered as monotherapy or in combination 

with dabrafenib. 

 

Non-Caucasian patients 

 

The safety and efficacy of trametinib in non-Caucasian patients have not been established. No data are 

available. 

 

Elderly 

 

No initial dose adjustment is required in patients >65 years of age. More frequent dose adjustments 

(see Tables 1 and 2 above) may be required in patients >65 years of age (see section 4.8). 

 



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Paediatric population 

 

The safety and efficacy of trametinib have not been established in children and adolescents 

(<18 years). No data are available. Studies in juvenile animals have shown adverse effects of 

trametinib which were not observed in adult animals (see section 5.3). 

 

Method of administration 

 

Trametinib should be taken orally with a full glass of water. The tablets should not be chewed or 

crushed and they should be taken without food, at least 1 hour before or 2 hours after a meal. 

 

It is recommended that the dose of trametinib is taken at a similar time every day. When trametinib 

and dabrafenib 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. 

 

If a patient vomits after taking trametinib, the patient should not retake the dose and should take the 

next scheduled dose. 

 

Please refer to dabrafenib SmPC for information on method of administration when given in 

combination with trametinib. 

 

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

prior to initiation of treatment. For additional information on warnings and precautions associated with 

dabrafenib treatment, please refer to the dabrafenib SmPC. 

 

BRAF V600 testing 

 

The efficacy and safety of trametinib have not been evaluated in patients whose melanoma tested 

negative for the BRAF V600 mutation. 

 

Trametinib monotherapy compared to BRAF inhibitors 

 

Trametinib monotherapy has not been compared with a BRAF inhibitor in a clinical study in patients 

with BRAF V600 mutation positive unresectable or metastatic melanoma. Based on cross-study 

comparisons, overall survival and progression-free survival data appear to show similar effectiveness 

between trametinib and BRAF inhibitors; however, overall response rates were lower in patients 

treated with trametinib than those reported in patients treated with BRAF inhibitors. 

 

Trametinib in combination with dabrafenib in patients with melanoma who have progressed on a 

BRAF inhibitor 

 

There are limited data in patients taking the combination of trametinib with dabrafenib 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 trametinib is used in combination 

with dabrafenib. 

 

Cutaneous malignancies 

 

Cutaneous squamous cell carcinoma (cuSCC) 

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

combination with dabrafenib. Cases of cuSCC can be managed with excision and do not require 

treatment modification. Please refer to the dabrafenib SmPC (section 4.4). 

 

New primary melanoma 

New primary melanoma was reported in patients receiving trametinib in combination with dabrafenib. 

Cases of new primary melanoma can be managed with excision and do not require treatment 

modification. Please refer to the dabrafenib SmPC (section 4.4). 

 

Non-cutaneous malignancies 

 

Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies 

when RAS mutations are present. When trametinib is used in combination with dabrafenib please refer 

to the dabrafenib SmPC (section 4.4). No dose modification of trametinib is required for RAS 

mutation positive malignancies when taken in combination with dabrafenib. 

 

Haemorrhage 

 

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

patients taking trametinib as monotherapy and in combination with dabrafenib (see section 4.8). The 

potential for these events in patients with low platelet counts (<75,000) has not been established as 

such patients were excluded from clinical trials. The risk of haemorrhage may be increased with 

concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should be 

treated as clinically indicated. 

 

LVEF reduction/Left ventricular dysfunction 

 

Trametinib has been reported to decrease LVEF, when used as monotherapy or in combination with 

dabrafenib (see section 4.8). In clinical trials, the median time to onset of the first occurrence of left 

ventricular dysfunction, cardiac failure and LVEF decrease was between 2 and 5 months. 

 

Trametinib should be used with caution in patients with impaired left ventricular function. Patients 

with left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acute 

coronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, and 

uncontrolled hypertension were excluded from clinical trials; safety of use in this population is 

therefore unknown. LVEF should be evaluated in all patients prior to initiation of treatment with 

trametinib, one month after initiation of therapy, and then at approximately 3-monthly intervals while 

on treatment (see section 4.2 regarding dose modification). 

 

In patients receiving trametinib in combination with dabrafenib, there have been occasional reports of 

acute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed when 

stopping treatment. Physicians should be alert to the possibility of myocarditis in patients who develop 

new or worsening cardiac signs or symptoms. 

 



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Pyrexia 

 

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

dabrafenib (see section 4.8). The incidence and severity of pyrexia are increased with the combination 

therapy (see dabrafenib SmPC section 4.4). In patients receiving trametinib in combination with 

dabrafenib, pyrexia may be accompanied by severe rigors, dehydration, and hypotension which in 

some cases can lead to acute renal insufficiency. 

 

When trametinib is used in combination with dabrafenib and the patient’s temperature is ≥38.5oC 

please refer to the dabrafenib SmPC (section 4.2) for dose modifications for dabrafenib. No dose 

modification of trametinib is required when taken in combination with dabrafenib. 

 

Hypertension 

 

Elevations in blood pressure have been reported in association with trametinib as monotherapy and in 

combination with dabrafenib, in patients with or without pre-existing hypertension (see section 4.8). 

Blood pressure should be measured at baseline and monitored during treatment with trametinib, with 

control of hypertension by standard therapy as appropriate. 

 

Interstitial lung disease (ILD)/Pneumonitis 

 

In a Phase III trial, 2.4% (5/211) of patients treated with trametinib monotherapy developed ILD or 

pneumonitis; all five patients required hospitalisation. The median time to first presentation of ILD or 

pneumonitis was 160 days (range: 60 to 172 days). In studies MEK115306 and MEK116513 <1% 

(2/209) and 1 % (4/350), respectively, of patients treated with trametinib in combination with 

dabrafenib developed pneumonitis or ILD (see section 4.8). 

 

Trametinib should be withheld in patients with suspected ILD or pneumonitis, including patients 

presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, 

hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Trametinib should be 

permanently discontinued for patients diagnosed with treatment-related ILD or pneumonitis (see 

section 4.2). If trametinib is being used in combination with dabrafenib then therapy with dabrafenib 

may be continued at the same dose. 

 

Visual impairment 

 

Disorders associated with visual disturbance, including RPED and RVO, may occur with trametinib as 

monotherapy and in combination with dabrafenib. Symptoms such as blurred vision, decreased acuity, 

and other visual phenomena have been reported in the clinical trials with trametinib (see section 4.8). 

In clinical trials uveitis and iridocyclitis have also been reported in patients treated with trametinib in 

combination with dabrafenib. 

 

Trametinib is not recommended in patients with a history of RVO. The safety of trametinib in subjects 

with predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension, 

uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or 

hypercoagulability syndromes, has not been established. 

 

If patients report new visual disturbances, such as diminished central vision, blurred vision or loss of 

vision at any time while on trametinib therapy, a prompt ophthalmological assessment is 

recommended. If RPED is diagnosed, the dose modification schedule in Table 3 should be followed 

(see section 4.2); if uveitis is diagnosed, please refer to dabrafenib SmPC section 4.4. In patients who 

are diagnosed with RVO, treatment with trametinib should be permanently discontinued. No dose 

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

of RVO or RPED. No dose modification of trametinib is required when taken in combination with 

dabrafenib following diagnosis of uveitis. 

