MEKINIST 2mg tablets medication leaflet

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

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

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Yellow, modified oval, biconvex, film-coated tablets, approximately 5.0 x 9.0 mm, with the companylogo debossed on one face and “TT” on the opposing face.

Pink, round, biconvex, film-coated tablets, approximately 7.6 mm, with the company logo debossedon one face and “LL” on the opposing face.

Trametinib as monotherapy or in combination with dabrafenib is indicated for the treatment of adultpatients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and5.1).

Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on aprior BRAF inhibitor therapy (see section 5.1).

Trametinib in combination with dabrafenib is indicated for the adjuvant treatment of adult patientswith Stage III melanoma with a BRAF V600 mutation, following complete resection.

Trametinib in combination with dabrafenib is indicated for the treatment of adult patients withadvanced non-small cell lung cancer with a BRAF V600 mutation.

Treatment with trametinib should only be initiated and supervised by a physician experienced in theadministration of anti-cancer medicinal products.

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

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.

It is recommended that patients continue treatment with trametinib until patients no longer derivebenefit 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 unacceptabletoxicity.

If a dose of trametinib is missed, it should only be taken if it is more than 12 hours until the nextscheduled dose.

If a dose of dabrafenib is missed, when trametinib is given in combination with dabrafenib, the dose ofdabrafenib should only be taken if it is more than 6 hours until the next scheduled dose.

The management of adverse reactions may require dose reduction, treatment interruption or treatmentdiscontinuation (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 Dabrafenib dose*

Used as monotherapy or in Only when used in combination withcombination with dabrafenib trametinib

Starting dose 2 mg once daily 150 mg twice daily1st dose reduction 1.5 mg once daily 100 mg twice daily2nd dose reduction 1 mg once daily 75 mg twice daily3rd dose reduction 1 mg once daily 50 mg twice daily(combination only)

Dose adjustment for trametinib below 1 mg once daily is not recommended, whether used asmonotherapy or in combination with dabrafenib. Dose adjustment for dabrafenib below 50 mgtwice daily is not recommended when used in combination with trametinib.

*Please refer to the dabrafenib SmPC, Posology and method of administration, for dosing instructions fortreatment with dabrafenib monotherapy.

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

Grade (CTCAE)* Recommended trametinib dose modifications

Used as monotherapy or in combination with dabrafenib

Grade 1 or Grade 2 Continue treatment and monitor as clinically indicated.

(Tolerable)

Grade 2 (Intolerable) or Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one dose

Grade 3 level when resuming therapy.

Grade 4 Discontinue permanently, or interrupt therapy until Grade 0 to 1 andreduce by one dose level when resuming therapy.

* The intensity of clinical adverse reactions graded by the Common Terminology Criteria for Adverse

Events (CTCAE)

When an individual’s adverse reactions are under effective management, dose re-escalation followingthe same dosing steps as de-escalation may be considered. The trametinib dose should not exceed2 mg once daily.

If a patient’s temperature is ≥38oC, therapy should be interrupted (trametinib when used asmonotherapy, and both trametinib and dabrafenib when used in combination). In case of recurrence,therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such asibuprofen or acetaminophen/paracetamol should be initiated. The use of oral corticosteroids should beconsidered in those instances in which anti-pyretics are insufficient. Patients should be evaluated forsigns and symptoms of infection and, if necessary, treated in line with local practice (see section 4.4).

Trametinib, or both trametinib and dabrafenib when used in combination, should be restarted if thepatient is symptom-free for at least 24 hours either (1) at the same dose level, or (2) reduced by onedose level if pyrexia is recurrent and/or was accompanied by other severe symptoms includingdehydration, hypotension or renal failure.

If treatment-related toxicities occur when trametinib is used in combination with dabrafenib, then bothtreatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dosemodifications are necessary for only one of the two treatments are detailed below for uveitis, RASmutation-positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricularejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelialdetachment (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 selectedadverse reactions

No dose modifications are required for uveitis as long as effective local therapies can control ocularinflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld untilresolution 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 (seesection 4.4).

RAS mutation-positive non-cutaneous malignancies

The benefits and risks must be considered before continuing treatment with dabrafenib in patients witha non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is requiredwhen taken in combination with dabrafenib.

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 incombination with dabrafenib. If the LVEF recovers, treatment with trametinib may be restarted, butthe 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 cardiacdysfunction or clinically significant LVEF reduction which does not recover within 4 weeks (seesection 4.4).

If patients report new visual disturbances such as diminished central vision, blurred vision or loss ofvision at any time while on trametinib therapy, a prompt ophthalmological assessment isrecommended. In patients who are diagnosed with RVO, treatment with trametinib, whether given asmonotherapy or in combination with dabrafenib, should be permanently discontinued. No dosemodification 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 (seesection 4.4).

Table 3 Recommended dose modifications for trametinib for RPED

Grade 1 RPED Continue treatment with retinal evaluation monthly untilresolution. If RPED worsens follow instructions belowand 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 Resume trametinib at a lower dose (reduced by 0.5 mg)

Grade 0-1 within 3 weeks or discontinue trametinib in patients taking trametinib1 mg daily.

Grade 2-3 RPED that does not improve Permanently discontinue trametinib.

to at least Grade 1 within 3 weeks

Trametinib must be withheld in patients with suspected ILD or pneumonitis, including patientspresenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea,hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Trametinib must bepermanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis. No dosemodification of dabrafenib is required when trametinib is taken in combination with dabrafenib forcases of ILD or pneumonitis.

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 potentialneed for starting dose adjustment cannot be determined. Trametinib should be used with caution inpatients with severe renal impairment when administered as monotherapy or in combination withdabrafenib.

No dosage adjustment is required in patients with mild hepatic impairment. Available data from aclinical pharmacology study indicate a limited impact of moderate to severe hepatic impairment ontrametinib exposure (see section 5.2). Trametinib should be used with caution in patients withmoderate or severe hepatic impairment when administered as monotherapy or in combination withdabrafenib.

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

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).

The safety and efficacy of trametinib tablets in children and adolescents (<18 years) have not beenestablished. No data are available. Studies in juvenile animals have shown adverse effects oftrametinib which were not observed in adult animals (see section 5.3).

Trametinib should be taken orally with a full glass of water. The tablets should not be chewed orcrushed 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 trametiniband dabrafenib are taken in combination, the once-daily dose of trametinib should be taken at the sametime 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 thenext scheduled dose.

Please refer to dabrafenib SmPC for information on method of administration when given incombination with trametinib.

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

When trametinib is given in combination with dabrafenib, the SmPC of dabrafenib must be consultedprior to initiation of treatment. For additional information on warnings and precautions associated withdabrafenib treatment, please refer to the dabrafenib SmPC.

The efficacy and safety of trametinib have not been evaluated in patients whose melanoma testednegative for the BRAF V600 mutation.

