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.

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.

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

Grade (CTCAE)*

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 (CTCAE)

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.

Pyrexia

If a patient's temperature is ≥38°C, therapy should be interrupted (trametinib when used as monotherapy, 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 as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patients should be evaluated for signs and symptoms of infection and, if necessary, treated in line with local practice (see section 4.4). Trametinib, or both trametinib and dabrafenib when used in combination, should be restarted if the patient is symptom-free for at least 24 hours either (1) at the same dose level, or (2) reduced by one dose level if pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.

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 uveitis, RAS mutation-positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lung disease (ILD)/pneumonitis (primarily related to trametinib).

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

Uveitis

No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld until resolution of ocular inflammation, and then dabrafenib should be restarted reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib (see section 4.4).

RAS mutation-positive non-cutaneous malignancies

The benefits and risks 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).

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.

Special populations

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. Available data from a clinical pharmacology study indicate a limited impact of moderate to severe hepatic impairment on trametinib exposure (see section 5.2). 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).

Paediatric population

The safety and efficacy of trametinib tablets in children and adolescents (<18 years) have not been established. 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.

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.

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.

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

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.

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.

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.

Sarcoidosis

Cases of sarcoidosis have been reported in patients treated with trametinib in combination with dabrafenib, 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 disease progression.

Haemophagocytic lymphohistiocytosis

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

Tumour lysis syndrome (TLS)

The occurrence of TLS, which may be fatal, has been associated with the use of trametinib in combination 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. Patients with risk factors for TLS should be closely monitored and prophylactic hydration should be considered. TLS should be treated promptly, as clinically indicated.

Sodium

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

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.

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

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).

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.

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 and 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.

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 associated with trametinib obtained from clinical studies and post-marketing surveillance are tabulated below for trametinib monotherapy (Table 4) and trametinib in combination with 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

Common

Uncommon

Rare

Very rare

Not known

≥1/10

≥1/100 to <1/10

≥1/1 000 to <1/100

≥1/10 000 to <1/1 000

<1/10 000

(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.

Table 4 Adverse reactions with trametinib monotherapy

System Organ Class

Frequency (all grades)

Adverse Reactions

Infections and infestations

Common

Folliculitis

Paronychia

Cellulitis

Rash pustular

Blood and lymphatic system disorders

Common

Anaemia

Immune system disorders

Common

Hypersensitivitya

Metabolism and nutrition disorders

Common

Dehydration

Nervous system disorders

Common

Peripheral neuropathy (including sensory and motor neuropathy)

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

Not known

Atrioventricular blockb

Vascular disorders

Very common

Hypertension

Haemorrhagec

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 tissue 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

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 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 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 carcinomaa

Papillomab

Seborrhoeic keratosis

Uncommon

New primary melanomac

Acrochordon (skin tags)

Blood and lymphatic system disorders

Common

Neutropenia

Anaemia

Thrombocytopenia

Leukopenia

Immune system disorders

Uncommon

Hypersensitivityd

Sarcoidosis

Rare

Haemophagocytic lymphohistiocytosis

Metabolism and nutrition disorders

Very common

Decreased appetite

Common

Dehydration

Hyponatraemia

Hypophosphataemia

Hyperglycaemia

Not known

Tumour lysis syndrome

Nervous system disorders

Very common

Headache

Dizziness

Common

Peripheral neuropathy (including sensory and motor neuropathy)

Eye disorders

Common

Vision blurred

Visual impairment

Uveitis

Uncommon

Chorioretinopathy

Retinal detachment

Periorbital oedema

Cardiac disorders

Common

Ejection fraction decreased

Uncommon

Atrioventricular blocke

Bradycardia

Not known

Myocarditis

Vascular disorders

Very common

Hypertension

Haemorrhagef

Common

Hypotension

Lymphoedema

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Common

Dyspnoea

Uncommon

Pneumonitis

Gastrointestinal disorders

Very common

Abdominal paing

Constipation

Diarrhoea

Nausea

Vomiting

Common

Dry mouth

Stomatitis

Uncommon

Pancreatitis

Colitis

Rare

Gastrointestinal perforation

Skin and subcutaneous tissue 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

Uncommon

Acute febrile neutrophilic dermatosis

Not Known

Stevens-Johnson syndrome

Drug reaction with eosinophilia and systemic symptoms

Dermatitis exfoliative generalised

Tattoo-associated skin reactions

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

Investigations

Very common

Alanine aminotransferase increased

Aspartate aminotransferase increased

Common

Blood alkaline phosphatase increased

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 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).

a Cutaneous squamous cell carcinoma (cuSCC): SCC, SCC of the skin, SCC in situ (Bowen's disease) and keratoacanthoma

b Papilloma, skin papilloma

c Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma Stage III

d Includes drug hypersensitivity

e Including atrioventricular block complete

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% (8/1 076) 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% (65/1 076) 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.

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.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.