 



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Rash 

 

Rash has been observed in about 60% of patients in trametinib monotherapy studies and in about 24% 

of patients when trametinib is used in combination with dabrafenib (see section 4.8). The majority of 

these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions. 

 

Rhabdomyolysis 

 

Rhabdomyolysis has been reported in patients taking trametinib as monotherapy or in combination 

with dabrafenib (see section 4.8). In some cases, patients were able to continue trametinib. In more 

severe cases hospitalisation, interruption or permanent discontinuation of trametinib or trametinib and 

dabrafenib combination was required. Signs or symptoms of rhabdomyolysis should warrant an 

appropriate clinical evaluation and treatment as indicated. 

 

Renal failure 

 

Renal failure has been identified in patients treated with trametinib in combination with dabrafenib in 

clinical trials. Please refer to the dabrafenib SmPC (section 4.4). 

 

Pancreatitis 

 

Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib in 

clinical trials. Please refer to the dabrafenib SmPC (section 4.4). 

 

Hepatic events 

 

Hepatic adverse  reactions have been reported in clinical trials with trametinib as monotherapy and in 

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

with trametinib monotherapy or in combination with dabrafenib have liver function monitored every 

four weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued 

thereafter as clinically indicated. 

 

Hepatic impairment 

 

As metabolism and biliary excretion are the primary routes of elimination of trametinib, administration 

of trametinib should be undertaken with caution in patients with moderate to severe hepatic 

impairment (see sections 4.2 and 5.2). 

 

Deep vein thrombosis (DVT)/Pulmonary embolism (PE) 

 

Pulmonary embolism or deep vein thrombosis can occur when trametinib is used as monotherapy or in 

combination with dabrafenib. 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. 

 



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Gastrointestinal disorders 

 

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

trametinib as monotherapy and in combination with dabrafenib (see section 4.8). Treatment with 

trametinib monotherapy or in combination with dabrafenib should be used with caution in patients 

with risk factors for gastrointestinal perforation, including history of diverticulitis, metastases to the 

gastrointestinal tract and concomitant use of medicinal products with a recognised risk of 

gastrointestinal perforation. 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

Effect of other medicinal products on trametinib 

 

As trametinib is metabolised predominantly via deacetylation mediated by hydrolytic enzymes (e.g. 

carboxyl-esterases), its pharmacokinetics are unlikely to be affected by other agents through metabolic 

interactions (see section 5.2). Drug-drug interactions via these hydrolytic enzymes cannot be ruled out 

and could influence the exposure to trametinib. 

 

Trametinib is an in vitro substrate of the efflux transporter P-gp. As it cannot be excluded that strong 

inhibition of hepatic P-gp may result in increased levels of trametinib, caution is advised when 

co-administering trametinib with medicinal products that are strong inhibitors of P-gp (e.g. verapamil, 

cyclosporine, ritonavir, quinidine, itraconazole). 

 

Effect of trametinib on other medicinal products 

 

Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the pharmacokinetics of 

other medicinal products via interaction with CYP enzymes or transporters (see section 5.2). 

Trametinib may result in transient inhibition of BCRP substrates (e.g. pitavastatin) in the gut, which 

may be minimised with staggered dosing (2 hours apart) of these agents and trametinib. 

 

Combination with dabrafenib 

 

When trametinib is used in combination with dabrafenib see sections 4.4 and 4.5 of the dabrafenib 

SmPC for interactions. 

 

Effect of food on trametinib 

 

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

prior to or two hours after a meal due to the effect of food on trametinib absorption (see section 4.2 

and 5.2). 

 

  



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4.6 Fertility, pregnancy and lactation 
 

Women of childbearing potential/Contraception in females 

 

Female patients of reproductive potential must be advised to use effective methods of contraception 

during treatment with trametinib and for 16 weeks after stopping treatment. 

 

It is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, 

female patients using hormonal contraception are advised to use an additional or alternative method 

during treatment and for 16 weeks following discontinuation of trametinib. 

 

Use with dabrafenib may render hormonal contraceptives less effective and therefore an alternative 

method of contraception, such as a barrier method, should be used when trametinib is used in 

combination with dabrafenib. Refer to the dabrafenib SmPC for further information. 

 

Pregnancy 

 

There are no adequate and well-controlled studies of trametinib in pregnant women. Animal studies 

have shown reproductive toxicity (see section 5.3). Trametinib should not be administered to pregnant 

women. If trametinib is used during pregnancy, or if the patient becomes pregnant while taking 

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

 

Breast-feeding 

 

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

excreted in human milk, a risk to the breast-feeding infant cannot be excluded. Trametinib should not 

be administered to breast-feeding mothers. A decision should be made whether to discontinue 

breast-feeding or discontinue trametinib, 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 trametinib as monotherapy or in combination with dabrafenib. In 

animals, no fertility studies have been performed, but adverse effects were seen on female 

reproductive organs (see section 5.3). Trametinib may impair fertility in humans. 

 

Men taking trametinib in combination with dabrafenib 

 

Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients taking 

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

spermatogenesis, which may be irreversible. Refer to the dabrafenib SmPC for further information. 

 

4.7 Effects on ability to drive and use machines 
 

Trametinib has minor influence on the ability to drive or use machines. The clinical status of the 

patient and the adverse reaction profile should be borne in mind when considering the patient’s ability 

to perform tasks that require judgement, motor and cognitive skills. Patients should be made aware of 

potential for fatigue, dizziness or eye problems that might affect these activities. 

 

  



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4.8 Undesirable effects 

 

Summary of the safety profile 

 

The safety of trametinib monotherapy has been evaluated in the integrated safety population of 

329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with trametinib 

2 mg once daily in studies MEK114267, MEK113583, and MEK111054. Of these patients, 211 were 

treated with trametinib for BRAF V600 mutant melanoma in the randomised open-label Phase III 

study MEK114267 (METRIC) (see section 5.1). The most common adverse reactions (incidence 

≥20%) for trametinib were rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis 

acneiform. 

 

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

population of 1,076 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 trametinib 2 mg once daily and dabrafenib 150 mg twice daily. Of these patients, 

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

studies, 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 trametinib in combination with dabrafenib 

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

 
Tabulated list of adverse reactions 

 

Adverse reactions are listed below by MedDRA body system organ class. 

The following convention has been utilised for the classification of frequency: 

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 

Not known  (cannot be estimated from the available data) 

Categories have been assigned based on absolute frequencies in the clinical trial data. Within each 

frequency grouping, adverse reactions are presented in order of decreasing seriousness. 