Trametinib monotherapy has not been compared with a BRAF inhibitor in a clinical study in patientswith BRAF V600 mutation-positive unresectable or metastatic melanoma. Based on cross-studycomparisons, overall survival and progression-free survival data appear to show similar effectivenessbetween trametinib and BRAF inhibitors; however, overall response rates were lower in patientstreated 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 haveprogressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will belower in these patients (see section 5.1). Therefore other treatment options should be considered beforetreatment with the combination in this prior BRAF inhibitor treated population. The sequencing oftreatments following progression on a BRAF inhibitor therapy has not been established.

New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combinationwith dabrafenib.

Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with trametinib incombination with dabrafenib. Cases of cuSCC can be managed with excision and do not requiretreatment modification. Please refer to the dabrafenib SmPC (section 4.4).

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

Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancieswhen RAS mutations are present. When trametinib is used in combination with dabrafenib please referto the dabrafenib SmPC (section 4.4). No dose modification of trametinib is required for RASmutation-positive malignancies when taken in combination with dabrafenib.

Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, have occurred inpatients taking trametinib as monotherapy and in combination with dabrafenib (see section 4.8). Thepotential for these events in patients with low platelet counts (<75 000) has not been established assuch patients were excluded from clinical trials. The risk of haemorrhage may be increased withconcomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should betreated as clinically indicated.

Trametinib has been reported to decrease LVEF, when used as monotherapy or in combination withdabrafenib (see section 4.8). In clinical trials, the median time to onset of the first occurrence of leftventricular 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. Patientswith left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acutecoronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, anduncontrolled hypertension were excluded from clinical trials; safety of use in this population istherefore unknown. LVEF should be evaluated in all patients prior to initiation of treatment withtrametinib, one month after initiation of therapy, and then at approximately 3-monthly intervals whileon treatment (see section 4.2 regarding dose modification).

In patients receiving trametinib in combination with dabrafenib, there have been occasional reports ofacute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed whenstopping treatment. Physicians should be alert to the possibility of myocarditis in patients who developnew or worsening cardiac signs or symptoms.

Fever has been reported in clinical trials with trametinib as monotherapy and in combination withdabrafenib (see section 4.8). The incidence and severity of pyrexia are increased with the combinationtherapy (see dabrafenib SmPC section 4.4). In patients receiving trametinib in combination withdabrafenib, pyrexia may be accompanied by severe rigors, dehydration, and hypotension which insome cases can lead to acute renal insufficiency.

Therapy (trametinib when used as monotherapy, and both trametinib and dabrafenib when used incombination) should be interrupted if the patient’s temperature is ≥38ºC (see section 5.1). In case ofrecurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oralcorticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patientsshould be evaluated for signs and symptoms of infection. Therapy can be restarted once the feverresolves. If fever is associated with other severe signs or symptoms, therapy should be restarted at areduced dose once fever resolves and as clinically appropriate (see section 4.2).

Elevations in blood pressure have been reported in association with trametinib as monotherapy and incombination 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, withcontrol of hypertension by standard therapy as appropriate.

In a Phase III trial, 2.4% (5/211) of patients treated with trametinib monotherapy developed ILD orpneumonitis; all five patients required hospitalisation. The median time to first presentation of ILD orpneumonitis 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 withdabrafenib developed pneumonitis or ILD (see section 4.8).

Trametinib should be withheld in patients with suspected ILD or pneumonitis, including patientspresenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea,hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Trametinib should bepermanently discontinued for patients diagnosed with treatment-related ILD or pneumonitis (seesection 4.2). If trametinib is being used in combination with dabrafenib then therapy with dabrafenibmay be continued at the same dose.

Visual impairment

Disorders associated with visual disturbance, including RPED and RVO, may occur with trametinib asmonotherapy 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 incombination with dabrafenib.

Trametinib is not recommended in patients with a history of RVO. The safety of trametinib in subjectswith predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension,uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity orhypercoagulability syndromes, has not been established.

If patients report new visual disturbances, such as diminished central vision, blurred vision or loss ofvision at any time while on trametinib therapy, a prompt ophthalmological assessment isrecommended. 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 whoare diagnosed with RVO, treatment with trametinib should be permanently discontinued. No dosemodification of dabrafenib is required when taken in combination with trametinib following diagnosisof RVO or RPED. No dose modification of trametinib is required when taken in combination withdabrafenib following diagnosis of uveitis.

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

Rhabdomyolysis has been reported in patients taking trametinib as monotherapy or in combinationwith dabrafenib (see section 4.8). In some cases, patients were able to continue trametinib. In moresevere cases hospitalisation, interruption or permanent discontinuation of trametinib or trametinib anddabrafenib combination was required. Signs or symptoms of rhabdomyolysis should warrant anappropriate clinical evaluation and treatment as indicated.

Renal failure has been identified in patients treated with trametinib in combination with dabrafenib inclinical trials. Please refer to the dabrafenib SmPC (section 4.4).

Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib inclinical trials. Please refer to the dabrafenib SmPC (section 4.4).

Hepatic adverse reactions have been reported in clinical trials with trametinib as monotherapy and incombination with dabrafenib (see section 4.8). It is recommended that patients receiving treatmentwith trametinib monotherapy or in combination with dabrafenib have liver function monitored everyfour weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continuedthereafter as clinically indicated.

As metabolism and biliary excretion are the primary routes of elimination of trametinib, administrationof trametinib should be undertaken with caution in patients with moderate to severe hepaticimpairment (see sections 4.2 and 5.2).

Pulmonary embolism or deep vein thrombosis can occur when trametinib is used as monotherapy or incombination with dabrafenib. If patients develop symptoms of pulmonary embolism or deep veinthrombosis such as shortness of breath, chest pain, or arm or leg swelling, they should immediatelyseek medical care. Permanently discontinue trametinib and dabrafenib for life-threatening pulmonaryembolism.

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drugreaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal,have been reported during treatment with dabrafenib/trametinib combination therapy. Before initiatingtreatment, patients should be advised of the signs and symptoms and monitored closely for skinreactions. If signs and symptoms suggestive of SCARs appear, dabrafenib and trametinib should bewithdrawn.

Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients takingtrametinib as monotherapy and in combination with dabrafenib (see section 4.8). Treatment withtrametinib monotherapy or in combination with dabrafenib should be used with caution in patientswith risk factors for gastrointestinal perforation, including history of diverticulitis, metastases to thegastrointestinal tract and concomitant use of medicinal products with a recognised risk ofgastrointestinal perforation.

Cases of sarcoidosis have been reported in patients treated with trametinib in combination withdabrafenib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases,treatment with trametinib and dabrafenib was maintained. In case of a diagnosis of sarcoidosis,relevant treatment should be considered. It is important not to misinterpret sarcoidosis as diseaseprogression.

Haemophagocytic lymphohistiocytosis

In post-marketing experience, haemophagocytic lymphohistiocytosis (HLH) has been observed inpatients treated with trametinib in combination with dabrafenib. Caution should be taken whentrametinib is administered in combination with dabrafenib. If HLH is confirmed, administration oftrametinib and dabrafenib should be discontinued and treatment for HLH initiated.

The occurrence of TLS, which may be fatal, has been associated with the use of trametinib incombination with dabrafenib (see section 4.8). Risk factors for TLS include high tumour burden,pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Patientswith risk factors for TLS should be closely monitored and prophylactic hydration should beconsidered. TLS should be treated promptly, as clinically indicated.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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 metabolicinteractions (see section 5.2). Drug-drug interactions via these hydrolytic enzymes cannot be ruled outand could influence the exposure to trametinib.

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

Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the pharmacokinetics ofother 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, whichmay be minimised with staggered dosing (2 hours apart) of these agents and trametinib.

Based on clinical data, no loss of efficacy of hormonal contraceptives is expected when co-administered with trametinib monotherapy (see section 5.2).

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

SmPC for interactions.

Patients should take trametinib as monotherapy or in combination with dabrafenib at least one hourprior to or two hours after a meal due to the effect of food on trametinib absorption (see section 4.2and 5.2).

Female patients of reproductive potential must be advised to use effective methods of contraceptionduring treatment with trametinib and for 16 weeks after stopping treatment.

Use with dabrafenib may render hormonal contraceptives less effective and therefore an alternativemethod of contraception, such as a barrier method, should be used when trametinib is used incombination with dabrafenib. Refer to the dabrafenib SmPC for further information.

There are no adequate and well-controlled studies of trametinib in pregnant women. Animal studieshave shown reproductive toxicity (see section 5.3). Trametinib should not be administered to pregnantwomen. If trametinib is used during pregnancy, or if the patient becomes pregnant while takingtrametinib, the patient should be informed of the potential hazard to the foetus.

It is not known whether trametinib is excreted in human milk. Because many medicinal products areexcreted in human milk, a risk to the breast-feeding infant cannot be excluded. Trametinib should notbe 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 andthe benefit of therapy for the woman.

There are no data in humans for trametinib as monotherapy or in combination with dabrafenib. Inanimals, no fertility studies have been performed, but adverse effects were seen on femalereproductive organs (see section 5.3). Trametinib may impair fertility in humans.

Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients takingtrametinib in combination with dabrafenib should be informed of the potential risk for impairedspermatogenesis, which may be irreversible. Refer to the dabrafenib SmPC for further information.

Trametinib has minor influence on the ability to drive and use machines. The clinical status of thepatient and the adverse reaction profile should be borne in mind when considering the patient’s abilityto perform tasks that require judgement, motor and cognitive skills. Patients should be made aware ofpotential for fatigue, dizziness or eye problems that might affect these activities.

The safety of trametinib monotherapy has been evaluated in the integrated safety population of329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with trametinib2 mg once daily in studies MEK114267, MEK113583, and MEK111054. Of these patients, 211 weretreated with trametinib for BRAF V600 mutant melanoma in the randomised open-label Phase IIIstudy MEK114267 (METRIC) (see section 5.1). The most common adverse reactions (incidence≥20%) for trametinib were rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitisacneiform.

The safety of trametinib in combination with dabrafenib has been evaluated in the integrated safetypopulation 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 IIIstudies, MEK115306 (COMBI-d) and MEK116513 (COMBI-v), 435 were treated with thecombination in the adjuvant treatment of Stage III BRAF V600 mutant melanoma after completeresection in a randomised Phase III study BRF115532 (COMBI-AD) and 82 were treated with thecombination 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 dabrafenibwere: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.

Adverse reactions associated with trametinib obtained from clinical studies and post-marketingsurveillance are tabulated below for trametinib monotherapy (Table 4) and trametinib in combinationwith dabrafenib (Table 5).

Adverse reactions are listed below by MedDRA 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

Very rare <1/10 000

Not known (cannot be estimated from the available data)

Categories have been assigned based on absolute frequencies in the clinical trial data. Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions with trametinib monotherapy

System Organ Class Frequency (all Adverse Reactionsgrades)

Folliculitis

Paronychia

Infections and infestations Common

Cellulitis

Rash pustular

Blood and lymphatic system

Common Anaemiadisorders

Immune system disorders Common Hypersensitivitya

Metabolism and nutrition

Common Dehydrationdisorders

Peripheral neuropathy (including sensory

Nervous system disorders Commonand motor neuropathy)

Vision blurred

Common Periorbital oedema

Visual impairment

Eye disorders Chorioretinopathy

Papilloedema

Uncommon

Retinal detachment

Retinal vein occlusion

Common Ejection fraction decreased

Cardiac disorders Bradycardia

Uncommon Cardiac failure

Not known Atrioventricular blockb

Very common

Vascular disorders Haemorrhagec

Common Lymphoedema

Cough

Very common

Respiratory, thoracic and Dyspnoeamediastinal disorders Common Pneumonitis

Uncommon Interstitial lung disease

Nausea

Very common

Gastrointestinal disorders Abdominal pain

Dry mouth

Common Stomatitis

Uncommon Gastrointestinal perforation

Very common Dry skin

Pruritus

Skin and subcutaneous tissue Alopeciadisorders Erythema

Palmar-plantar erythrodysaesthesia

Common syndrome

Skin fissures

Skin chapped

Musculoskeletal and

Uncommon Rhabdomyolysisconnective tissue disorders

Very common Oedema peripheral

General disorders and

Pyrexiaadministration site

Face oedemaconditions

Common Mucosal inflammation

Asthenia

Very common Aspartate aminotransferase increased

Alanine aminotransferase increased

Common Blood alkaline phosphatase increased

Blood creatine phosphokinase increaseda May present with symptoms such as fever, rash, increased liver transaminases, and visual disturbances.b Including atrioventricular block complete.c 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 with trametinib in combination with dabrafenib

System Organ Class Frequency (all Adverse Reactionsgrades)

Very common Nasopharyngitis

Cellulitis

Common Folliculitis

Paronychia

Rash pustular

Cutaneous squamous cell carcinomaa

Neoplasms benign, Common Papillomabmalignant and unspecified Seborrhoeic keratosis(incl cysts and polyps) New primary melanomac

Uncommon

Acrochordon (skin tags)

Blood and lymphatic system Anaemia

Commondisorders Thrombocytopenia

Leukopenia

Hypersensitivityd

Uncommon

Immune system disorders Sarcoidosis

Rare Haemophagocytic lymphohistiocytosis

Very common Decreased appetite

Metabolism and nutrition Hyponatraemia

Commondisorders Hypophosphataemia

Not known Tumour lysis syndrome

Very common

Dizziness

Peripheral neuropathy (including sensory

Commonand motor neuropathy)