 



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

monotherapy (n=329) 

 

System Organ Class Frequency (all 

grades) 

Adverse Reactions 

Infections and infestation Common 

Folliculitis 

Paronychia 

Cellulitis 

Rash pustular 

Blood and lymphatic system 

disorders 
Common Anaemia 

Immune system disorders Common Hypersensitivitya 

Metabolism and nutrition 

disorders 
Common Dehydration 

Eye disorders 

Common 

Vision blurred 

Periorbital oedema 

Visual impairment 

Uncommon 

Chorioretinopathy 

Papilloedema 

Retinal detachment 

Retinal vein occlusion 

Cardiac disorders 
Common 

Left ventricular dysfunction 

Ejection fraction decreased 

Bradycardia 

Uncommon Cardiac failure 

Vascular disorders 
Very common 

Hypertension 

Haemorrhageb 

Common Lymphoedema 

Respiratory, thoracic and 

mediastinal disorders 

Very common 
Cough 

Dyspnoea 

Common Pneumonitis 

Uncommon Interstitial lung disease 

Gastrointestinal disorders 

Very common 

Diarrhoea 

Nausea 

Vomiting 

Constipation 

Abdominal pain 

Dry mouth 

Common Stomatitis 

Uncommon Gastrointestinal perforation 

Colitis 

Skin and subcutaneous 

disorders 

Very common 

Rash 

Dermatitis acneiform 

Dry skin 

Pruritus 

Alopecia 

Common 

Erythema 

Palmar-plantar erythrodysaesthesia 

syndrome 

Skin fissures 

Skin chapped 

Musculoskeletal and 

connective tissue disorders 
Uncommon Rhabdomyolysis 



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General disorders and 

administration site 

conditions 

Very common 

Fatigue 

Oedema peripheral 

Pyrexia 

Common 

Face oedema 

Mucosal inflammation 

Asthenia 

Investigations 

Very common Aspartate aminotransferase increased 

Common 

Alanine aminotransferase increased 

Blood alkaline phosphatase increased 

Blood creatine phosphokinase increased 
a May present with symptoms such as fever, rash, increased liver transaminases, and visual disturbances 
b Events include but are not limited to: epistaxis, haematochezia, gingival bleeding, haematuria, and rectal, 

haemorrhoidal, gastric, vaginal, conjunctival, intracranial and post-procedural haemorrhage. 

 

Table 5 Adverse reactions reported in the integrated safety population of trametinib in 

combination with dabrafenib in the studies MEK115306, MEK116513a, BRF113928, 

and BRF115532 (n=1,076) 

 

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 



15 

Vascular disorders 

Very common 
Hypertension 

Haemorrhagef 

Common 
Hypotension 

Lymphoedema 

Respiratory, thoracic and 

mediastinal disorders 

Very common Cough 

Common Dyspnoea 

Uncommon Pneumonitis 

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 



16 

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 

 

New malignancies 

 

New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination 

with dabrafenib. Please refer to the dabrafenib SmPC. 

 

Haemorrhage 

 

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

patients taking trametinib as monotherapy and in combination with dabrafenib. The majority of 

bleeding events were mild. Fatal intracranial haemorrhages occurred in the integrated safety 

population of trametinib in combination with dabrafenib in <1% (8/1076) of patients. The median time 

to onset of the first occurrence of haemorrhagic events for the combination of trametinib and 

dabrafenib was 94 days in the melanoma Phase III studies and 75 days in the NSCLC study for the 

patients who had received prior anti-cancer therapy. 

 

The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant 

therapy. If haemorrhage occurs, treat as clinically indicated (see section 4.4). 

 

LVEF reduction/Left ventricular dysfunction 

 

Trametinib has been reported to decrease LVEF when used as monotherapy or in combination with 

dabrafenib. In clinical trials, the median time to first occurrence of left ventricular dysfunction, cardiac 

failure and LVEF decrease was between 2 to 5 months. In the integrated safety population of 

trametinib in combination with dabrafenib, decreased LVEF has been reported in 6% (65/1076) of 

patients, with most cases being asymptomatic and reversible. Patients with LVEF lower than the 

institutional lower limit of normal were not included in clinical trials with trametinib. Trametinib 

should be used with caution in patients with conditions that could impair left ventricular function (see 

sections 4.2 and 4.4). 

 

Pyrexia 

 

Pyrexia has been reported in clinical trials with trametinib as monotherapy and in combination with 

dabrafenib; however, the incidence and severity of pyrexia are increased with the combination 

therapy. Please refer to sections 4.4 and 4.8 of the dabrafenib SmPC. 



17 

 

Hepatic events 

 

Hepatic adverse reactions have been reported in clinical trials with trametinib as monotherapy and in 

combination with dabrafenib. Of the hepatic adverse reactions, increased ALT and AST were the most 

common events and the majority were either Grade 1 or 2. For trametinib monotherapy, more than 

90% of these liver events occurred within the first 6 months of treatment. Liver events were detected 

in clinical trials with monitoring every four weeks. It is recommended that patients receiving treatment 

with trametinib monotherapy or in combination with dabrafenib have liver function monitored every 

four weeks for 6 months. Liver monitoring may be continued thereafter as clinically indicated (see 

section 4.4). 

 

Hypertension 

 

Elevations in blood pressure have been reported in association with trametinib as monotherapy and in 

combination with dabrafenib, 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 (see section 4.4). 

 

Interstitial lung disease (ILD)/Pneumonitis 

 

Patients treated with trametinib or combination with dabrafenib may develop ILD or pneumonitis. 

Trametinib should be withheld in patients with suspected ILD or pneumonitis, including patients 

presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, 

hypoxia, pleural effusion, or infiltrates, pending clinical investigations. For patients diagnosed with 

treatment-related ILD or pneumonitis trametinib should be permanently discontinued (see sections 4.2 

and 4.4). 

 

Visual impairment 

 

Disorders associated with visual disturbances, including RPED and RVO, have been observed with 

trametinib. Symptoms such as blurred vision, decreased acuity, and other visual disturbances have 

been reported in the clinical trials with trametinib (see sections 4.2 and 4.4). 

 

Rash 

 

Rash has been observed in about 60% of patients when given as monotherapy and in about 24% of 

patients in trametinib and dabrafenib combination studies in the integrated safety population. The 

majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions 

(see sections 4.2 and 4.4). 

 

Rhabdomyolysis 

 

Rhabdomyolysis has been reported in patients taking trametinib alone or in combination with 

dabrafenib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation 

and treatment as indicated (see section 4.4). 

 

Pancreatitis 

 

Pancreatitis has been reported with dabrafenib in combination with trametinib. Please see the 

dabrafenib SmPC. 

 

Renal failure 

 

Renal failure has been reported with dabrafenib in combination with trametinib. Please see the 

dabrafenib SmPC. 

 



18 

Special populations 

 

Elderly 

 

In the Phase III study with trametinib in patients with unresectable or metastatic melanoma (n=211), 

49 patients (23%) were ≥65 years of age, and 9 patients (4%) were ≥75 years of age. The proportion of 

subjects experiencing adverse reactions (AR) and serious adverse reactions (SAR) was similar in the 

subjects aged <65 years and those aged ≥65 years. Patients ≥65 years were more likely to experience 

ARs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption 

than those <65 years. 

 

In the integrated safety population of trametinib in combination with dabrafenib (n=1,076) 

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

patients experiencing ARs was similar in those aged <65 years and those aged ≥65 years in all studies. 

Patients ≥65 years were more likely to experience SARs and ARs leading to permanent 

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

 

Renal impairment 

 

No dosage adjustment is required in patients with mild or moderate renal impairment (see section 5.2). 

Trametinib should be used with caution in patients with severe renal impairment (see sections 4.2 and 

4.4). 