Vision blurred

Common Visual impairment

Chorioretinopathy

Uncommon Retinal detachment

Periorbital oedema

Common Ejection fraction decreased

Atrioventricular blocke

Cardiac disorders Uncommon

Bradycardia

Not known Myocarditis

Very common

Haemorrhagef

Common

Lymphoedema

Very common Cough

Respiratory, thoracic and

Common Dyspnoeamediastinal disorders

Uncommon Pneumonitis

Abdominal paing

Very common Diarrhoea

Nausea

Gastrointestinal disorders Dry mouth

Common

Stomatitis

Uncommon

Rare Gastrointestinal perforation

Dry skin

Pruritus

Very common

Erythemah

Actinic keratosis

Night sweats

Hyperkeratosis

Alopecia

Palmar-plantar erythrodysaesthesia

Skin and subcutaneous tissue Commonsyndromedisorders

Skin lesion

Hyperhidrosis

Panniculitis

Skin fissures

Uncommon Acute febrile neutrophilic dermatosis

Stevens-Johnson syndrome

Drug reaction with eosinophilia and

Not Knownsystemic symptoms

Dermatitis exfoliative generalised

Arthralgia

Musculoskeletal and Myalgia

Very commonconnective tissue disorders Pain in extremity

Muscle spasmsi

Renal and urinary disorders Uncommon

Nephritis

Chills

Asthenia

General disorders and Very common

Oedema peripheraladministration site

Pyrexiaconditions

Influenza-like illness

Mucosal inflammation

Common

Face oedema

Alanine aminotransferase increased

Very common

Aspartate aminotransferase increased

Investigations Blood alkaline phosphatase increased

Common Gamma-glutamyltransferase increased

Blood creatine phosphokinase increased

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 followingadverse reactions have occurred in MEK116513 but not in MEK115306: cardiac failure, left ventriculardysfunction, interstitial lung disease (uncommon); 3) The following adverse reaction has occurred in

MEK116513 and BRF115532 but not in MEK115306 and BRF113928: rhabdomyolysis (uncommon).a Cutaneous squamous cell carcinoma (cuSCC): SCC, SCC of the skin, SCC in situ (Bowen’s disease) andkeratoacanthomab Papilloma, skin papillomac Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma Stage IIId Includes drug hypersensitivitye Including atrioventricular block completef Bleeding from various sites, including intracranial bleeding and fatal bleedingg Abdominal pain upper and abdominal pain lowerh Erythema, generalised erythemai Muscle spasms, musculoskeletal stiffness

New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combinationwith dabrafenib. Please refer to the dabrafenib SmPC.

Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, occurred inpatients taking trametinib as monotherapy and in combination with dabrafenib. The majority ofbleeding events were mild. Fatal intracranial haemorrhages occurred in the integrated safetypopulation of trametinib in combination with dabrafenib in <1% (8/1 076) of patients. The mediantime to onset of the first occurrence of haemorrhagic events for the combination of trametinib anddabrafenib was 94 days in the melanoma Phase III studies and 75 days in the NSCLC study for thepatients who had received prior anti-cancer therapy.

The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulanttherapy. If haemorrhage occurs, treat as clinically indicated (see section 4.4).

Trametinib has been reported to decrease LVEF when used as monotherapy or in combination withdabrafenib. In clinical trials, the median time to first occurrence of left ventricular dysfunction, cardiacfailure and LVEF decrease was between 2 to 5 months. In the integrated safety population oftrametinib in combination with dabrafenib, decreased LVEF has been reported in 6% (65/1 076) ofpatients, with most cases being asymptomatic and reversible. Patients with LVEF lower than theinstitutional lower limit of normal were not included in clinical trials with trametinib. Trametinibshould be used with caution in patients with conditions that could impair left ventricular function (seesections 4.2 and 4.4).

Pyrexia has been reported in clinical trials with trametinib as monotherapy and in combination withdabrafenib; however, the incidence and severity of pyrexia are increased with the combinationtherapy. Please refer to sections 4.4 and 4.8 of the dabrafenib SmPC.

Hepatic adverse reactions have been reported in clinical trials with trametinib as monotherapy and incombination with dabrafenib. Of the hepatic adverse reactions, increased ALT and AST were the mostcommon events and the majority were either Grade 1 or 2. For trametinib monotherapy, more than90% of these liver events occurred within the first 6 months of treatment. Liver events were detectedin clinical trials with monitoring every four weeks. It is recommended that patients receiving treatmentwith trametinib monotherapy or in combination with dabrafenib have liver function monitored everyfour weeks for 6 months. Liver monitoring may be continued thereafter as clinically indicated (seesection 4.4).

Elevations in blood pressure have been reported in association with trametinib as monotherapy and incombination with dabrafenib, in patients with or without pre-existing hypertension. Blood pressureshould be measured at baseline and monitored during treatment, with control of hypertension bystandard therapy as appropriate (see section 4.4).

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 patientspresenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea,hypoxia, pleural effusion, or infiltrates, pending clinical investigations. For patients diagnosed withtreatment-related ILD or pneumonitis trametinib should be permanently discontinued (see sections 4.2and 4.4).

Visual impairment

Disorders associated with visual disturbances, including RPED and RVO, have been observed withtrametinib. Symptoms such as blurred vision, decreased acuity, and other visual disturbances havebeen reported in the clinical trials with trametinib (see sections 4.2 and 4.4).

Rash has been observed in about 60% of patients when given as monotherapy and in about 24% ofpatients in trametinib and dabrafenib combination studies in the integrated safety population. Themajority 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 has been reported in patients taking trametinib alone or in combination withdabrafenib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluationand treatment as indicated (see section 4.4).

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

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

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 ofsubjects experiencing adverse reactions (AR) and serious adverse reactions (SAR) was similar in thesubjects 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 interruptionthan 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 ofpatients 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 permanentdiscontinuation of medicinal product, dose reduction and dose interruption than those <65 years.

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 and4.4).

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 (seesections 4.2 and 4.4).

The safety and efficacy of the combination of trametinib and dabrafenib have been evaluated in amulti-cohort, open-label, Phase II study in patients with BRAF V600 mutant melanoma with brainmetastases. The safety profile observed in these patients appears to be consistent with the integratedsafety profile of the combination.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical trials with trametinib monotherapy one case of accidental overdose was reported; a singledose of 4 mg. No AEs were reported following this event of trametinib overdose. In clinical trials withthe 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 shouldbe treated supportively with appropriate monitoring as necessary.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, Mitogen-activated proteinkinase (MEK) inhibitors, ATC code: L01EE01

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellularsignal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins arecomponents 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 inhibitsactivation 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 mutantmelanoma animal models.

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutiveactivation of the RAS/RAF/MEK/ERK pathway. Thus, trametinib and dabrafenib inhibit two kinasesin this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of thepathway. 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.

Before taking trametinib or the combination with dabrafenib, patients must have BRAF V600mutation-positive tumour status confirmed by a validated test.

In clinical trials, central testing for BRAF V600 mutation using a BRAF mutation assay wasconducted on the most recent tumour sample available. Primary tumour or tumour from a metastaticsite 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 V600Kmutations. Only patients with BRAF V600E or V600K mutation-positive tumours were eligible forstudy 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 DNAextracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and V600Kmutations 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 withretrospective bi-directional Sanger sequencing analyses have shown that the test also detects the lesscommon BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of thespecimens 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 assaywas 94%.

Trametinib suppressed levels of phosphorylated ERK in BRAF mutant melanoma tumour cell linesand melanoma xenograft models.

In patients with BRAF and NRAS mutation-positive melanoma, administration of trametinib resultedin 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). Themean trametinib concentrations observed following repeat dose administration of 2 mg once dailyexceeds the preclinical target concentration over the 24-hr dosing interval, thereby providing sustainedinhibition of the MEK pathway.

In the clinical trials only patients with cutaneous melanoma were studied. Efficacy in patients withocular or mucosal melanoma has not been assessed.

* Trametinib in combination with dabrafenib

The efficacy and safety of the recommended dose of trametinib (2 mg once daily) in combination withdabrafenib (150 mg twice daily) for the treatment of adult patients with unresectable or metastaticmelanoma with a BRAF V600 mutation was studied in two Phase III studies and one supportive

Phase I/II study.

MEK115306 was a Phase III, randomised, double-blinded study comparing the combination ofdabrafenib 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. Theprimary endpoint of the study was progression-free survival (PFS), with a key secondary endpoint ofoverall survival (OS). Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limitof 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 visceraldisease (73%) at baseline. The majority of subjects had a BRAF V600E mutation (85%). Subjects withbrain 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 approximately7 months longer than for dabrafenib monotherapy (25.8 months versus 18.7 months) with 5-yearsurvival 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 overallsurvival 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 atbaseline, and 16% (95% CI: 8.4, 26.0) in the combination arm versus 14% (95% CI: 6.8, 23.1) in thedabrafenib monotherapy arm for patients with an elevated lactate dehydrogenase level at baseline.

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

OS analysis 5-year OS analysis(data cut-off: 12-Jan-2015) (data cut-off: 10-Dec-2018)

Dabrafenib + Dabrafenib + Dabrafenib + Dabrafenib+

Trametinib Placebo Trametinib Placebo(n=211) (n=212) (n=211) (n=212)

Number of patients

Died (event), n99 (47) 123 (58) 135 (64) 151 (71)(%)

Estimates of OS (months)25.1 18.7 25.8 18.7

Median (95% CI)(19.2, NR) (15.2, 23.7) (19.2, 38.2) (15.2, 23.1)

Hazard ratio 0.71 0.80(95% CI) (0.55, 0.92) (0.63, 1.01)p-value 0.011 NA

Overall survival

Dabrafenib + Trametinib Dabrafenib + Placeboestimate, % (95%(n=211) (n=212)

CI)

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)1.0 Dabrafenib + Trametinib

Dabrafenib + Placebo0.80.60.40.20.00 6 12 18 24 30 36 42 48 54 60 66 72 78

Time since Randomisation (Months)

Subjects at Risk:

Dabrafenib + Trametinib 211 188 145 113 98 86 79 71 63 60 57 54 12 0

Dabrafenib + Placebo 212 175 137 104 84 69 60 56 54 51 50 46 10 0

Estimated Survival Function

Improvements for the primary endpoint of PFS were sustained over a 5 year timeframe in thecombination arm compared to dabrafenib monotherapy. Improvements were also observed for overallresponse rate (ORR) and a longer duration of response (DoR) was observed in the combination armcompared to dabrafenib monotherapy (Table 7).

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

Primary analysis (data cut- Updated analysis (data cut- 5-year analysis (data cut-off: 26-Aug-2013) off: 12-Jan-2015) off: 10-Dec-2018)

Endpoint Dabrafenib Dabrafenib Dabrafenib Dabrafenib Dabrafenib Dabrafenib+ + + + + +

Trametinib Placebo Trametinib Placebo Trametinib Placebo(n=211) (n=212) (n=211) (n=212) (n=211) (n=212)

PFSa

Progressive disease or 102 (48) 109 (51) 139 (66) 162 (76) 160 (76) 166 (78)death, n (%)

Median PFS (months) 9.3 8.8 11.0 8.8 10.2 8.8(95% CI) (7.7, 11.1) (5.9, 10.9) (8.0, 13.9) (5.9, 9.3) (8.1, 12.8) (5.9, 9.3)

Hazard Ratio 0.75 0.67 0.73(95% CI) (0.57, 0.99) (0.53, 0.84) (0.59, 0.91)

P value 0.035 <0.001f NA

ORRb 67 51 69 53 69 54% (95% CI) (59.9, 73.0) (44.5, 58.4) (61.8, 74.8) (46.3, 60.2) (62.5, 75.4) (46.8, 60.6)

ORR difference 15e 15e NA(95% CI) (5.9, 24.5) (6.0, 24.5)

P value 0.0015 0.0014f NA

DoRc (months)

Median 9.2d 10.2d 12.9 10.6 12.9 10.2(95% CI) (7.4, NR) (7.5, NR) (9.4,19.5) (9.1, 13.8) (9.3, 18.4) (8.3, 13.8)a - Progression-free survival (investigator assessed)b - Overall Response Rate = Complete Response + Partial Responsec - Duration of responsed - 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 roundedf - Updated analysis was not pre-planned and the p-value was not adjusted for multiple testing

NR = Not reached

NA = Not applicable

Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing dabrafenib andtrametinib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positiveunresectable or metastatic melanoma. The primary endpoint of the study was OS with a key secondaryendpoint of PFS. Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit ofnormal (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). Themajority 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 subjectshad <3 disease sites at baseline. The majority of subjects had BRAF V600E mutation-positivemelanoma (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 approximately8 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 lactatedehydrogenase 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 lactatedehydrogenase level at baseline.

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

OS analysis 5-year OS analysisdata cut-off: 13-Mar-2015) (data cut-off: 08-Oct-2018)

Dabrafenib + Dabrafenib +

Vemurafenib Vemurafenib

Trametinib Trametinib(n=352) (n=352)(n=352) (n=352)

Number of patients

Died (event), n155 (44) 194 (55) 216 (61) 246 (70)(%)

Estimates of OS (months)

Median (95% CI)25.6 18.0 26.0 17.8(22.6, NR) (15.6, 20.7) (22.1, 33.8) (15.6, 20.7)

Adjusted hazard 0.66 0.70ratio (95% CI) (0.53, 0.81) (0.58, 0.84)p-value <0.001 NA

Overall survival

Dabrafenib + Trametinib Vemurafenibestimate, % (95%(n=352) (n=352)

CI)

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 MEK1165131.0

Dabrafenib + Trametinib

Vemurafenib0.80.60.40.20.00 6 12 18 24 30 36 42 4 8 5 4 60 66 72 78

Time since Randomisation (Months)

Subjects at Risk:

Dabrafenib + Trametinib 352 311 246 201 171 151 140 130 118 109 104 49 4 0

Vemurafenib 352 287 201 154 120 104 94 86 78 72 65 30 1 0

Estimated Survival Function

Improvements for the secondary endpoint of PFS were sustained over a 5 year timeframe in thecombination arm compared to vemurafenib monotherapy. Improvements were also observed for ORRand 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- 5-year analysis (Data cut-off: 08-