 

Hepatic impairment 

 

No dosage adjustment is required in patients with mild hepatic impairment (see section 5.2). 

Trametinib should be used with caution in patients with moderate or severe hepatic impairment (see 

sections 4.2 and 4.4). 

 

Trametinib in combination with dabrafenib in patients with brain metastases 

 

The safety and efficacy of the combination of trametinib and dabrafenib 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 
 

In clinical trials with trametinib monotherapy one case of accidental overdose was reported; a single 

dose of 4 mg. No AEs were reported following this event of trametinib overdose. In clinical trials with 

the combination of trametinib and dabrafenib 11 patients reported trametinib overdose (4 mg); no 

SAEs were reported. There is no specific treatment for overdose. If overdose occurs, the patient should 

be treated supportively with appropriate monitoring as necessary. 

 

 

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


19 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE25 

 

Mechanism of action 

 

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. In melanoma and other cancers, 

this pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits 

activation of MEK by BRAF and inhibits MEK kinase activity. Trametinib inhibits growth of BRAF 

V600 mutant melanoma cell lines and demonstrates anti-tumour effects in BRAF V600 mutant 

melanoma animal models. 

 

Combination with dabrafenib 

 

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

activation of the RAS/RAF/MEK/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 trametinib with dabrafenib 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 trametinib or the combination with dabrafenib, patients must have BRAF V600 

mutation-positive tumour status confirmed by a validated test. 

 

In clinical trials, central testing for BRAF V600 mutation using a BRAF mutation assay was 

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

site was tested with a validated polymerase chain reaction (PCR) assay developed by Response 

Genetics Inc. The assay was specifically designed to differentiate between the V600E and V600K 

mutations. Only patients with BRAF V600E or V600K mutation positive tumours were eligible for 

study participation. 

 

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

BRAF validated assay. 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%. 

 

  



20 

Pharmacodynamic effects 

 

Trametinib suppressed levels of phosphorylated ERK in BRAF mutant melanoma tumour cell lines 

and melanoma xenograft models. 

 

In patients with BRAF and NRAS mutation positive melanoma, administration of trametinib resulted 

in dose-dependent changes in tumour biomarkers including inhibition of phosphorylated ERK, 

inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). The 

mean trametinib concentrations observed following repeat dose administration of 2 mg once daily 

exceeds the preclinical target concentration over the 24-hr dosing interval, thereby providing sustained 

inhibition of the MEK pathway. 

 

Clinical efficacy and safety 

 

Unresectable or metastatic melanoma 

 

In the clinical trials only patients with cutaneous melanoma were studied. Efficacy in patients with 

ocular or mucosal melanoma has not been assessed. 

 

 Trametinib in combination with dabrafenib 
 

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 studies 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. 

 



21 

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
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u
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iv
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F

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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 



22 

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% 

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



23 

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 curves Updated OS analysis 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 

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Vemurafenib 

Dabrafenib + Trametinib 



24 

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 trametinib with dabrafenib 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 (see section 4.4). 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). 

 



25 

Patients with brain metastases 

The efficacy and safety of trametinib in combination with dabrafenib 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 

 

  



26 

 Trametinib monotherapy 
 

Treatment naïve patients 

The efficacy and safety of trametinib in patients with BRAF unresectable or metastatic mutant 

melanoma (V600E and V600K) were evaluated in a randomised open-label Phase III study 

(MEK114267 [METRIC]). Measurement of patients’ BRAF V600 mutation status was required. 

 

Patients (N=322) who were treatment naïve or may have received one prior chemotherapy treatment in 

the metastatic setting [Intent to Treat (ITT) population] were randomised 2:1 to receive trametinib 

2 mg once daily or chemotherapy (dacarbazine 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 

every 3 weeks). Treatment for all patients continued until disease progression, death or withdrawal. 

 

The primary endpoint of the study was to evaluate the efficacy of trametinib compared to 

chemotherapy with respect to PFS in patients with advanced/metastatic BRAF V600E/K 

mutation-positive melanoma without a prior history of brain metastases (N=273) which is considered 

the primary efficacy population. The secondary endpoints were PFS in the ITT population and OS, 

ORR, and DoR in the primary efficacy population and ITT population. Patients in the chemotherapy 

arm were allowed to cross over to the trametinib arm after independent confirmation of progression. 

Of the patients with confirmed disease progression in the chemotherapy arm, a total of 51 (47%) 

crossed over to receive trametinib. 

 

Baseline characteristics were balanced between treatment groups in the primary efficacy population 

and the ITT population. In the ITT population, 54% of patients were male and all were Caucasian. The 

median age was 54 years (22% were 65 years); all patients had an ECOG performance score of 0 or 

1; and 3 % had history of brain metastases. Most patients (87%) in the ITT population had BRAF 

V600E mutation and 12% of patients had BRAF V600K. Most patients (66%) received no prior 

chemotherapy for advanced or metastatic disease. 

 

The efficacy results in the primary efficacy population were consistent with those in the ITT 

population; therefore, only the efficacy data for the ITT population are presented in Table 11. 

Kaplan-Meier curves of investigator-assessed OS (post-hoc analysis 20 May 2013) is presented in 

Figure 3. 

 

Table 11 Investigator-assessed efficacy results (ITT population) 

 

Endpoint Trametinib Chemotherapya 

Progression-Free Survival (N=214) (N=108) 

Median PFS (months) 

 (95% CI) 

4.8 

(4.3, 4.9) 

1.5 

(1.4, 2.7) 

Hazard Ratio 

 (95% CI) 

 P value 

0.45 

(0.33, 0.63) 

<0.0001 

Overall Response Rate (%) 22 8 
ITT = Intent to Treat; PFS = Progression-free survival; CI = confidence interval. 
a Chemotherapy included patients on dacarbazine (DTIC) 1000 mg/m2 every 3 weeks or paclitaxel 

175 mg/m2 every 3 weeks. 

 

The PFS result was consistent in the subgroup of patients with V600K mutation positive melanoma 

(HR=0.50; [95% CI: 0.18, 1.35], p=0.0788). 

 

An additional OS analysis was undertaken based upon the 20 May 2013 data cut, see Table 12. 

 

For October 2011, 47% of subjects had crossed over, while for May 2013, 65% of subjects had 

crossed over. 

 



27 

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

 

Cut-off 

dates 

Treatment Number 

of deaths 

(%) 

Median 

months OS 

(95% CI) 

Hazard ratio 

(95% CI) 

Percent 

survival at 

12 months 

(95% CI) 

October 26, 

2011 

Chemotherapy 

(n=108) 

29 (27) NR  

0.54 (0.32, 0.92) 

NR 

Trametinib 

(n=214) 

35 (16) NR NR 

May 20, 

2013 

Chemotherapy 

(n=108) 

67 (62) 11.3 (7.2, 14.8)  

0.78 (0.57, 1.06) 

50 (39,59) 

Trametinib 

(n=214) 

137 (64) 15.6 (14.0, 

17.4) 

61(54, 67) 

NR=not reached 

 

Figure 3 Kaplan-Meier curves of overall survival (OS –ad hoc analysis 20 May 2013) 

 

 
 

  



28 

Prior BRAF inhibitor therapy 

In a single-arm Phase II study, designed to evaluate the objective response rate, safety, and 

pharmacokinetics following dosing of trametinib at 2 mg once daily in patients with BRAF V600E, 

V600K, or V600D mutation-positive metastatic melanoma (MEK113583), two separate cohorts were 

enrolled: Cohort A: patients with prior treatment with a BRAF inhibitor either with or without other 

prior therapy, Cohort B: patients with at least 1 prior chemotherapy or immunotherapy, without prior 

treatment with a BRAF inhibitor. 

 

In Cohort A of this study, trametinib did not demonstrate clinical activity in patients who had 

progressed on a prior BRAF inhibitor therapy. 

 

Adjuvant treatment of Stage III melanoma 

 

BRF115532 (COMBI-AD) 

The efficacy and safety of trametinib in combination with dabrafenib 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 

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 13. 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. 

 



29 

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) 

Table 13 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 

 

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 

 

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 



30 

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. 

 

Non-small cell lung cancer 

 

Study BRF113928 

The efficacy and safety of trametinib in combination with dabrafenib 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 14). 

 



31 

Table 14 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 

 

Paediatric population 

 

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

trametinib in all subsets of the paediatric population in melanoma and malignant neoplasms 

(see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

 

Trametinib is absorbed orally with median time to achieve peak concentrations of 1.5 hours post-dose. 

The mean absolute bioavailability of a single 2 mg tablet dose is 72% relative to an intravenous (IV) 

microdose. The increase in exposure (Cmax and AUC) was dose-proportional following repeat dosing. 

Following administration of 2 mg once daily, steady-state geometric mean Cmax, AUC(0-) and predose 

concentration were 22.2 ng/ml, 370 ng*hr/ml and 12.1 ng/ml, respectively with a low peak:trough 

ratio (1.8). Inter-subject variability at steady state was low (<28%). 

 

Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0 at 2 mg once 

daily dose. Steady state was achieved by Day 15. 

 

Administration of a single dose of trametinib with a high-fat, high-calorie meal resulted in a 70% and 

10% decrease in Cmax and AUC, respectively compared to fasted conditions (see sections 4.2 and 4.5). 

 

Distribution 

 

Binding of trametinib to human plasma proteins is 97.4%. Trametinib has a volume of distribution of 

approximately 1200 L determined following administration of a 5 g intravenous microdose. 

 



32 

Biotransformation 

 

In vitro and in vivo studies demonstrated that trametinib is metabolised predominantly via 

deacetylation alone or in combination with mono-oxygenation. The deacetylated metabolite was 

further metabolised by glucuronidation. CYP3A4 oxidation is considered a minor pathway of 

metabolism. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with possible 

contributions by other hydrolytic enzymes. 

 

Following single and repeated doses of trametinib, trametinib as parent is the main circulating 

component in plasma. 

 

Elimination 

 

Mean terminal half-life is 127 hours (5.3 days) after single dose administration. Trametinib plasma IV 

clearance is 3.21 L/hr. 

 

Total dose recovery was low after a 10-day collection period (<50%) following administration of a 

single oral dose of radiolabelled trametinib as a solution, due to the long elimination half-life. 

Drug-related material was excreted predominantly in the faeces (>80% of recovered radioactivity) and 

to a minor extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered as parent in 

urine. 

 

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 trametinib oral 

clearance. No data are available in patients with moderate or severe hepatic impairment. As 

metabolism and biliary excretion are the primary routes of elimination of trametinib, administration of 

trametinib should be undertaken with caution in patients with moderate to severe hepatic impairment 

(see section 4.2). 

 

Renal impairment 

 

Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics given 

the low renal excretion of trametinib. The pharmacokinetics of trametinib were characterised in 

223 patients enrolled in clinical trials with trametinib who had mild renal impairment and 35 patients 

with moderate renal impairment using a population pharmacokinetic analysis. Mild and moderate 

renal impairment had no effect on trametinib exposure (<6% for either group). No data are available in 

patients with severe renal impairment (see section 4.2). 

 

Elderly 

 

Based on the population pharmacokinetic analysis (range 19 to 92 years), age had no relevant clinical 

effect on trametinib pharmacokinetics. Safety data in patients ≥75 years is limited (see section 4.8). 

 

Race 

 

There are insufficient data to evaluate the potential effect of race on trametinib pharmacokinetics as 

clinical experience is limited to Caucasians. 

 

Paediatric population 

 

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

patients. 

 



33 

Body weight and gender 

 

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

trametinib oral clearance. Although smaller female subjects are predicted to have higher exposure than 

heavier male subjects, these differences are unlikely to be clinically relevant and no dosage adjustment 

is warranted. 

 

Medicinal product interactions 

 

Effects of trametinib on drug-metabolising enzymes and transporters: In vitro and in vivo data suggest 

that trametinib is unlikely to affect the pharmacokinetics of other medicinal products. Based on in 

vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. 

Trametinib was found to be an in vitro inhibitor of CYP2C8, CYP2C9 and CYP2C19, an inducer of 

CYP3A4 and an inhibitor of the transporters OAT1, OAT3, OCT2, MATE1, OATP1B1, OATP1B3, 

P-gp and BCRP. However, based on the low dose and low clinical systemic exposure relative to the in 

vitro potency of inhibition or induction values, trametinib is not considered to be an in vivo inhibitor or 

inducer of these enzymes or transporters, although transient inhibition of BCRP substrates in the gut 

may occur (see section 4.5). 

 

Effects of other drugs on trametinib: In vivo and in vitro data suggest that the pharmacokinetics of 

trametinib are unlikely to be affected by other medicinal products. Trametinib is not a substrate of 

CYP enzymes or of the transporters BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2, and 

MATE1. Trametinib is an in vitro substrate of BSEP and the efflux transporter P-gp. Although 

trametinib exposure is unlikely to be affected by inhibition of BSEP, increased levels of trametinib 

upon strong inhibition of hepatic P-gp cannot be excluded (see section 4.5). 

 

5.3 Preclinical safety data 
 

Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in 

studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells and 

micronuclei in the bone marrow of rats. 

 

Trametinib may impair female fertility in humans, as in repeat-dose studies, increases in cystic 

follicles and decreases in corpora lutea were observed in female rats at exposures below the human 

clinical exposure based on AUC. 

 

Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in hallmarks of 

female sexual maturation (vaginal opening and increased incidence of prominent terminal end buds 

within the mammary gland) and slight hypertrophy of the surface epithelium of the uterus were 

observed. All of these effects were reversible following an off-treatment period and attributable to 

pharmacology. However, in rat and dog toxicity studies up to 13 weeks in duration, there were no 

treatment effects observed in male reproductive tissues. 

 

In embryo-foetal developmental toxicity studies in rats and rabbits, trametinib induced maternal and 

developmental toxicity. In rats decreased foetal weights and increased post-implantation loss were 

seen at exposures below or slightly above the clinical exposures based on AUC. In an embryo-foetal 

developmental toxicity study with rabbits, decreased foetal body weight, increased abortions, 

increased incidence of incomplete ossification and skeletal malformations were seen at sub-clinical 

exposures based on AUC). 