Apr-2014) Oct-2018)

Endpoint Dabrafenib + Vemurafenib Dabrafenib + Vemurafenib

Trametinib (n=352) Trametinib (n=352)(n=352) (n=352)

PFSa

Progressive 166 (47) 217 (62) 257 (73) 259 (74)disease or death,n (%)

Median PFS 11.4 7.3 12.1 7.3(months) (9.9, 14.9) (5.8, 7.8) (9.7, 14.7) (6.0, 8.1)(95% CI)

Hazard Ratio 0.56 0.62(95% CI) (0.46, 0.69) (0.52, 0.74)

P value <0.001 NA

ORRb % 64 51 67 53(95% CI) (59.1, 69.4) (46.1, 56.8) (62.2, 72.2) (47.2, 57.9)

ORR difference 13 NA(95% CI) (5.7, 20.2)

P value 0.0005 NA

DoRc (months)

Median 13.8d 7.5d 13.8 8.5(95% CI) (11.0, NR) (7.3, 9.3) (11.3, 18.6) (7.4, 9.3)a - Progression-free survival (investigator assessed)b - Overall Response Rate = Complete Response + Partial Responsec - Duration of responsed - At the time of the reporting the majority (59% of dabrafenib+trametinib and 42% of vemurafenib) ofinvestigator-assessed responses were still ongoing

NR = Not reached

NA = Not applicable

There are limited data in patients taking the combination of trametinib with dabrafenib who haveprogressed 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 limitedclinical activity in patients who had progressed on a BRAF inhibitor (see section 4.4). Theinvestigator-assessed confirmed response rate was 15% (95% CI: 4.4, 34.9) and the median PFS was3.6 months (95% CI: 1.9, pct. 5.2). Similar results were seen in the 45 patients who crossed over fromdabrafenib monotherapy to the trametinib 2 mg once daily and dabrafenib 150 mg twice dailycombination in Part C of this study. In these patients a 13% (95% CI: 5.0, 27.0) confirmed responserate was observed with a median PFS of 3.6 months (95% CI: 2, 4).

The efficacy and safety of trametinib in combination with dabrafenib in patients with BRAF mutation-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 fourcohorts:

* Cohort A: patients with BRAF V600E mutant melanoma with asymptomatic brain metastaseswithout prior local brain-directed therapy and ECOG performance status of 0 or 1.

* Cohort B: patients with BRAF V600E mutant melanoma with asymptomatic brain metastaseswith prior local brain-directed therapy and ECOG performance status of 0 or1.

* Cohort C: patients with BRAF V600D/K/R mutant melanoma with asymptomatic brainmetastases, with or without prior local brain-directed therapy and ECOG performance status of0 or 1.

* Cohort D: patients with BRAF V600D/E/K/R mutant melanoma with symptomatic brainmetastases, with or without prior local brain-directed therapy and ECOG performance status of0 or 1 or 2.

The primary endpoint of the study was intracranial response in Cohort A, defined as the percentage ofpatients 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 theinvestigator in Cohorts B, C and D were secondary endpoints of the study. Due to small sample sizereflected 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/ Cohort A Cohort B Cohort C Cohort Dassessment N=76 N=16 N=16 N=17

Intracranial response rate, % (95 % CI)59% 56% 44% 59%(47.3, 70.4) (29.9, 80.2) (19.8, 70.1) (32.9, 81.6)

Duration of intracranial response, median, months (95% CI)6.5 7.3 8.3 4.5(4.9, 8.6) (3.6, 12.6) (1.3, 15.0) (2.8, 5.9)

Overall response rate, % (95% CI)59% 56% 44% 65%(47.3, 70.4) (29.9, 80.2) (19.8, 70.1) (38.3, 85.8)

Progression-free survival, median, months (95% CI)5.7 7.2 3.7 5.5(5.3, 7.3) (4.7, 14.6) (1.7, 6.5) (3.7, 11.6)

Overall survival, median, months (95% CI)10.8 24.3 10.1 11.5(8.7, 17.9) (7.9, NR) (4.6, 17.6) (6.8, 22.4)

CI = Confidence Interval

NR = Not reached

* Trametinib monotherapy

The efficacy and safety of trametinib in patients with BRAF unresectable or metastatic mutantmelanoma (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 inthe metastatic setting [Intent to Treat (ITT) population] were randomised 2:1 to receive trametinib2 mg once daily or chemotherapy (dacarbazine 1 000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2every 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 tochemotherapy 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 theprimary 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 armwere allowed to cross over to the trametinib arm after independent confirmation of progression. Of thepatients with confirmed disease progression in the chemotherapy arm, a total of 51 (47%) crossed overto receive trametinib.

Baseline characteristics were balanced between treatment groups in the primary efficacy populationand the ITT population. In the ITT population, 54% of patients were male and all were Caucasian. Themedian age was 54 years (22% were 65 years); all patients had an ECOG performance score of 0 or1; 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 priorchemotherapy for advanced or metastatic disease.

The efficacy results in the primary efficacy population were consistent with those in the ITTpopulation; 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) 4.8 1.5(95% CI) (4.3, 4.9) (1.4, 2.7)

Hazard Ratio 0.45(95% CI) (0.33, 0.63)

P value <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) 1 000 mg/m2 every 3 weeks or paclitaxel175 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 hadcrossed over.

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

Cut-off Treatment Number Median Hazard ratio Percentdates of deaths months OS (95% CI) survival at(%) (95% CI) 12 months(95% CI)

October 26, Chemotherapy 29 (27) NR NR2011 (n=108) 0.54 (0.32, 0.92)

Trametinib 35 (16) NR NR(n=214)

May 20, Chemotherapy 67 (62) 11.3 (7.2, 14.8) 50 (39,59)2013 (n=108) 0.78 (0.57, 1.06)

Trametinib 137 (64) 15.6 (14.0, 61(54, 67)(n=214) 17.4)

NR=not reached

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

In a single-arm Phase II study, designed to evaluate the objective response rate, safety, andpharmacokinetics 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 wereenrolled: Cohort A: patients with prior treatment with a BRAF inhibitor either with or without otherprior therapy, Cohort B: patients with at least 1 prior chemotherapy or immunotherapy, without priortreatment with a BRAF inhibitor.

In Cohort A of this study, trametinib did not demonstrate clinical activity in patients who hadprogressed on a prior BRAF inhibitor therapy.

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/Kmutation, following complete resection.