 

In repeat-dose studies the effects seen after trametinib exposure are found mainly in the skin, 

gastrointestinal tract, haematological system, bone and liver. Most of the findings are reversible after 

drug-free recovery. In rats, hepatocellular necrosis and transaminase elevations were seen after 

8 weeks at ≥0.062 mg/kg/day (approximately 0.8 times human clinical exposure based on AUC). 

 



34 

In mice, lower heart rate, heart weight and left ventricular function were observed without cardiac 

histopathology after 3 weeks at ≥0.25 mg/kg/day trametinib (approximately 3 times human clinical 

exposure based on AUC) for up to 3 weeks. In adult rats, mineralisation of multiple organs was 

associated with increased serum phosphorus and was closely associated with necrosis in heart, liver 

and kidney and haemorrhage in the lung at exposures comparable to the human clinical exposure. In 

rats, hypertrophy of the physis and increased bone turnover were observed, but the physeal 

hypertrophy is not expected to be clinically relevant for adult humans. In rats and dogs given 

trametinib at or below clinical exposures, bone marrow necrosis, lymphoid atrophy in thymus and 

GALT and lymphoid necrosis in lymph nodes, spleen and thymus were observed, which have the 

potential to impair immune function. In juvenile rats, increased heart weight with no histopathology 

was observed at 0.35 mg/kg/day (approximately twice the adult human clinical exposure based on 

AUC). 

 

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

significantly higher concentrations than clinical exposures (IC50 at 2.92 µg/ml, ≥130 times the clinical 

exposure based on Cmax), indicating that there is low risk for phototoxicity to patients taking 

trametinib. 

 

Combination with dabrafenib 

 

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

gastro-intestinal 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. 

 

 

  



35 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Mekinist 0.5 mg film-coated tablets 

Tablet core 

Mannitol (E421) 

Microcrystalline cellulose (E460) 

Hypromellose (E464) 

Croscarmellose sodium (E468) 

Magnesium stearate (E470b) 

Sodium laurilsulfate 

Colloidal silicon dioxide(E551) 

 

Tablet film coating 

Hypromellose (E464) 

Titanium dioxide (E171) 

Polyethylene glycol 

Iron oxide yellow(E172) 

 

Mekinist 2 mg film-coated tablets 

Tablet core 

Mannitol (E421) 

Microcrystalline cellulose (E460) 

Hypromellose (E464) 

Croscarmellose sodium (E468) 

Magnesium stearate (E470b) 

Sodium laurilsulfate 

Colloidal silicon dioxide(E551) 

 

Tablet film coating 

Hypromellose (E464) 

Titanium dioxide (E171) 

Polyethylene glycol 

Polysorbate 80 (E433) 

Iron oxide red (E172) 
 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

Unopened bottle 

 

2 years 

 

Opened bottle 

 

30 days at no more than 30ºC. 

 

  



36 

6.4 Special precautions for storage 
 

Store in a refrigerator (2°C to 8°C). 

Store in the original package in order to protect from light and moisture. 

Keep the bottle tightly closed. 

 

For storage conditions after first opening of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container 

 

High-density polyethylene (HDPE) bottle with child-resistant polypropylene closure. The bottle 

contains a desiccant. 

 

Pack sizes: One bottle contains either 7 or 30 tablets. 

 

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 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Mekinist 0.5 mg film-coated tablets 

EU/1/14/931/001 

EU/1/14/931/002 

 

Mekinist 2 mg film-coated tablets 

EU/1/14/931/005 

EU/1/14/931/006 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 30 June 2014 

Date of latest renewal: 14 February 2019 

 

 

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. 

  



37 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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 



38 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

 

Lek Pharmaceuticals d.d. 

Verovskova ulica 57 

1526, Ljubljana 

Slovenia 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

Glaxo Wellcome, S.A. 

Avda. Extremadura, 3 

09400, Aranda de Duero 

Burgos 

Spain 

 

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. 

  



39 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



40 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
 

  



41 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Mekinist 0.5 mg film-coated tablets 

trametinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 0.5 mg trametinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

7 film-coated tablets 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before 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 

 

Store in a refrigerator. 

Store in the original package to protect from light and moisture. Keep the bottle tightly closed. 

 



42 

 

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/1/14/931/001  7 film-coated tablets 

EU/1/14/931/002  30 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

mekinist 0.5 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 
 

  



43 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Mekinist 0.5 mg tablets 

trametinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 0.5 mg trametinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

7 tablets 

30 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before 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 

 

Store in a refrigerator in the original bottle. Keep the bottle tightly closed. 

 

 



44 

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/1/14/931/001  7 film-coated tablets 

EU/1/14/931/002  30 film-coated tablets 

 

 

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 

 

  



45 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Mekinist 2 mg film-coated tablets 

trametinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 2 mg trametinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

7 film-coated tablets 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before 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 

 

Store in a refrigerator. 

Store in the original package to protect from light and moisture. Keep the bottle tightly closed. 

 



46 

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/1/14/931/005  7 film-coated tablets 

EU/1/14/931/006  30 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

mekinist 2 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 
 

  



47 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Mekinist 2 mg tablets 

trametinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 2 mg trametinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

7 tablets 

30 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before 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 

 

Store in a refrigerator in the original bottle. Keep the bottle tightly closed. 

 

 



48 

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/1/14/931/005  7 film-coated tablets 

EU/1/14/931/006  30 film-coated tablets 

 

 

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 

  



49 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 



50 

Package leaflet: Information for the patient 

 

Mekinist 0.5 mg film-coated tablets 

Mekinist 2 mg film-coated tablets 

trametinib 

 

 

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, nurse or pharmacist. 
- 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, nurse or pharmacist. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
 

1. What Mekinist is and what it is used for 

2. What you need to know before you take Mekinist 

3. How to take Mekinist 

4. Possible side effects 

5. How to store Mekinist 

6. Contents of the pack and other information 

 

 

1. What Mekinist is and what it is used for 

 

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

combination with another medicine containing dabrafenib to treat a type of skin cancer called 

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

 

Mekinist in combination with dabrafenib is also used to prevent melanoma from coming back after it 

has been removed by surgery. 

 

Mekinist in combination with dabrafenib 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 Mekinist 
 

Mekinist 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 Mekinist and 

dabrafenib, read the dabrafenib 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 Mekinist: 

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

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



51 

 

Warnings and precautions 

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

 have any liver problems. Your doctor may take blood samples to monitor your liver function 
while you are taking this medicine. 

 have or have ever had kidney problems. 

 have or have ever had lung or breathing problems. 

 have heart problems such as heart failure (which can cause shortness of breath, difficulty in 
breathing when lying down, swelling of the feet or legs) or problems with the way your heart 

beats. Your doctor should check your heart function before and during treatment. 

 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 blockage (chorioretinopathy). 

 

Before you take Mekinist in combination with dabrafenib your doctor needs to know if you: 

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

 

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

 

Conditions you need to look out for 

 

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

important symptoms to look out for. 

 

Bleeding 

Taking Mekinist or the combination of Mekinist and dabrafenib 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 Mekinist or the combination of Mekinist and dabrafenib 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 

Mekinist can cause heart problems, or make existing heart problems worse (see also “Heart 

conditions” in section 4) in people taking Mekinist in combination with dabrafenib. 