Patients were randomised 1:1 to receive either combination therapy (dabrafenib 150 mg twice dailyand trametinib 2 mg once daily) or two placebos for a period of 12 months. Enrollment requiredcomplete resection of melanoma with complete lymphadenectomy within 12 weeks prior torandomisation. 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. Patientspresenting with malignancies with confirmed activating RAS mutations were not eligible. Patientswere stratified by BRAF mutation status (V600E versus V600K) and stage of disease prior to surgeryusing 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 sizeand ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), definedas the time from randomisation to disease recurrence or death from any cause. Radiological tumourassessment was conducted every 3 months for the first two years and every 6 months thereafter, untilfirst relapse was observed. Secondary endpoints include overall survival (OS; key secondaryendpoint), 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 tumourulceration. The majority of patients had a BRAF V600E mutation (91%).

The median duration of follow-up at the time of the primary analysis was 2.83 years in the dabrafeniband 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 statisticallysignificant difference for the primary outcome of investigator-assessed 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 wasconsistently demonstrated across subgroups of patients including age, sex and race. Results were alsoconsistent across stratification factors for disease stage and BRAF V600 mutation type.

Table 13 Investigator-assessed RFS results for Study BRF115532 (COMBI-AD primaryanalysis)

Dabrafenib + Trametinib Placebo

RFS parameter N=438 N=432

Number of events, n (%) 166 (38%) 248 (57%)

Recurrence 163 (37%) 247 (57%)

Relapsed with distant metastasis 103 (24%) 133 (31%)

Death 3 (<1%) 1 (<1%)

Median (months) NE 16.6(95% CI) (44.5, NE) (12.7, 22.1)

Hazard ratio[1] 0.47(95% CI) (0.39, 0.58)p-value[2] 1.53×10-141-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 log-rank test (stratification factors were diseasestage - IIIA vs. IIIB vs. IIIC - and BRAF V600 mutation type - V600E vs. V600K)

NE = not estimable

Based on updated data with an additional 29 months of follow-up compared to the primary analysis(minimum follow-up of 59 months), the RFS benefit was maintained with an estimated HR of 0.51(95% CI: 0.42, 0.61) (Figure 4). The 5-year RFS rate was 52% (95% CI: 48, 58) in the combinationarm compared to 36% (95% CI: 32, 41) in the placebo arm.

Figure 4 Kaplan-Meier RFS curves for Study BRF115532 (ITT population, updated results)1.00.90.80.70.60.50.40.30.2 Group N Events Median, months (95% CI)

Dabrafenib + t rametinib 438 190 NA (47.9, NA)0.1 Placebo 432 262 16.6 (12.7, 22.1)

HR for recurrence = 0.510.0 95% CI (0.42, 0.61)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80

Time from randomisation (months)

Subjects at risk

Dabrafenib+ T rametinib 438 413 405 391 381 372 354 335 324 298 281 275 262 256 249 242 236 233 229 228 221 217 213 210 204 202 199 195 176 156 133 109 92 80 45 38 17 8 6 2 0

Placebo 432 387 322 280 263 243 219 204 199 185 178 175 168 166 164 158 157 151 147 146 143 140 139 137 136 133 133 132 121 115 99 80 69 56 35 26 13 1 1 2 0

At the time of the final OS analysis, the median duration of follow-up was 8.3 years in thecombination arm and 6.9 years in the placebo arm. The observed difference in OS was not statisticallysignificant (HR: 0.80; 95% CI: 0.62, 1.01) with 125 events (29%) in the combination arm and136 events (31%) in the placebo arm. Estimated 5-year OS rates were 79% in the combination arm and70% in the placebo arm, and estimated 10-year OS rates were 66% in the combination arm and 63% inthe placebo arm.

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 assessedby the investigator. Secondary endpoints included DoR, PFS, OS, safety and populationpharmacokinetics. 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 hadprevious systemic treatment for their metastatic disease.

* Cohort B: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg oncedaily), 59 patients enrolled. 57 patients had 1-3 lines of previous systemic treatment for theirmetastatic disease. 2 patients had no previous systemic treatment and were included in theanalysis for patients enrolled in Cohort C.

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

Proportion alive and relapse free

Among the total of 93 patients who were enrolled in the combination therapy cohorts B and C, mostpatients were Caucasian (>90%), and similar female versus male (54% versus 46%), with a medianage 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 thepreviously-treated population, 38 patients (67%) had one line of systemic anti-cancer therapy formetastatic disease.

At the time of the primary analysis, the primary endpoint of investigator-assessed ORR in the first-linepopulation 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 equalto 30%. The ORR results assessed by IRC were consistent with the investigator assessment. The finalanalysis of efficacy performed 5 years after last subject first dose is presented in Table 14.

Table 14 Summary of efficacy in the combination treatment cohorts based on investigatorand independent radiology review

Endpoint Analysis Combination 1st Line Combination 2nd Line Plus

N=361 N=571

Overall confirmed By Investigator 23 (63.9%) 39 (68.4%)response n (%) (46.2, 79.2) (54.8, 80.1)(95% CI) By IRC 23 (63.9%) 36 (63.2%)(46.2, 79.2) (49.3, 75.6)

Median DoR By Investigator 10.2 (8.3, 15.2) 9.8 (6.9, 18.3)

Months (95% CI) By IRC 15.2 (7.8, 23.5) 12.6 (5.8, 26.2)

Median PFS By Investigator 10.8 (7.0, 14.5) 10.2 (6.9, 16.7)

Months (95% CI) By IRC 14.6 (7.0, 22.1) 8.6 (5.2, 16.8)

Median OS - 17.3 (12.3, 40.2) 18.2 (14.3, 28.6)

Months (95% CI)1 Data cut-off: 7 January 2021

Pyrexia is observed in patients treated with dabrafenib and trametinib combination therapy. The initialregistration studies for the combination therapy in the unresectable or metastatic melanoma setting(COMBI-d and COMBI-v; total N=559) and in the adjuvant melanoma setting (COMBI-AD, N=435)recommended to interrupt only dabrafenib in case of pyrexia (fever ≥38.5°C). In two subsequentstudies in unresectable or metastatic melanoma (COMBI-i control arm, N=264) and in the adjuvantmelanoma setting (COMBI-Aplus, N=552), interruption of both medicinal products when patient’stemperature is ≥38oC (COMBI-Aplus), or at the first symptom of pyrexia (COMBI-i; COMBI-Aplusfor recurrent pyrexia) was advised. In COMBI-i and COMBI-Aplus there was a lower incidence ofgrade 3/4 pyrexia, complicated pyrexia, hospitalisation due to serious pyrexia adverse events ofspecial interest (AESIs), the time spent in pyrexia AESIs, and permanent discontinuations from bothmedicinal products due to pyrexia AESIs (the latter in the adjuvant setting only) compared to COMBI-d, COMBI-v and COMBI-AD. The COMBI-Aplus study met its primary endpoint with a compositerate of 8.0% (95% CI: 5.9, 10.6) for grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanenttreatment discontinuation due to pyrexia compared to 20.0% (95% CI: 16.3, 24.1) for the historicalcontrol (COMBI-AD).

The European Medicines Agency has deferred the obligation to submit the results of studies withtrametinib in all subsets of the paediatric population in melanoma and malignant neoplasms(see section 4.2 for information on paediatric use).