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 this medicine. 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. 

 

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). 



52 

 

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). 

Mekinist can cause eye problems including blindness. Mekinist 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. 

 

Liver problems 
Mekinist, or the combination with dabrafenib, 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. 

 

Lung or breathing problems 

Tell your doctor if you have any lung or breathing problems, including difficulty in breathing 

often accompanied by a dry cough, shortness of breath and fatigue. Your doctor may arrange to check 

your lung function before you start taking your medicine. 

 

Muscle pain 

Mekinist 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. 

 

 Read the information “Possible serious side effects” in section 4 of this leaflet. 
 

Hole in the stomach or intestine (perforation) 

Taking Mekinist or the combination of Mekinist and dabrafenib 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 Mekinist in combination with dabrafenib. 

Tell your doctor immediately if you notice any changes to your skin (see section 4 for symptoms to be 

aware of). 

 

Children and adolescents 

Mekinist is not recommended for children and adolescents since the effects of Mekinist in people 

younger than 18 years old are not known. 

 



53 

Other medicines and Mekinist 
Before starting treatment, tell your doctor, nurse or pharmacist if you are taking, have recently taken or 

might take any other medicines. This includes medicines obtained without a prescription. Keep a list 

of the medicines you take, so you can show it to your doctor, nurse or pharmacist when you get a new 

medicine. 

 

Mekinist with food and drink 

It is important to take Mekinist on an empty stomach because food affects the way the medicine is 

absorbed into your body (see section 3). 

 

Pregnancy, breast-feeding and fertility 

Mekinist is not recommended for use during pregnancy. 

 If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor 
for advice before taking this medicine. Mekinist can harm the unborn baby. 

 If you are a woman who could become pregnant, you must use reliable birth control 
(contraception) while you are taking Mekinist and for at least 16 weeks after you stop taking it. 

 Birth control using hormones (such as pills, injections or patches) may not work as well if you 
are taking Mekinist or combination treatment (Mekinist as well as dabrafenib). 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, nurse or pharmacist for advice. 

 If you do become pregnant while you are taking Mekinist, tell your doctor immediately. 
 

Mekinist is not recommended while breast-feeding 

It is not known whether the ingredients of Mekinist can pass into breast milk. 

If you are breast-feeding, or planning to breast-feed, you must tell your doctor. It is recommended that 

you do not breast-feed while you are taking Mekinist. You and your doctor will decide whether you 

will take Mekinist or breast-feed. 

 

Fertility – both men and women 

Mekinist may impair fertility in both men and women. 

 

Taking Mekinist with dabrafenib: Dabrafenib may permanently reduce male fertility. In addition, men 

who are taking dabrafenib 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 dabrafenib, talk to your doctor about options to improve your chances 

to have children in the future. 

 

If you have any further questions on the effect of this medicine on fertility, ask your doctor, nurse or 

pharmacist. 

 

Driving and using machines 
Mekinist can have side effects that may affect your ability to drive or use machines. Avoid driving or 

using machines if you feel tired or weak, if you have problems with your vision or if your energy 

levels are low. 

Descriptions of these effects can be found in other sections (see sections 2 and 4). Read all the 

information in this leaflet for guidance. 

Discuss with your doctor, nurse or pharmacist if you are unsure about anything. Your disease  

symptoms and treatment situation may also affect your ability to drive or use machines. 

 

 

3. How to take Mekinist 

 

Always take Mekinist exactly as your doctor, nurse or pharmacist has told you. Check with your 

doctor, nurse or pharmacist if you are not sure. 

 



54 

How much to take 

The usual dose of Mekinist either used alone or in combination with dabrafenib is one 2 mg tablet 

once a day. The recommended dose of dabrafenib, when used in combination with Mekinist, is 150 mg 

twice daily. 

 

Your doctor may decide to lower the dose if you get side effects. 

 

Don’t take more Mekinist than your doctor has recommended, since this may increase the risk of 

side effects. 

 

How to take it 

Swallow the tablet whole, with a full glass of water. 

Take Mekinist once a day, on an empty stomach (at least 1 hour before a meal or 2 hours after a meal). 

This means that: 

 after taking Mekinist, you must wait at least 1 hour before eating, or 

 after eating, you must wait at least 2 hours before taking Mekinist. 
 

Take Mekinist at about the same time each day. 

 

If you take more Mekinist than you should 

If you take too many tablets of Mekinist, contact your doctor, nurse or pharmacist for advice. If 

possible, show them the Mekinist pack and this leaflet. 

 

If you forget to take Mekinist 

If the missed dose is less than 12 hours late, take it as soon as you remember. 

If the missed dose is more than12 hours late, skip that dose and take your next dose at the usual time. 

Then carry on taking your tablets at regular times as usual. 

Do not take a double dose to make up for a missed dose. 

 

If you stop taking Mekinist 

Take Mekinist for as long as your doctor recommends. Do not stop unless your doctor advises you to. 

 

If you have any further questions on how to take Mekinist, ask your doctor, nurse or pharmacist. 

 

How should you take Mekinist in combination with dabrafenib 

 Take Mekinist in combination with dabrafenib exactly as your doctor, nurse or pharmacist tells 
you. Do not change your dose or stop Mekinist or dabrafenib unless your doctor, nurse or 

pharmacist tells you to. 

 Take Mekinist once daily and take dabrafenib twice daily. It may be good for you to get into 
the habit of taking both medicines at the same times each day. Mekinist should be taken with 

either the morning dose of dabrafenib or the evening dose of dabrafenib. The dabrafenib doses 

should be about 12 hours apart. 

 Take Mekinist and dabrafenib 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 Mekinist or dabrafenib, 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 12 hours to your next scheduled dose of Mekinist, which is taken once 
daily. 

o If it is less than 6 hours to your next scheduled dose of dabrafenib, which is taken twice 
daily. 

 If you take too much Mekinist or dabrafenib, immediately contact your doctor, nurse or 
pharmacist. Take Mekinist tablets and dabrafenib capsules with you when possible. If possible, 

show them the Mekinist and dabrafenib pack with each leaflet. 

 If you get side effects your doctor may decide that you should take lower doses of Mekinist and 
dabrafenib. Take the doses of Mekinist and dabrafenib exactly as your doctor, nurse or 

pharmacist tells you. 

 



55 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Possible side effects in patients taking Mekinist alone 

 

Possible serious side effects 

 

Heart conditions 

Mekinist can affect how well your heart pumps blood. 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 Mekinist. 

Signs and symptoms of heart problems include: 

 feeling like your heart is pounding, racing, or beating irregularly 

 dizziness 

 tiredness 

 feeling light-headed 

 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. 

 

High blood pressure 

Mekinist can cause new or worsening high blood pressure (hypertension). Your doctor or nurse should 

check your blood pressure during treatment with Mekinist. Call your doctor or nurse right away if you 

develop high blood pressure, your blood pressure worsens, or you have severe headache, 

light-headedness, or dizziness. 