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 predoseconcentration were 22.2 ng/ml, 370 ng*hr/ml and 12.1 ng/ml, respectively with a low peak:troughratio (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 oncedaily 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% and10% decrease in Cmax and AUC, respectively compared to fasted conditions (see sections 4.2 and 4.5).

Binding of trametinib to human plasma proteins is 97.4%. Trametinib has a volume of distribution ofapproximately 1 200 L determined following administration of a 5 g intravenous microdose.

In vitro and in vivo studies demonstrated that trametinib is metabolised predominantly viadeacetylation alone or in combination with mono-oxygenation. The deacetylated metabolite wasfurther metabolised by glucuronidation. CYP3A4 oxidation is considered a minor pathway ofmetabolism. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with possiblecontributions by other hydrolytic enzymes.

Following single and repeated doses of trametinib, trametinib as parent is the main circulatingcomponent in plasma.

Mean terminal half-life is 127 hours (5.3 days) after single dose administration. Trametinib plasma IVclearance is 3.21 L/hr.

Total dose recovery was low after a 10-day collection period (<50%) following administration of asingle 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 aminor extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered as parent in urine.

Population pharmacokinetic analyses and data from a clinical pharmacology study in patients withnormal hepatic function or with mild, moderate or severe bilirubin and/or AST elevations (based on

National Cancer Institute [NCI] classification) indicate that hepatic function does not significantlyaffect trametinib oral clearance.

Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics giventhe low renal excretion of trametinib. The pharmacokinetics of trametinib were characterised in223 patients enrolled in clinical trials with trametinib who had mild renal impairment and 35 patientswith moderate renal impairment using a population pharmacokinetic analysis. Mild and moderaterenal impairment had no effect on trametinib exposure (<6% for either group). No data are available inpatients with severe renal impairment (see section 4.2).

Based on the population pharmacokinetic analysis (range 19 to 92 years), age had no relevant clinicaleffect on trametinib pharmacokinetics. Safety data in patients ≥75 years is limited (see section 4.8).

There are insufficient data to evaluate the potential effect of race on trametinib pharmacokinetics asclinical experience is limited to Caucasians.

The pharmacokinetic exposures of trametinib at a weight-adjusted dosage in adolescent patients werewithin range of those observed in adults.

Based on a population pharmacokinetic analysis, gender and body weight were found to influencetrametinib oral clearance. Although smaller female subjects are predicted to have higher exposure thanheavier male subjects, these differences are unlikely to be clinically relevant and no dosage adjustmentis warranted.

Effects of trametinib on drug-metabolising enzymes and transporters: In vitro and in vivo data suggestthat trametinib is unlikely to affect the pharmacokinetics of other medicinal products. Based on invitro 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 invitro potency of inhibition or induction values, trametinib is not considered to be an in vivo inhibitor orinducer of these enzymes or transporters, although transient inhibition of BCRP substrates in the gutmay occur (see section 4.5).

Effects of other medicinal products on trametinib: In vivo and in vitro data suggest that thepharmacokinetics of trametinib are unlikely to be affected by other medicinal products. Trametinib isnot 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 oftrametinib upon strong inhibition of hepatic P-gp cannot be excluded (see section 4.5).

Effects of trametinib on other medicinal products: the effect of repeat-dose trametinib on the steadystate pharmacokinetics of combination oral contraceptives, norethindrone and ethinyl estradiol, wasassessed in a clinical study that consisted of 19 female patients with solid tumours. Norethindroneexposure increased by 20% and ethinyl estradiol exposure was similar when co-administered withtrametinib. Based on these results, no loss of efficacy of hormonal contraceptives is expected when co-administered with trametinib monotherapy.

Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic instudies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells andmicronuclei in the bone marrow of rats.

Trametinib may impair female fertility in humans, as in repeat-dose studies, increases in cysticfollicles and decreases in corpora lutea were observed in female rats at exposures below the humanclinical exposure based on AUC.

Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in hallmarks offemale sexual maturation (vaginal opening and increased incidence of prominent terminal end budswithin the mammary gland) and slight hypertrophy of the surface epithelium of the uterus wereobserved. All of these effects were reversible following an off-treatment period and attributable topharmacology. However, in rat and dog toxicity studies up to 13 weeks in duration, there were notreatment effects observed in male reproductive tissues.

In embryo-foetal developmental toxicity studies in rats and rabbits, trametinib induced maternal anddevelopmental toxicity. In rats decreased foetal weights and increased post-implantation loss wereseen at exposures below or slightly above the human 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-clinicalhuman 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 afterdrug-free recovery. In rats, hepatocellular necrosis and transaminase elevations were seen after8 weeks at ≥0.062 mg/kg/day (approximately 0.8 times human clinical exposure based on AUC).

In mice, lower heart rate, heart weight and left ventricular function were observed without cardiachistopathology after 3 weeks at ≥0.25 mg/kg/day trametinib (approximately 3 times human clinicalexposure based on AUC) for up to 3 weeks. In adult rats, mineralisation of multiple organs wasassociated with increased serum phosphorus and was closely associated with necrosis in heart, liverand kidney and haemorrhage in the lung at exposures comparable to the human clinical exposure. Inrats, hypertrophy of the physis and increased bone turnover were observed, but the physealhypertrophy is not expected to be clinically relevant for adult humans. In rats and dogs giventrametinib at or below human clinical exposures, bone marrow necrosis, lymphoid atrophy in thymusand GALT and lymphoid necrosis in lymph nodes, spleen and thymus were observed, which have thepotential to impair immune function. In juvenile rats, increased heart weight with no histopathologywas 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 atsignificantly higher concentrations than human clinical exposures (IC50 at 2.92 µg/ml, ≥130 times thehuman clinical exposure based on Cmax), indicating that there is low risk for phototoxicity to patientstaking trametinib.

In a study in dogs in which trametinib and dabrafenib were given in combination for 4 weeks, signs ofgastro-intestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lowerexposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as incomparable monotherapy studies.

Mannitol (E421)

Microcrystalline cellulose (E460)

Hypromellose (E464)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Sodium laurilsulfate

Colloidal silicon dioxide(E551)

Hypromellose (E464)

Titanium dioxide (E171)

Polyethylene glycol

Iron oxide yellow(E172)

Mannitol (E421)

Microcrystalline cellulose (E460)

Hypromellose (E464)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Sodium laurilsulfate

Colloidal silicon dioxide(E551)

Hypromellose (E464)

Titanium dioxide (E171)

Polyethylene glycol

Polysorbate 80 (E433)

Iron oxide red (E172)

Not applicable.

Unopened bottle3 years

Opened bottle30 days at no more than 30ºC.

This medicinal product does not require any special temperature storage conditions.

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.

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

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

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

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Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/14/931/001

EU/1/14/931/002

EU/1/14/931/005

EU/1/14/931/006

Date of first authorisation: 30 June 2014

Date of latest renewal: 14 February 2019

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

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