 

Bleeding problems 

Mekinist can cause serious bleeding problems, especially in your brain or stomach. 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 
 

Eye (vision) problems 

Mekinist can cause eye problems. Mekinist 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 Mekinist and while you are taking it. Your doctor may ask you to stop taking Mekinist 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 
 



56 

Changes in your skin 

Serious skin reactions have been reported in people taking Mekinist in combination with dabrafenib 

(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 
 

Up to 3 in 100 people taking Mekinist in combination with dabrafenib may 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 Mekinist and dabrafenib can be continued without 

interruption. 

 

Some people taking Mekinist in combination with dabrafenib may also notice that new melanomas 

have appeared. These melanomas are usually removed by surgery and treatment with Mekinist and 

dabrafenib can be continued without interruption. 

 

Your doctor will check your skin before you start taking dabrafenib, 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, neck, mouth and 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. 

 

Mekinist as monotherapy or in combination with dabrafenib can cause rash or acne-like rash. Follow 

your doctor’s instructions for what to do to help prevent rash. Tell your doctor or nurse as soon as 

possible if you get any of these symptoms for the first time or if they get worse. 

Contact your doctor immediately if you get a severe skin rash with any of the following symptoms: 

blisters on your skin, blisters or sores in your mouth, peeling of your skin, fever, redness or swelling of 

your face, or soles of your feet. 

 

Tell your doctor or nurse as soon as possible if you get any skin rash, or if you have a rash that gets 

worse. 

 

Muscle pain 

Mekinist can result in the breakdown of muscle (rhabdomyolysis). Tell your doctor or nurse if you 

have any new or worsening symptoms, including: 

 muscle pain 

 dark urine due to kidney damage 
 

Lung or breathing problems 

Mekinist can cause inflammation of the lung (pneumonitis or interstitial lung disease). Tell your 

doctor or nurse if you have any new or worsening symptoms of lung or breathing problems, including: 

 shortness of breath 

 cough 

 fatigue 
 

  



57 

The other side effects that you may see when you take Mekinist alone are as follows: 

 

Very common side effects (may affect more than 1 in 10 people): 

 High blood pressure (hypertension) 

 Bleeding, at various sites in the body, which may be mild or serious 

 Cough 

 Shortness of breath 

 Diarrhoea 

 Feeling sick (nausea), being sick (vomiting) 

 Constipation 

 Stomach ache 

 Dry mouth 

 Skin rash, acne-like rash, redness of the face, dry or itching skin (see also “Changes in your 
skin” earlier in section 4) 

 Unusual hair loss or thinning 

 Lack of energy or feeling weak or tired 

 Swelling of the hands or feet (oedema peripheral) 

 Fever 
 

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): 

 Inflammation of hair follicles in the skin 

 Nail disorders such as nail bed changes, nail pain, infection and swelling of the cuticles 

 Infection of the skin (cellulitis) 

 Skin rash with pus-filled blisters (see also “Changes in your skin” earlier in section 4) 

 Allergic reaction (hypersensitivity) 

 Dehydration (low levels of water or fluid) 

 Blurred vision 

 Swelling around the eyes 

 Eyesight problems (see also “Eye (vision) problems” earlier in section 4) 

 Changes in how the heart pumps blood (left ventricular dysfunction) (see also “Heart 
conditions” earlier in section 4) 

 Heart rate that is lower than the normal range and/or a decrease in heart rate 

 Localised tissue swelling 

 Inflammation of the lung (pneumonitis or interstitial lung disease) 

 Sore mouth or mouth ulcers, inflammation of mucous membranes 

 Reddening, chapping or cracking of the skin 

 Red, painful hands and feet 

 Swelling of the face 

 Inflammation of the mucosa 

 Feeling weak 
 

Common side effects that may show up in your blood tests: 

 Decreased red blood cells (anaemia), abnormal test related to creatine phosphokinase, an 
enzyme found mainly in heart, brain, and skeletal muscle 

 

  



58 

Uncommon side effects (may affect up to 1 in 100 people): 

 Swelling in the eye caused by fluid leakage (chorioretinopathy) (see also “Eye (vision) 
problems” earlier in section 4) 

 Swelling of nerves at the back of the eye (papilloedema) (see also “Eye (vision) problems” 
earlier in section 4) 

 Separation of the light-sensitive membrane in the back of the eye (the retina) from its supporting 
layers (retinal detachment) (see also “Eye (vision) problems” earlier in section 4). 

 Blockage of the vein draining the eye (retinal vein occlusion) (see also “Eye (vision) problems” 
earlier in section 4) 

 Heart pumping less efficiently, causing shortness of breath, extreme tiredness and swelling in 
ankles and legs (heart failure) 

 A hole (perforation) in the stomach or intestines 

 Inflammation of the intestines (colitis) 

 Breakdown of muscle which can cause muscle pain and kidney damage (rhabdomyolysis) 
 

If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible 

side effects not listed in this leaflet. 

 

Side effects when Mekinist and dabrafenib are taken together 

 

When you take Mekinist and dabrafenib 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 dabrafenib at the same time as Mekinist in 

the list below. 

 

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 read the dabrafenib Package Leaflet for details of the side effects you may get when 

taking this medicine. 

 

The side effects that you may see when you take Mekinist in combination with dabrafenib 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 



59 

 

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 
 

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 
 



60 

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, nurse or pharmacist. 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 Mekinist 

 

Keep this medicine out of the sight and reach of children. 

Do not take Mekinist after the expiry date (EXP) which is stated on the bottle label and carton. The 

expiry date refers to the last day of that month. 

Store in a refrigerator (2°C to 8°C). 

Store in the original package in order to protect from light and moisture. 

Keep the bottle tightly closed with the dessicant inside (small cylinder shaped container). 

Once opened, the bottle may be stored for 30 days at not more than 30°C. 

Do not throw away medicines in wastewater or household waste. Ask your pharmacist how to throw 

away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Mekinist contains 

 

- The active substance is trametinib. Each film-coated tablet contains trametinib dimethyl 
sulfoxide equivalent to 0.5 mg or 2 mg of trametinib. 

- The other ingredients are 
- Tablet: mannitol (E421), microcrystalline cellulose (E460), hypromellose (E464), 

croscarmellose sodium (E468), magnesium stearate (E470b), sodium laurilsulfate and 

colloidal silicon dioxide (E551). 

- Film coating: hypromellose (E464), titanium dioxide (E171), polyethylene glycol, iron 
oxide yellow (E172) (for 0.5 mg tablets), polysorbate 80 (E433) and iron oxide red 

(E172) (for 2 mg tablets). 

 

What Mekinist looks like and contents of the pack 

 

The Mekinist 0.5 mg film-coated tablets are yellow, modified oval, biconvex, with “GS” debossed on 

one face and “TFC” on the opposing face. 

 

The Mekinist 2 mg film-coated tablets are pink, round, biconvex, with “GS” debossed on one face and 

“HMJ” on the opposing face. 

 

The film-coated tablets are supplied in opaque white plastic bottles with threaded plastic closures. One 

bottle contains either 7 or 30 tablets. 

 

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. 

 

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


61 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Lek Pharmaceuticals d.d. 

Verovskova ulica 57 

1526, Ljubljana 

Slovenia 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

Glaxo Wellcome, S.A. 

Avda. Extremadura, 3 

09400, Aranda de Duero 

Burgos 

Spain 

 

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 

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 



62 

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 MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET