Mekinist Dec2021.SIN App060722 PDF

1 Tradename
MEKINIST® 0.5 mg and 2 mg film-coated tablets.
2 Description and composition

Pharmaceutical form
0.5 mg film-coated tablets
Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’
on the opposing face.
2 mg film-coated tablets
Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the
opposing face.
Certain dosage strengths and dosage forms may not be available in all countries.
Active substance
0.5 mg film-coated tablets
Each film-coated tablet contains trametinib-dimethylsulfoxide (1:1) equivalent to 0.5 mg
trametinib.
2 mg film-coated tablets
Each film-coated tablet contains trametinib-dimethylsulfoxide (1:1) equivalent to 2 mg
trametinib.
Excipients
Tablet core: mannitol, microcrystalline cellulose, hypromellose, croscarmellose sodium,
magnesium stearate (vegetable source), sodium laurylsulfate, colloidal silicon dioxide.
Tablet film coating: hypromellose, titanium dioxide, polyethylene glycol, iron oxide yellow
(for 0.5 mg tablets), polysorbate 80 and iron oxide red (for 2 mg tablets).
Pharmaceutical formulations may vary between countries.
3 Indications
Unresectable or metastatic 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
section 6 Warnings and Precautions and section 12 Clinical studies).
Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed
on a prior BRAF inhibitor therapy (see section 12 Clinical studies).
Adjuvant treatment of melanoma
Mekinist Dec 2021.SIN Page 1 of 45

Trametinib in combination with dabrafenib is indicated for the adjuvant treatment of patients
with melanoma with BRAF V600 mutation and involvement of lymph node(s), following
complete resection.
Advanced non-small cell lung cancer

Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with
advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation.
Locally advanced or metastatic anaplastic thyroid cancer

Trametinib in combination with dabrafenib is indicated for the treatment of patients with locally
advanced or metastatic anaplastic thyroid cancer (ATC) with a BRAF V600 mutation and with
no satisfactory locoregional treatment options (see section 12 Clinical studies).
4 Dosage regimen and 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.
When Mekinist is used in combination with Tafinlar, please also refer to the full Tafinlar
Package Insert.
Dosage regimen
General target population

Adults
Recommended Dosage for Unresectable or Metastatic Melanoma
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 derive benefit or the development of
unacceptable toxicity.
Recommended Dosage for the Adjuvant Treatment of Melanoma

The recommended dose of trametinib 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, until disease recurrence or unacceptable toxicity for up to 1 year.
Recommended Dosage for NSCLC

The recommended dose of trametinib in combination with dabrafenib, is 2 mg once daily. The
daily. It is recommended that patients continue treatment with trametinib until patients no
longer derive benefit or the development of unacceptable toxicity.
Recommended Dosage for ATC

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

daily, until 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 adjustments
Mekinist as monotherapy and in combination with Tafinlar
The management of adverse events/ adverse drug reactions may require treatment interruption,
dose reduction, or treatment discontinuation.
Dose modifications are not recommended for adverse reactions of cutaneous squamous cell
carcinoma (cuSCC) or new primary melanoma (see dabrafenib Package Insert for further
details).
Recommended dose level reductions are provided in Table 4-1. Doses below 1 mg once daily
are not recommended.
Table 4-1 Recommended dose level reductions

Dose level Trametinib dose Dabrafenib dose*
Used as monotherapy or in Only when used in
combination with dabrafenib 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 1 mg once daily 50 mg twice daily
(combination only)
Dose adjustment for dabrafenib below 50 mg twice daily is not recommended when used in
combination with trametinib.
*Please refer to the dabrafenib Package Insert, Dosing and administration, for dosing instructions
for treatment with dabrafenib monotherapy.
The recommended dose modification schedule is provided in Table 4-2. 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 Mekinist dose should not exceed 2 mg
once daily.
Table 4-2 Dose modification schedule based on the grade of any Adverse
Events (AE) (excluding pyrexia)
Grade (CTC-AE)* 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
Grade 3 dose level when resuming therapy.
Grade 4 Discontinue permanently, or interrupt therapy until Grade 0 to 1 and
reduce by one dose level when resuming therapy.
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse
Events v4.0 (CTC-AE)

If treatment-related toxicities occur when trametinib is used in combination with dabrafenib,
then both treatments should be simultaneously dose reduced, interrupted or discontinued.
Exceptions where dose modifications are necessary for only one of the two treatments are
detailed below for pyrexia, uveitis, RAS mutation positive non-cutaneous malignancies
(primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal
vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lung
disease (ILD)/pneumonitis (primarily related to trametinib).
Dose modification exceptions (where only one of the two therapies is dose reduced) for selected
adverse reactions
Pyrexia
Therapy should be interrupted (Mekinist when used as monotherapy, and both Mekinist and
Tafinlar when used in combination) if the patient’s temperature is ≥38oC (100.4°F). 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. Patients should
be evaluated for signs and symptoms of infection (see section 6 Warnings and precautions).
Mekinist, or both Mekinist and Tafinlar when used in combination, should be restarted if 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. The use of oral corticosteroids should be considered
in those instances in which anti-pyretics are insufficient.
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 Warnings and Precautions).
RAS-mutation-positive non-cutaneous malignancies

Consider the benefits and risks 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 below the institution’s lower
limit of normal (LLN) (see section Warnings and Precautions). 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 Warnings and Precautions).
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 Warnings and Precautions).

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 4-3 below for trametinib (see section Warnings and Precautions).
Table 4-3 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 Resume trametinib at a lower dose (reduced by 0.5 mg) or
Grade 0-1 within 3 weeks discontinue trametinib in patients taking trametinib 1 mg
daily.
Grade 2-3 RPED that does not Permanently discontinue trametinib.
improve to at least Grade 1 within 3
weeks
Interstitial lung disease (ILD)/Pneumonitis

Withhold trametinib 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. Permanently
discontinue trametinib for 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. Mild or
moderate renal impairment had no significant effect on the population pharmacokinetics of
Mekinist (see section Clinical pharmacology, Pharmacokinetics). There are no clinical data 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. In a population
pharmacokinetic analysis, trametinib oral clearance and thus exposure was not significantly
different in patients with mild hepatic impairment compared to patients with normal hepatic
function. Available data in patients with moderate or severe hepatic impairment from a clinical
pharmacology study indicate a limited impact on trametinib exposure (see section Clinical
pharmacology, Pharmacokinetics). 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.
Geriatric patients (65 years of age or above)

No dose adjustment is required in patients 65 years of age or older (see section Clinical
pharmacology, Pharmacokinetics). More frequent dose adjustments (see Tables 4-1 and 4-2
above) may be required in patients 65 years of age or older (see section Adverse Drug
Reactions).
Pediatric patients (below 18 years)

The safety and efficacy of trametinib in pediatric patients have not been established. Mekinist
is not recommended in this age group. No data are available. Studies in juvenile animals have
shown adverse effects of trametinib which had not been observed in adult animals (see section
Non-clinical safety data).
Method of administration
Trametinib should be taken orally with a full glass of water. Trametinib tablets should not be
chewed or crushed. Trametinib should be taken without food, at least 1 hour before or 2 hours
after a meal (see section Clinical pharmacology).
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 Package Insert for information on method of administration when
given in combination with trametinib.
5 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed.
6 Warnings and precautions

When trametinib is given in combination with dabrafenib, the Package Insert of dabrafenib
must be consulted prior to intiation of treatment. For additional information on warnings and
precautions associated with dabrafenib treatment, please refer to the dabrafenib Package Insert.
BRAF V600 testing

The efficacy and safety of trametinib have not been evaluated in patients whose melanoma,
NSCLC or ATC 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 Clinical pharmacology). 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.
Trametinib in combination with dabrafenib in patients with brain metastases

The safety and efficacy of the combination of trametinib and dabrafenib have not been
evaluated in patients with a BRAF V600 mutation-positive melanoma which has metastasised
to the brain.
New malignancies
New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in
combination with dabrafenib.
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 Package Insert.
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 Package Insert.
Non-cutaneous malignancy
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 Package Insert. 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 Adverse drug reactions).
The potential for these events in patients with unstable and/or symptomatic brain metastases or
low platelets (<75,000) is not established as patients with these conditions 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.

Out of the 559 unresectable or metastatic melanoma patients treated with Mekinist in
combination with Tafinlar, there were seven fatal intracranial hemorrhagic cases (1%). Three
cases were from study MEK115306 (COMBI-d) and three cases were from study MEK116513
(COMBI-v). During the COMBI-v three year extended follow-up, one fatal intracranial
hemorrhage occurred in one additional patient. No fatal hemorrhagic events occurred in the
Phase III study in the adjuvant treatment of melanoma. Two out of 93 patients (2%) receiving
Mekinist in combination with Tafinlar in a Phase II NSCLC trial had fatal intracranial
hemorrhagic events. If patients develop symptoms of hemorrhage they should immediately seek
medical care.
LVEF reduction/Left ventricular dysfunction

Trametinib has been reported to decrease LVEF, when used as monotherapy or in combination
with dabrafenib (see section Adverse drug reactions). In clinical trials, the median time to onset
of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was
between two and five 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 Dosage regimen and administration
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
Pyrexia was reported in the clinical trials with trametinib as monotherapy and in combination
with dabrafenib (see section Adverse drug reactions). The incidence and severity of pyrexia are
increased with the combination therapy with dabrafenib (see dabrafenib Package Insert). In
patients with unresectable or metastatic melanoma who received the combination dose of
Mekinist 2 mg once daily and Tafinlar 150 mg twice daily developed pyrexia, approximately
half of the first occurrences of pyrexia happened within the first month of therapy. About one
third of the patients receiving combination therapy who experienced pyrexia had three or more
events Pyrexia may be accompanied by severe rigors, dehydration, and hypotension, which in
some cases can lead to acute renal insufficiency. Serum creatinine and other evidence of renal
function should be monitored during and following severe events of pyrexia. Serious non-
infectious febrile events have been observed. These events responded well to dose interruption
and/or dose reduction and supportive care in clinical trials.
A cross-study comparison in 1,810 patients treated with combination therapy demonstrated a

reduction in the incidence of high-grade pyrexia and other pyrexia-related adverse outcomes
when both Mekinist and Tafinlar were interrupted, compared to when only Tafinlar was
interrupted. Therefore, interruption of both Mekinist and Tafinlar is recommended if patient’s
temperature is ≥38oC (100.4°F), and in case of recurrence, therapy can also be interrupted at
the first symptom of pyrexia (see sections 4 Dosage regimen and administration and 12 Clinical
studies)

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 Adverse drug reactions). Blood pressure should be measured at baseline and monitored
during treatment with trametinib, with control of hypertension by standard therapy as
appropriate.

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
Adverse drug reactions).
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 Dosage regimen and administration). 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 chorioretinopathy or 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 Adverse drug reactions). 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. A thorough
ophthalmological evaluation should be performed at baseline and during treatment with
Mekinist, if clinically warranted. 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 visual disturbances, such as diminished central vision, blurred vision or loss
of vision at any time while on trametinib therapy, additional ophthalmological evaluation
should be undertaken. If a retinal abnormality is noted, treatment with Mekinist should be
interrupted immediately and referral to a retinal specialist should be considered. If RPED is
diagnosed, the dose modification schedule in Table 4-3 should be followed (see section Dosage
regimen and administration); if uveitis is diagnosed, please refer to dabrafenib Package Insert.
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.

Skin Toxicity
Rash
In clinical studies, rash has been observed in about 60% of patients receiving trametinib as
monotherapy and 20 to 30% receiving trametinib in combination with dabrafenib (see section
Adverse drug reactions). The majority of these cases were Grade 1 or 2 and did not require any
dose interruptions or dose reductions.
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 Mekinist in combination with
Tafinlar. 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,
Mekinist and Tafinlar should be withdrawn
Rhabdomyolysis
Rhabdomyolysis has been reported in patients taking trametinib as monotherapy or in
combination with dabrafenib (see section Adverse drug reactions). 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 studies. Please refer to the dabrafenib Package Insert.
Pancreatitis
Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib
in clinical studies. Please refer to the dabrafenib Package Insert.
Hepatic events
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy and
in combination with dabrafenib (see section Adverse drug reactions). 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 section Dosage regimen and administration and section
Clinical pharmacology, Pharmacokinetics).
Venous thromboembolism (VTE)

VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur on
Mekinist monotherapy and when Mekinist is used in combination with Tafinlar. Patients should
be advised to immediately seek medical care if they develop symptoms of VTE (see section
Adverse drug reactions).

Colitis and gastrointestinal perforation
Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients
taking trametinib as monotherapy and in combination with dabrafenib (see section Adverse drug
reactions). 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
medications with a recognised risk of gastrointestinal perforation.
If patients develop symptoms of colitis and gastrointestinal perforation they should immediately
seek medical care.
7 Adverse drug reactions
Summary of the safety profile

The safety of trametinib monotherapy has been evaluated in the integrated population of
329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with
trametinib 2 mg orally 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 Clinical Studies).
The most common adverse reactions (≥20%) for trametinib were rash, diarrhea, fatigue, edema
peripheral, nausea, and dermatitis acneiform.
The safety of trametinib in combination with dabrafenib has been evaluated in the integrated
safety population of 641 patients with BRAF V600 mutant unresectable or metastatic
melanoma 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), and 82 were treated with the combination for BRAF V600 mutant
NSCLC in a multi-cohort, non-randomised Phase II study BRF113928 (see section Clinical
Studies).
The most common adverse reactions (≥ 20 %) for trametinib in combination with dabrafenib
were pyrexia, nausea, diarrhea, fatigue, chills, headache, vomiting, arthralgia, hypertension,
rash and cough.
The safety profile observed in study BRF117277/DRB436B2204 (COMBI-MB) in metastatic
melanoma patients with brain metastases is consistent with the safety profile of Mekinist in
combination with Tafinlar in unresectable or metastatic melanoma (see also section Clinical
studies).
Tabulated summary of adverse reactions

Adverse reactions are listed below by MedDRA body system organ class.
The following convention has been utilised for the classification of frequency:
Very common ≥1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1,000 to <1/100
Rare ≥1/10,000 to <1/1,000
Not known (cannot be estimated from the available data)
Categories have been assigned based on absolute frequencies in the clinical trial data. Within
each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 7-1 Adverse reactions reported in the integrated safety population of

trametinib monotherapy (n=329)
System Organ Class Frequency category Adverse Reactions
Integrated Safety Data
N=329
Folliculitis
Paronychia
Infections and infestation Common
Cellulitis
Rash pustular
Blood and lymphatic system
disorders Common Anaemia
Immune system disorders Common Hypersensitivitya

Metabolism and nutrition
Common Dehydration
disorders
Vision blurred
Common Periorbital oedema
Visual impairment
Eye disorders Chorioretinopathy
Papilloedema
Uncommon
Retinal detachment
Retinal vein occlusion
Left ventricular dysfunction
Common Ejection fraction decreased
Cardiac disorders
Bradycardia
Uncommon Cardiac failure
Hypertension
Very common
Vascular disorders Haemorrhageb
Common Lymphoedema
Cough
Very common
Respiratory, thoracic and Dyspnoea
mediastinal disorders Common Pneumonitis
Uncommon Interstitial lung disease
Diarrhoea
Nausea
Vomiting
Very common
Constipation
Gastrointestinal disorders
Abdominal pain
Dry mouth
Common Stomatitis
Uncommon Gastrointestinal perforation

Colitis
Rash
Dermatitis acneiform
Very common Dry skin
Pruritus
Skin and subcutaneous
Alopecia
disorders
Erythema
Palmar-plantar erythrodysaesthesia syndrome
Common
Skin fissures
Skin chapped
Musculoskeletal and connective
Uncommon Rhabdomyolysis
tissue disorders
Fatigue
Very common Oedema peripheral
General disorders and Pyrexia
administration site conditions Face oedema
Common Mucosal inflammation
Asthenia
Very common Aspartate aminotransferase increased
Investigations Alanine aminotransferase increased
Common Blood alkaline phosphatase increased
Blood creatine phosphokinase increased
a
May present with symptoms such as fever, rash, increased liver transaminases, and visual disturbances
b
Events include but are not limited to: epistaxis, haematochezia, gingival bleeding, haematuria, and rectal, haemorrhoidal, gastric,
vaginal, conjunctival, intracranial and post procedural haemorrhage.
Table 7-2 Unresectable or metastatic melanoma and Advanced NSCLC Adverse

reactions reported in the integrated safety population of trametinib in
combination with dabrafenib (n=641)
System Organ Class Frequency (all grades) Adverse Reactions
Urinary tract infection
Very common
Nasopharyngitis
Cellulitis
Infections and Infestations
Folliculitis
Common
Paronychia
Rash pustular
Cutaneous squamous cell carcinomaa
Neoplasms benign, malignant Common Papillomab
and unspecified (incl cysts and Seborrhoeic keratosis
polyps) New primary melanoma
Uncommon
Acrochordon (skin tags)
Very common Neutropenia
Blood and lymphatic system Anaemia
disorders Common Thrombocytopenia
Leukopenia
Immune system disorders Uncommon Hypersensitivityc
Very common Decreased appetite
Dehydration
Metabolism and nutrition
Hyponatraemia
disorders Common
Hypophosphataemia
Hyperglycaemia
Headache
Nervous system disorders Very common
Dizziness

Vision blurred
Common
Visual impairment
Chorioretinopathy
Eye disorders
Uveitis
Uncommon
Retinal detachment
Periorbital oedema
Common Ejection fraction decreased
Cardiac disorder Uncommon Bradycardia
Unknown Myocarditis
Hypertension
Very common
Haemorrhaged
Vascular disorders
Hypotension
Common
Lymphoedema
Very common Cough
Respiratory, thoracic and
Dyspnoea
mediastinal disorders Common
Pneumonitis
Abdominal pain
Constipation
Very common Diarrhoea
Nausea
Vomiting
Gastrointestinal disorders Dry mouth
Common
Stomatitis
Pancreatitis
Uncommon Gastrointestinal perforation
Colitis
Dry skin
Pruritus
Very common
Rash
Erythema
Dermatitis acneiform
Actinic keratosis
Night sweats
Skin and subcutaneous Hyperkeratosis
disorders Alopecia
Palmar-plantar erythrodysaesthesia syndrome
Common
Skin lesion
Hyperhidrosis
Panniculitis
Photosensitivitye
Skin fissures

Arthralgia
Musculoskeletal and connective Myalgia
Very common
tissue disorders Pain in extremity
Muscle spasms
Common Renal failure
Renal and urinary disorders
Uncommon Nephritis
Fatigue
Chills
Very common Asthenia
General disorders and Oedema peripheral
administration site conditions Pyrexia
Mucosal inflammation
Common Influenza-like illness
Face oedema
Alanine aminotransferase increased
Very common
Aspartate aminotransferase increased
Investigations Blood alkaline phosphatase increased
Common Gamma-glutamyltransferase increased
Blood creatine phosphokinase increased
a
cu SCC: SCC, SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma
b
Papilloma, skin papilloma
c
Includes drug hypersensitivity
d
Bleeding from various sites, including intracranial bleeding and fatal bleeding
e Photosensitivity cases were also observed in post-marketing experience. All cases reported in the COMBI-d and COMBI-v
clinical trials were Grade 1 and no dose modification was required.
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 Package Insert.
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% (8/641) 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 Warnings and
precautions).
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 8% (54/641) 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 section Dosage regimen and administration and Section
Warnings and precautions).
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 section Warnings and precautions and 7 Adverse drug
reaction of the dabrafenib Package Insert.
Hepatic events
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy and
in combination with dabrafenib. Of the hepatic AEs, 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 Warnings and precautions).
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 Warnings and precautions).

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 section Dosage regimen and administration and 6
Warnings and precautions).
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 section dosage
regimen and administration and 6 Warnings and precautions).
Rash
Rash has been observed in about 60% of patients when given as monotherapy and in about 25%
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 section Dosage regimen and administration and 6 Warnings and
precautions).

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 Warnings and precautions).
Pancreatitis
Pancreatitis has been reported with dabrafenib in combination with trametinib. Please see the
dabrafenib Package Insert.
Renal failure
Renal failure has been reported with dabrafenib in combination with trametinib. Please see the
dabrafenib Package Insert.
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 events (AE) and serious adverse events (SAE)
was similar in the subjects aged <65 years and those aged ≥65 years. Patients ≥65 years were
more likely to experience AEs 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=641),

180 patients (28%) were ≥65 years of age; 50 patients (8%) were ≥75 years of age. The
proportion of patients experiencing AEs was similar in those aged <65 years and those aged
≥65 years in all studies. Patients ≥65 years were more likely to experience SAEs and AEs
leading to permanent discontinuation of medicinal product, dose reduction and dose
interruption than those <65 years.
Renal impairment
No dosage adjustment is required in patients with mild or moderate renal impairment (see
section Pharmacokinetics). Trametinib should be used with caution in patients with severe renal
impairment (see section Dosage regimen and administration and 6 Warnings and precautions).
Hepatic impairment
No dosage adjustment is required in patients with mild hepatic impairment (see section
Pharmacokinetics). Trametinib should be used with caution in patients with moderate or severe
hepatic impairment (see section Dosage regimen and administration and 6 Warnings and
precautions).

Mekinist in combination with Tafinlar
The safety of Mekinist in combination with Tafinlar was evaluated in a Phase III, randomized,
double-blind study of Mekinist in combination with Tafinlar versus two placebos in the
adjuvant treatment of Stage III BRAF V600 mutation-positive melanoma after surgical
resection (see section Clinical studies).

In the Mekinist 2 mg once daily and Tafinlar 150 mg twice daily arm, the most common adverse
reactions (≥20%) were pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting,
arthralgia, and myalgia.
Table 7-3 lists the adverse drug reactions in study BRF115532 (COMBI-AD) occurring at an
incidence ≥10% for all grade adverse reactions or at an incidence ≥2% for Grade 3 and Grade
4 adverse drugs reactions or adverse events that are medically significant in the Mekinist in
combination with Tafinlar arm.
Adverse drug reactions are listed by MedDRA system organ class. Within each system organ
class, the adverse drug reactions are ranked by frequency, with the most frequent adverse drug
reactions first. In addition, the corresponding frequency category for each adverse drug reaction
is based on the following convention (CIOMS III): 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).
Table 7-3 Adjuvant treatment of melanoma - Adverse drug reactions for Mekinist
in combination with Tafinlar vs. placebo
Adverse drug reactions Mekinist in combination Placebo Frequency
with Tafinlar category
N=435 N=432 (combination
arm, all
grades)
All Grades Grade 3/4 All Grades Grade 3/4
% % % %
Infections and infestations
Nasopharyngitis1) 12 <1 12 NR Very common
Blood and lymphatic system disorders
Neutropenia2) 10 5 <1 NR Very common
Metabolism and nutrition disorders
Decreased appetite 11 <1 6 NR Very common
Nervous system disorders
Headache3) 39 1 24 NR Very common
Dizziness4) 11 <1 10 NR Very common
Eye disorders
Uveitis 1 <1 <1 NR Common
Chorioretinopathy5) 1 <1 <1 NR Common
Retinal detachment6) 1 <1 <1 NR Common
Vascular disorders
Haemorrhage7) 15 <1 4 <1 Very common
Hypertension8) 11 6 8 2 Very common
Respiratory, thoracic, and mediastinal disorders
Cough9) 17 NR 8 NR Very common
Nausea 40 <1 20 NR Very common
Diarrhoea 33 <1 15 <1 Very common
Vomiting 28 <1 10 NR Very common
Abdominal pain10) 16 <1 11 <1 Very common
Constipation 12 NR 6 NR Very common
Skin and subcutaneous tissue disorders
Rash11) 37 <1 16 <1 Very common
Dry skin12) 14 NR 9 NR Very common
Dermatitis acneiform 12 <1 2 NR Very common
Erythema13) 12 NR 3 NR Very common
Pruritus14) 11 <1 10 NR Very common

Adverse drug reactions Mekinist in combination Placebo Frequency
with Tafinlar category
N=435 N=432 (combination
arm, all
grades)
All Grades Grade 3/4 All Grades Grade 3/4
% % % %
Palmar-plantar erythrodysaesthesia 6 <1 1 <1 Common
syndrome
Musculoskeletal and connective tissue disorders
Arthralgia 28 <1 14 NR Very common
Myalgia15) 20 <1 14 NR Very common
Pain in extremity 14 <1 9 NR Very common
Muscle spasms16) 11 NR 4 NR Very common
Rhabdomyolysis <1 <1 NR NR Uncommon
Renal and urinary disorders
Renal failure <1 NR NR NR Uncommon
General disorders and administration site conditions
Pyrexia17) 63 5 11 <1 Very common
Fatigue18) 59 5 37 <1 Very common
Chills 37 1 4 NR Very common
Oedema peripheral19) 16 <1 6 NR Very common
Influenza-like illness 15 <1 7 NR Very common
Investigations
Alanine aminotransferase 17 4 2 <1 Very common
increased20)
Aspartate aminotransferase 16 4 2 <1 Very common
increased21)
Alkaline phosphatase increased 7 <1 <1 <1 Common
Ejection fraction decreased 5 NR 2 <1 Common
1)
Nasopharyngitis also includes pharyngitis.
2)
Neutropenia also includes febrile neutropenia and cases of neutrophil count decreased that met the criteria for neutropenia.
3)
Headache also includes tension headache.
4)
Dizziness also includes vertigo.
5)
Chorioretinopathy also includes chorioretinal disorder.
6) Retinal detachment also includes detachment of macular retinal pigment epithelium and detachment of retinal pigment
epithelium.
7)
Haemorrhage includes a comprehensive list of hundreds of event terms that capture bleeding events.
8)
Hypertension also includes hypertensive crisis.
9)
Cough also includes productive cough.
10)
Abdominal pain also includes abdominal pain upper and abdominal pain lower.
11)
Rash also includes rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic,
nodular rash, rash vesicular, and rash pustular.
12)
Dry skin also includes xerosis and xeroderma.
13)
Erythema also includes generalized erythema.
14)
Pruritus also includes puritus generalized and pruritus genital.
15)
Myalgia also includes musculoskeletal pain and musculoskeletal chest pain.
16)
Muscle spasms also includes musculoskeletal stiffness.
17)
Pyrexia also includes hyperpyrexia.
18)
Fatigue also includes asthenia and malaise.
19)
Oedema peripheral also includes peripheral swelling.
20)
Alanine aminotransferase increased also includes hepatic enzyme increased, liver function test increased, liver function test
abnormal, and hypertransaminasaemia.
21)
Aspartate aminotransferase increased also includes hepatic enzyme increased, liver function test increased, liver function test
abnormal, and hypertransaminasaemia.
NR: not reported

Mekinist in combination with Tafinlar:
The efficacy and safety of Mekinist in combination with Tafinlar was studied in a Phase II,
nine-cohort, multicenter, non-randomized, open-label study in patients with rare cancers with
the BRAF V600E mutation, including locally advanced or metastatic ATC (see section
12 Clinical studies).
The ‘All Treated Subjects (ATS)’ population was the primary safety population for the study
and includes all patients who received at least one dose of Mekinist or Tafinlar from all the
histologic cohorts. The safety profiles in the ATS population and in the ATC cohort are
consistent.
At the time of safety analysis, the most common adverse events (≥20%) reported for Mekinist
in combination with Tafinlar in the ATS population were fatigue, pyrexia, rash, nausea, chills,
vomiting, cough, and headache.
Table 7-4 lists the adverse drug reactions for Mekinist in combination with Tafinlar occurring
at an incidence ≥10% for all grade adverse drug reactions or at an incidence ≥2% for Grade 3
and Grade 4 adverse drug reactions or events which are medically significant in Study
BRF117019.
Adverse drug reactions are listed by MedDRA system organ class. Within each system organ
class, the adverse drug reactions are ranked by frequency, with the most frequent adverse drug
reactions first. In addition, the corresponding frequency category for each adverse drug reaction
is based on the following convention (CIOMS III): 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).
Table 7-4 Anaplastic Thyroid Cancer - Adverse drug reactions for Mekinist in
combination with Tafinlar in the ATS population
Adverse drug reactions Mekinist in combination with Tafinlar
N=100
All grades Grades 3/4 Frequency

% % category
Blood and lymphatic system disorders
Neutropenia1) 15 6 Very common
Anaemia 14 2 Very common
Leukopenia2) 13 NR Very common
Metabolism and nutrition disorders
Hyperglycaemia 12 3 Very common
Decreased appetite 11 NR Very common
Hypophosphataemia 6 3 Common
Hyponatremia 3 3 Common
Nervous system disorders
Headache 20 2 Very common
Dizziness3) 13 NR Very common
Eye disorders
Detachment of retinal pigment epithelium 1 NR Common
Vascular disorders
Haemorrhage4) 16 NR Very common
Hypertension 4 2 Common

Adverse drug reactions Mekinist in combination with Tafinlar
N=100
All grades Grades 3/4 Frequency

% % category
Respiratory, thoracic and mediastinal disorders
Cough5) 21 NR Very common
Nausea 31 1 Very common
Vomiting 22 1 Very common
Diarrhoea 17 1 Very common
Constipation 15 NR Very common
Dry mouth 11 NR Very common
Skin and subcutaneous tissue disorders
Rash6) 31 4 Very common
Musculoskeletal and connective tissue disorders
Myalgia7) 11 1 Very common
Arthralgia 11 NR Very common
Rhabdomyolysis 1 1 Common
General disorders and administration site conditions
Fatigue8) 45 5 Very common
Pyrexia 35 4 Very common
Chills 25 1 Very common
Oedema9) 17 NR Very common
Investigations
Alanine aminotransferase increased 13 3 Very common
Aspartate aminotransferase increased 12 2 Very common
Blood alkaline phosphatase increased 11 3 Very common
Ejection fraction decreased 3 1 Common
1)
Neutropenia includes neutropenia, neutrophil count decreased and febrile neutropenia. Neutrophil count decreased qualified
as a neutropenia event.
2)
Leukopenia includes leukopenia, white blood cell count decreased and lymphopenia.
3)
Dizziness includes dizziness, vertigo and vertigo positional.
4)
Haemorrhage includes haematuria, purpura, epistaxis, eye contusion, gingival bleeding, haemoptysis, melaena, petechiae,
prothrombin time prolonged, rectal haemorrhage, retinal haemorrhage and vaginal haemorrhage.
5)
Cough includes cough and productive cough.
6)
Rash includes rash, rash maculo-papular, rash generalized and rash papular.
7)
Myalgia includes myalgia and musculoskeletal pain.
8)
Fatigue includes fatigue, asthenia and malaise.
9.)
Oedema includes oedema and peripheral oedema.
NR: not reported
Adverse drug reactions (ADRs) from post-marketing experience and pooled

clinical trials
The following ADRs have been derived from post-marketing experience including spontaneous
case reports with Mekinist in combination with Tafinlar. Because post-marketing ADRs are
reported from a population of uncertain size, it is not always possible to reliably estimate their
frequency. Where applicable, these ADR frequencies have been calculated from the pooled
clinical trials across indications. ADRs are listed according to system organ classes in
MedDRA. Within each system organ class, ADRs are presented in order of decreasing
seriousness.

Table 7-5 ADRs from post-marketing experience and pooled clinical trials
across indications
Adverse drug reaction Frequency category
Immune system disorders
Sarcoidosis Uncommon
Vascular disorders
Venous thrombo-embolism (VTE)1 Common
1)
VTE includes, pulmonary embolism, deep vein thrombosis, embolism and venous thrombosis.
8 Interactions
Monotherapy
As trametinib is metabolised predominantly via deacetylation mediated by hydrolytic enzymes
(including carboxylesterases), its pharmacokinetics are unlikely to be affected by other agents
through metabolic interactions. A small, non-clinically relevant, decrease in trametinib
bioavailability (16 %) was noted with co-administration with a cytochrome P450 (CYP) 3A4
inducer.
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 trametininb 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 of other medicinal products via interaction with CYP enzymes or transporters
(see section Clinical pharmacology, Pharmacokinetics). Repeat-dose administration of
Mekinist 2 mg once daily had no clinically relevant effect on the single dose Cmax and AUC of
dabrafenib, a CYP2C8/CYP3A4 substrate. Trametinib may result in transient inhibition of
BCRP substrates (e.g. pitavastatin) in the gut, which may be minimised with staggered dosing
(2 hours apart) of these agents and trametinib.
Combination therapy and non-fixed dose combination therapy

Combination with dabrafenib
Co-administration of repeat dosing of Mekinist 2 mg once daily and Tafinlar 150 mg twice
daily resulted in a 16% increase in dabrafenib Cmax and a 23% increase in dabrafenib AUC. A
small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was
estimated when Mekinist is administered in combination with Tafinlar using a population
pharmacokinetic analysis. These changes in dabrafenib or trametinib Cmax and AUC are
considered not clinically relevant. When trametinib is used in combination with dabrafenib see
dabrafenib Package Insert 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 Dosage regimen and administration and section Clinical pharmacology,
Pharmacokinetics).

9 Pregnancy, lactation, females and males of reproductive
potential
9.1 Pregnancy
Risk summary
MEKINIST can cause fetal harm when administered to a pregnant woman. Pregnant women
should be advised of the potential risk to the foetus.
There are no adequate and well-controlled studies of MEKINIST in pregnant women.
MEKINIST should not be administered to pregnant women or nursing mothers. Women of
childbearing potential should use effective methods of contraception during therapy and for 4
months following discontinuation of MEKINIST. When MEKINIST is used in combination
with dabrafenib, patients should use a non-hormonal method of contraception since dabrafenib
can render hormonal contraceptives ineffective. If MEKINIST is used during pregnancy, or if
the patient becomes pregnant while taking MEKINIST, the patient should be informed of the
potential hazard to the foetus.
Reproductive studies in animals (rats and rabbits) with trametinib have demonstrated maternal
and developmental toxicity. In embryofetal development studies in rats, maternal and
developmental toxicity (decreased foetal weights) were seen following maternal exposure to
trametinib at ≥ 0.031 mg/kg/day (approximately 0.3 times the exposure in humans at the highest
recommended dose of 2 mg once daily based on AUC). Post implantation loss was increased at
0.125 mg trametinib/kg/day. In pregnant rabbits, maternal and developmental toxicity
(decreased foetal body weight and increased incidence of variations in ossification) were seen
at ≥ 0.039 mg/kg/day (approximately 0.1 times the exposure in humans at the highest
recommended dose of 2 mg once daily based on AUC). Post implantation loss and incidence of
skeletal defects were increased at 0.154 mg trametinib/kg/day.
9.2 Lactation
Risk summary
There are no data on the effect of Mekinist on the breast-fed child, or the effect of Mekinist on
milk production. Because many drugs are transferred into human milk and because of the
potential for adverse reactions in nursing infants from Mekinist, a nursing woman should be
advised on the potential risks to the child. The developmental and health benefits of breast-
feeding should be considered along with the mother’s clinical need for Mekinist and any
potential adverse effects on the breast-fed child from Mekinist or from the underlying maternal
condition
9.3 Females and males of reproductive potential

Contraception
Females
Females of reproductive potential should be advised that animal studies have been performed
showing Mekinist to be harmful to the developing fetus. Sexually-active females of
reproductive potential are recommended to use effective contraception (methods that result in
less than 1% pregnancy rates) when taking Mekinist and for at least 16 weeks after stopping
treatment with Mekinist.
Females of reproductive potential receiving Mekinist in combination with Tafinlar should be

advised that Tafinlar may decrease the efficacy of oral or any other systemic hormonal

contraceptives and an alternative method of contraception should be used.
Males
Male patients (including those that have had a vasectomy) with sexual partners who are
pregnant, possibly pregnant, or who could become pregnant should use condoms during sexual
intercourse while taking Mekinist monotherapy or in combination with Tafinlar and for at least
16 weeks after stopping treatment with Mekinist.
Infertility
There is no information on the effect of Mekinist on human fertility. In animals, no fertility
studies have been performed, but adverse effects were seen on female reproductive organs (see
section Non-clinical safety data). 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 Package Insert
for further information.
10 Overdosage
No cases of overdose have been reported. There were no cases of Mekinist dose above 4 mg
once daily reported from the clinical trials. Doses up to 4 mg orally once daily and loading
doses of 10 mg orally once daily, administered on two consecutive days, have been evaluated
in clinical trials. Further management should be as clinically indicated or as recommended by
the national poisons center, where available. There is no specific treatment for an overdose of
Mekinist. If overdose occurs, the patient should be treated supportively with appropriate
monitoring as necessary. Hemodialysis is not expected to enhance the elimination as trametinib
is highly bound to plasma proteins.
11 Clinical pharmacology
Pharmacotherapeutic group, ATC
Mitogen-activated protein kinase (MEK) inhibitors, ATC code: L01EE01.
Mechanism of action (MOA)

Mekinist Monotherapy – Melanoma, NSCLC and ATC
Trametinib (Mekinist) is a reversible, highly selective, allosteric inhibitor of mitogen-activated
extracellular signal regulated kinases 1 (MEK1) and MEK2 activation and kinase activity.
MEK proteins are critical components of the extracellular signal-regulated kinase (ERK)
pathway. In melanoma and other cancers, this pathway is often activated by mutated forms of
BRAF which activate MEK and stimulate tumor cell growth. Trametinib inhibits MEK kinase
activity, suppresses growth of BRAF V600 mutant melanoma, non-small cell lung cancer
(NSCLC) and ATC cell lines in vitro and demonstrates anti-tumour effects in BRAF V600
mutant melanoma xenograft models.
Mekinist in combination with Tafinlar – Melanoma, NSCLC and ATC

Dabrafenib (Tafinlar) is a potent, selective, ATP-competitive inhibitor of the BRAF (both wild-
type and V600 variants) and wild type CRAF kinases. Oncogenic mutations in BRAF lead to

constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumor cell
growth. Because co-treatment with trametinib and dabrafenib results in concomitant inhibition
of two kinases in this pathway, BRAF and MEK, the combination provides superior pathway
suppression relative to either agent alone. The combination of trametinib with dabrafenib is
synergistic/additive in BRAF V600 mutation positive melanoma, NSCLC and ATC cell lines
in vitro, and delays the emergence of resistance in vivo in BRAF V600 mutation positive
melanoma xenografts.
Determination of BRAF mutation status

Before taking trametinib or the combination with dabrafenib, patients must have BRAF V600
mutation-positive tumour status confirmed by a validated test.
In clinical trials, central testing for BRAF V600 mutation using a BRAF mutation assay was
conducted on the most recent tumour sample available. Primary tumour or tumour from a
metastatic site was tested with a validated polymerase chain reaction (PCR) assay developed
by Response Genetics Inc. The assay was specifically designed to differentiate between the
V600E and V600K mutations. Only patients with BRAF V600E or V600K mutation positive
tumours were eligible for study participation.
Subsequently, all patient samples were re-tested using the CE-marked bioMerieux (bMx)
THxID BRAF validated assay. The bMx THxID BRAF assay is an allele-specific PCR
performed on DNA extracted from FFPE tumour tissue. The assay was designed to detect the
BRAF V600E and V600K mutations with high sensitivity (down to 5% V600E and V600K
sequence in a background of wild-type sequence using DNA extracted from FFPE tissue). Non-
clinical and clinical studies with retrospective bi-directional Sanger sequencing analyses have
shown that the test also detects the less common BRAF V600D mutation and V600E/K601E
mutation with lower sensitivity. Of the specimens from the non-clinical and clinical studies
(n=876) that were mutation positive by the THxID BRAF assay and subsequently were
sequenced using the reference method, the specificity of the assay was 94%.
Pharmacodynamics (PD)
Trametinib suppressed levels of phosphorylated ERK in BRAF mutant melanoma and NSCLC
tumor cell lines and melanoma xenograft models.
In patients with BRAF and NRAS mutation positive melanoma, administration of trametinib
resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated
ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of
apoptosis). The mean trametinib concentrations observed following repeat-dose administration
of 2 mg once daily exceeds the preclinical target concentration over the 24-hr dosing interval,
thereby providing sustained inhibition of the MEK pathway.
Cardiac electrophysiology
Based on the results of a dedicated QT study, Mekinist does not prolong the QT interval to any
clinically relevant extent.
Pharmacokinetics (PK)
Absorption
Trametinib is absorbed orally with median time to achieve peak concentrations of 1.5 hours
post-dose. The mean absolute bioavailability of a single 2 mg tablet dose is 72% relative to an
intravenous (IV) microdose. The increase in exposure (Cmax and AUC) was dose-proportional

following repeat dosing. Following administration of 2 mg once daily, steady-state geometric
mean Cmax, AUC(0-τ) and predose concentration were 22.2 ng/ml, 370 ng*hr/ml and 12.1 ng/ml,
respectively with a low peak:trough ratio (1.8). Inter-subject variability at steady state was low
(<28%).
Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0
following a 2 mg once daily dose. Steady-state was achieved by Day 15.
Administration of a single dose of trametinib with a high-fat, high-calorie meal resulted in a

70% and 10% decrease in Cmax and AUC, respectively compared to fasted conditions (see
section Dosage regimen and administration and section Interactions).
Distribution
Binding of trametinib to human plasma proteins is 97.4%. Trametinib has a volume of
distribution of 1,060 L determined following administration of a 5 microgram IV microdose.
Biotransformation/metabolism
In vitro and in vivo studies demonstrated that trametinib is metabolised predominantly via
deacetylation alone or in combination or with mono-oxygenation. The deacetylated metabolite
was further metabolised by glucuronidation. CYP3A4 oxidation is considered a minor pathway
of metabolism. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, and may
also be mediated by other hydrolytic enzymes.
Following single and repeated doses of trametinib, trametinib as parent is the main circulating
component in plasma.
Elimination
Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0
following a 2 mg once-daily dose. Mean terminal half-life is 127 hours (5.3 days) after single
dose administration. Steady-state was achieved by Day 15. Trametinib plasma IV clearance is
3.21 L/hr.
Total dose recovery is low after a 10-day collection period (<50%) following administration of
a single oral dose of radiolabelled trametinib as a solution, due to the long half-life. Drug-related
material was excreted predominantly in the faeces (>81% of recovered radioactivity) and to a
small extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered as parent in
urine.
In Vitro evaluation of drug interaction potential

Effects of other drugs on trametinib:
In vitro and in vivo data suggest that the pharmacokinetics (PK) of trametinib are unlikely to be
affected by other drugs. Trametinib is deacetylated via carboxylesterases and possibly other
hydrolytic enzymes. There is little evidence from clinical studies for drug interactions mediated
by carboxylesterases. CYP enzymes play a minor role in the elimination of trametinib and the
compound is not a substrate of the following transporters: breast cancer resistance protein
(BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic
cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2, and the multidrug
and toxin extrusion protein (MATE) 1. Trametinib is an in vitro substrate of the efflux
transporter P-glycoprotein (Pgp), but is unlikely to be significantly affected by inhibition of this
transporter given its high passive permeability and high bioavailability.

Special populations
Hepatic impairment
Population pharmacokinetic analyses and data from a clinical pharmacology study in patients
with normal 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
significantly affect trametinib oral clearance.
Renal impairment
Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics
given the low renal excretion of trametinib. The pharmacokinetics of trametinib were
characterised in 223 patients enrolled in clinical trials with trametinib who had mild renal
impairment and 35 patients with moderate renal impairment using a population
pharmacokinetic analysis. Mild and moderate renal impairment had no effect on trametinib
exposure (<6% for either group). No data are available in patients with severe renal impairment
(see section Dosage regimen and administration).
Geriatric patients (65 years of age or above)

Based on the population pharmacokinetics analysis (range 19 to 92 years), age had no relevant
clinical effect on trametinib pharmacokinetics.
Race/Ethnicity
There are insufficient data to evaluate the potential effect of race on trametinib
pharmacokinetics as clinical experience is limited to Caucasians.
Pediatric population (below 18 years)

No studies have been conducted to investigate the pharmacokinetics of trametinib in pediatric
patients.
Gender/Weight
Based on a population pharmacokinetic analysis, gender and body weight were found to
influence trametinib oral clearance. Although smaller female subjects are predicted to have
higher exposure than heavier male subjects, these differences are unlikely to be clinically
relevant and no dosage adjustment is warranted.
Medicinal product interactions

Effects of trametinib on drug-metabolising enzymes and transporters: In vitro and in vivo data
suggest that trametinib is unlikely to affect the pharmacokinetics of other medicinal products.
Based on in vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6,
CYP2D6 and CYP3A4. Trametinib was found to be an in vitro inhibitor of CYP2C8, CYP2C9
and CYP2C19, an inducer of CYP3A4 and an inhibitor of the transporters OAT1, OAT3,
OCT2, MATE1, OATP1B1, OATP1B3, Pgp and BCRP. However, based on the low dose and
low clinical systemic exposure relative to the in vitro potency of inhibition or induction values,
trametinib is not considered to be an in vivo inhibitor or inducer of these enzymes or
transporters, although transient inhibition of BCRP substrates in the gut may occur (see section
Interactions).
Effects of other drugs on trametinib: In vivo and in vitro data suggest that the pharmacokinetics

(PK) of trametinib are unlikely to be affected by other drugs. Trametinib is deacetylated via
carboxylesterases and possibly other hydrolytic enzymes. There is little evidence from clinical
studies for drug interactions mediated by carboxylesterases. CYP enzymes play a minor role in
the elimination of trametinib and the compound is is not a substrate of the following
transporters: breast cancer resistance protein (BCRP), organic anion transporting polypeptide
(OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, multidrug resistance-
associated protein (MRP) 2, and the multidrug and toxin extrusion protein (MATE) 1.
Trametinib is an in vitro substrate of the efflux transporter P-glycoprotein (Pgp), but is unlikely
to be significantly affected by inhibition of this transporter given its high passive permeability
and high bioavailability. Although trametinib exposure is unlikely to be affected by inhibition
of BSEP, increased levels of trametinib upon strong inhibition of hepatic P-gp cannot be
excluded (see section Interactions).
12 Clinical studies
Unresectable or metastatic melanoma
In the clinical studies only patients with cutaneous melanoma were studied. Efficacy in patients
with ocular or mucosal melanoma has not been assessed.
• Trametinib monotherapy
Treatment naïve patients

Study MEK114267
The efficacy and safety of trametinib in patients with BRAF mutant unresectable or metastatic
melanoma (V600E and V600K) were evaluated in a randomized open-label Phase III study
(MEK114267 [METRIC]). Measurement of patients’ BRAF V600 mutation status was
required. Screening included central testing of BRAF mutation (V600E and V600K) using a
BRAF mutation assay conducted on the most recent tumor sample available.
Patients (N = 322) who were treatment naïve or may have received one prior chemotherapy
treatment in the metastatic setting [Intent to Treat (ITT) population] were randomized 2:1 to
receive trametinib 2 mg once daily or chemotherapy (dacarbazine 1000 mg/m2 every 3 weeks
or paclitaxel 175 mg/m2 every 3 weeks). Treatment for all patients continued until disease
progression, death or withdrawal.
The primary endpoint of the study was to evaluate the efficacy of trametinib compared to
chemotherapy with respect to progression-free survival (PFS) in patients with advanced
(unresectable or metastatic) BRAF V600E mutation-positive melanoma without a prior history
of brain metastases (N=273) which is considered the primary efficacy population. The
secondary endpoints were PFS in the ITT population and overall survival (OS), overall response
rate (ORR), and duration of response (DoR) in the primary efficacy population and ITT
population. Patients in the chemotherapy arm were allowed to cross-over to the trametinib arm
after independent confirmation of progression. Of the patients with confirmed disease
progression in the chemotherapy arm, a total of fifty-one (47%) crossed over to receive
trametinib.
Baseline characteristics were balanced between treatment groups in the primary efficacy
population and the ITT population. In the ITT population, 54% of patients were male and all
were Caucasian (100%). The median age was 54 years (22% were ≥65 years); all patients had

an ECOG performance score of 0 or 1; and 11 patients (3%) had history of brain metastases.
Most patients (87%) in the ITT population had BRAF V600E mutation and 12% of patients had
BRAF V600K mutation. Most patients (66%) had received no prior chemotherapy for advanced
or metastatic disease.
The efficacy results in the primary efficacy population were consistent with those in the ITT
population; therefore, only the efficacy data for the ITT population are presented in Table 12-
1. Kaplan-Meier curves of investigator assessed OS (post-hoc analysis 20 May 2013) is
presented in Figure 12-1.
Table 12-1 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) 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every
3 weeks.
The PFS result was consistent in the subgroup of patients with V600K mutation positive
melanoma (HR=0.50; [95% CI: 0.18, 1.35], p=0.0788).
An additional OS analysis was undertaken based upon the 20 May 2013 data cut, see Table 12-
2.
For October 2011, 47% of subjects had crossed over, while for May 2013, 65% of subjects had
crossed over.
Table 12-2 Survival data from the primary and post-hoc analyses
Cut-off dates Treatment Number Median months Hazard ratio (95% Percent
of deaths OS (95% CI) CI) survival at
(%) 12 months
(95% CI)
October 26, Chemotherapy 29 (27) NR NR
2011 (n=108) 0.54 (0.32, 0.92)
Trametinib 35 (16) NR NR
(n=214)
May 20, 2013 Chemotherapy 67 (62) 11.3 (7.2, 14.8) 50 (39,59)
(n=108) 0.78 (0.57, 1.06)
Trametinib 137 (64) 15.6 (14.0, 17.4) 61(54, 67)
(n=214)
NR=not reached

Figure 12-1 Kaplan-Meier curves of overall survival (OS –ad hoc analysis 20 May
2013)
Prior BRAF inhibitor therapy

In a single-arm Phase II study, designed to evaluate the objective response rate, safety, and
pharmacokinetics following dosing of trametinib at 2 mg once daily in patients with BRAF
V600E, V600K, or V600D mutation-positive metastatic melanoma (MEK113583), two
separate cohorts were enrolled: Cohort A: patients with prior treatment with a BRAF inhibitor
either with or without other prior therapy, Cohort B: patients with at least 1 prior chemotherapy
or immunotherapy, without prior treatment with a BRAF inhibitor.
In Cohort A of this study, trametinib did not demonstrate clinical activity in patients who had
progressed on a prior BRAF inhibitor therapy.
• Trametinib in combination with dabrafenib
The efficacy and safety of the recommended dose of trametinib (2 mg once daily) in
combination with dabrafenib (150 mg twice daily) for the treatment of adult patients with
unresectable or metastatic melanoma with a BRAF V600 mutation were studied in two pivotal
Phase III studies and one supportive Phase I/II study.
MEK115306 (COMBI-d):
MEK115306 (COMBI-d) was a Phase III, randomized, double-blinded study comparing the

combination of dabrafenib and trametinib to dabrafenib and placebo in first-line therapy for
subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-
positive cutaneous melanoma. The primary endpoint of the study was investigator-assessed
progression-free survival (PFS), with a key secondary endpoint of overall survival (OS).
Patients were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal
(ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).
A total of 423 patients were randomised 1:1 to either the combination therapy arm (Mekinist 2
mg once daily and Tafinlar 150 mg twice daily) (N = 211) or dabrafenib monotherapy arm (150
mg twice daily) (N = 212). Baseline characteristics were balanced between treatment groups.
Most patients were Caucasian (>99%) and male (53%), with a median age of 56 years (28%
were ≥65 years). The majority of patients had Stage IVM1c disease (67%). Most subjects had
LDH ≤ULN (65%), Eastern Cooperative Oncology Group (ECOG) performance status of 0
(72%), and visceral disease (73%) at baseline. The majority of patients had a BRAF V600E
mutation (85%); the remaining 15% of patients had the BRAF V600K mutation. Patients 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 12-2. An OS analysis at 5 years demonstrated continued benefit for the combination
of dabrafenib and trametinib compared with dabrafenib monotherapy; the median OS for the
combination arm was approximately 7 months longer than the median OS for dabrafenib
monotherapy (25.8 months versus 18.7 months) with 5 year survival rates of 32% for the
combination versus 27% for dabrafenib monotherapy (Table 12-3, Figure 12-2). The Kaplan-
Meier OS curve appears to stabilize from 3 to 5 years (see Figure 12-2).
The 5-year overall survival rate was 40% (95% CI: 31.2, 48.4) in the combination arm versus
33% (95% CI: 25.0, 41.0) in the dabrafenib monotherapy arm for patients who had a normal
lactate dehydrogenase level at baseline, and 16% (95% CI: 8.4, 26.0) in the combination arm
versus 14% (95% CI: 6.8, 23.1) in the dabrafenib monotherapy arm for patients with an elevated
lactate dehydrogenase level at baseline.
Table 12-3 COMBI-d - Overall Survival results (ITT population)

OS analysis* 3-year OS analysis* 5-year OS analysis*
Dabrafenib Dabrafenib Dabrafenib + Dabrafenib Dabrafenib + Dabrafenib +
+ Trametinib + Placebo Trametinib + Placebo Trametinib Placebo
(n=211) (n=212) (n=211) (n=212) (n=211) (n=212)
Number of Patients
Died (event), n (%) 99 (47) 123 (58) 114 (54) 139 (66) 135 (64) 151 (71)
Estimates of OS (months)
Median (95% CI) 25.1 18.7 26.7 18.7 25.8 18.7
(19.2, NR) (15.2, 23.7) (19.0, 38.2) (15.2, 23.1) (19.2, 38.2) (15.2, 23.1)
Hazard ratio (95% 0.71 0.75 0.80
CI) (0.55, 0.92) (0.58, 0.96) (0.63, 1.01)
p-value 0.011 NA NA

Overall survival Dabrafenib + Trametinib Dabrafenib + placebo
Estimate, % (95% CI) (n=211) (n=212)
At 1 year 74 (66.8, 79.0) 68 (60.8, 73.5)
At 2 years 52 (44.7, 58.6) 42 (35.4, 48.9)
At 3 years 43 (36.2, 50.1) 31 (25.1, 37.9)
At 4 years 35 (28.2, 41.8) 29 (22.7, 35.2)
At 5 years 32 (25.1, 38.3) 27 (20.7, 33.0)
*OS analysis data cut-off: 12-Jan-2015; 3-year OS analysis data cut-off: 15-Feb-2016; 5-year OS analysis data cut-off:
10-Dec-2018
NR = Not reached, NA = Not applicable
Figure 12-2 COMBI-d - Kaplan-Meier overall survival curves (ITT Population)
Clinically meaningful improvements for the primary endpoint of PFS were sustained over a
5 year timeframe in the combination arm compared to dabrafenib monotherapy. Clinically
meaningful improvements were also observed for overall response rate (ORR) and a longer
duration of response (DoR) was observed in the combination arm compared to dabrafenib
monotherapy (Table 12-4).
Table 12-4 Investigator-assessed efficacy results for MEK115306 (COMBI-d)

study
Primary Analysis* Updated Analysis* 3 Year Analysis* 5 Year Analysis*
Dabrafen Dabrafeni Dabrafe Dabrafe Dabrafeni Dabrafe Dabrafe
Endpoin ib + Dabrafe b+ nib + nib + b+ nib + nib +
ts Trametin nib + Trametini Placebo Trametin Placebo Trameti Placebo
ib Placebo b (n=212) ib (n=212) nib (n=212)
(n = 211) (n = 212) (n=211) (n=211) (n=211)
Investigator Assessed PFS
Progress 102 109 139 162 153 168f 160 166
ive (48) (51) (66) (76) (73) (79) (76) (78)
disease
or death,
n
(%)

Median, 11.0 8.8 10.2 7.6 10.2 8.8
9.3 8.8
months (8.0, 13.9) (5.9, 9.3) (8.0, (5.8, 9.3) (8.1, (5.9, 9.3)
(7.7, (5.9,
(95% 12.8) 12.8)
11.1) 10.9)
CIa)
Hazard 0.67 0.71 0.73
0.75
Ratio (0.53, 0.84) (0.57, 0.88) (0.59, 0.91)
(0.57, 0.99)
(95% CI)
P value <0.001g NA NA
(log-rank 0.035
test)
Overall 68 55 69 54
Respons 69 53 (61.5, (47.8, (62.5, (46.8,
e Rateb 51
67 (61.8, (46.3, 74.5) 61.5) 75.4) 60.6)
(%) (44.5,
(59.9, 73.0) 74.8) 60.2)
58.4)
(95% CI)
Differenc 15d 15d NA NA
e in
response
5.9, 24.5 6.0, 24.5
rate (CRc
+PRc), % 0.0015 0.0014g
95% CI
for
differenc
e
P value
Duration of Response (months)
Median 9.2e 10.2e 12.9 10.6 12.0 10.6 12.9 10.2
(95% CI) (7.4, NR) (7.5, (9.4,19.5) (9.1,13.8) (9.3, (8.3, 12.9) (9.3, (8.3,
NR) 17.1) 18.4) 13.8)
* Primary analysis data cut-off: 26-Aug-2013, Final analysis data cut-off: 12-Jan-2015, 3 year analysis data cut-off: 15-Feb-2016, 5 year
analysis data cut-off: 10-Dec-2018
a - Confidence interval
b - Overall Response Rate = Complete Response + Partial Response
c - CR: Complete Response, PR: Partial Response
d - ORR difference calculated based on the ORR result not rounded
e - At the time of the reporting the majority (≥59%) of investigator-assessed responses were still ongoing
f - Two patients were counted as progressed or died in the 3 year analysis but had an extended time without adequate assessment prior to
the events, meaning they were censored in the 5-year analysis.
g - Updated analysis was not pre-planned and the p-value was not adjusted for multiple testing.
NR = Not reached
NA= Not applicable
MEK116513 (COMBI-v)
Study MEK116513 was a two-arm, randomized, open-label, Phase III study comparing
dabrafenib and trametinib combination therapy with vemurafenib monotherapy in BRAF V600
mutation-positive unresectable or metastatic melanoma. The primary endpoint of the study was
OS with a key secondary endpoint of PFS. Patients were stratified by lactate dehydrogenase
(LDH) level (> the upper limit of normal (ULN) versus ≤ULN) and BRAF mutation (V600E
versus V600K).
A total of 704 patients were randomized 1:1 to either combination therapy arm (Mekinist 2mg
once daily and Tafinlar 150mg twice daily) or vemurafenib monotherapy arm (960mg twice
daily). Most patients were Caucasian (>96%) and male (55%), with a median age of 55 years
(24% were ≥65 years). The majority of patients had Stage IV M1c disease (61%). Most subjects
had LDH ≤ULN (67%), ECOG performance status of 0 (70%), and visceral disease (78%) at
baseline. Overall, 54% of subjects had <3 disease sites at baseline. The majority of patients had
BRAF V600E mutation-positive melanoma (89%). Subjects with brain metastases were not
included in the trial.

An OS analysis at 5 years demonstrated continued benefit for the combination of dabrafenib
and trametinib compared with vemurafenib monotherapy; the median OS for the combination
arm was approximately 8 months longer than the median OS for vemurafenib monotherapy
(26.0 months versus 17.8 months) with 5 year survival rates of 36% for the combination versus
23% for vemurafenib monotherapy (Table 12-5, Figure 12-3). The Kaplan-Meier OS curve
appears to stabilize from 3 years to 5 years (see Figure 12-3). The 5-year overall survival rate
was 46% (95% CI: 38.8, 52.0) in the combination arm versus 28% (95% CI: 22.5, 34.6) in the
vemurafenib monotherapy arm for patients who had a normal lactate dehydrogenase level at
baseline, and 16% (95% CI: 9.3, 23.3) in the combination arm versus 10% (95% CI: 5.1, 17.4)
in the vemurafenib monotherapy arm for patients with an elevated lactate dehydrogenase level
at baseline.
Table 12-5 Overall Survival results for Study MEK116513 (COMBI-v)

OS analysis* 3-year OS analysis* 5-year OS analysis*
Dabrafenib Vemurafenib Dabrafenib Vemurafenib Dabrafenib Vemurafenib
+ (n=352) + Trametinib (n=352) + Trametinib (n=352)
Trametinib (n=352) (n=352)
(n=352)
Number of patients
Died 100 (28) 122 (35) 190 (54) 224 (64) 216 (61) 246 (70)
(event),
n (%)
Estimates of OS (months)
Median NR 17.2 26.1 17.8 26.0 17.8
(95% CI) (18.3, NR) (16.4, NR) (22.6, 35.1) (15.6, 20.7) (22.1, 33.8) (15.6, 20.7)
Adjusted 0.69 0.68 0.70
hazard (0.53, 0.89) (0.56, 0.83) (0.58, 0.84)
ratio
(95% CI)
p-value 0.005 NA NA
Overall Dabrafenib + Trametinib Vemurafenib
survival (n=352) (n=352)
Estimate,
% (95% 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
* Primary OS analysis data cut-off: 17-Apr-2014, 3 year OS analysis data cut-off: 15-Jul-2016, 5 year data cut-off: 8-Oct-2018

Figure 12-3 COMBI-v - Kaplan-Meier overall survival curves (ITT Population)
Clinically meaningful improvements for the secondary endpoint of PFS were sustained over a
5 year timeframe in the combination arm compared to vemurafenib monotherapy. Clinically
meaningful improvements were also observed for overall response rate (ORR) and a longer
duration of response (DoR) was observed in the combination arm compared to vemurafenib
monotherapy (Table 12-6).
Table 12-6 Investigator-assessed efficacy results for MEK116513 (COMBI-v) study

Endpoint Primary Analysis* 3-year analysis* 5-year analysis*
+ (n=352) + (n=352) + (n=352)
Trametinib Trametinib Trametinib
(n=352) (n=352) (n=352)
Investigator Assessed PFS
Progressive 166 217 250 257 257 259
disease or (47) (62) (71) (73) (73) (74)
death, n
(%)
Median, 11.4 7.3 12.1 7.3 12.1 7.3
months (9.9, 14.9) (5.8, 7.8) (9.7, 14.7) (5.7, 7.8) (9.7, 14.7) (6.0, 8.1)
(95% CI)
Hazard Ratio 0.56 0.61 0.62
(95% CI) (0.46, 0.69) (0.51, 0.73) (0.52, 0.74)
P value <0.001 NA NA
Overall 64 51 67 53 67 53
Response (59.1, 69.4) (46.1, 56.8) (61.9, 71.9) (47.8, 58.4) (62.2, 72.2) (47.2, 57.9)
Rate(%)
(95% CI)
Difference in NA NA
response 13
rate (5.7, 20.2)
(CR+PR), %
(95% CI for
difference)
P value 0.0005 NA NA
Duration of Response (months)

Endpoint Primary Analysis* 3-year analysis* 5-year analysis*
+ (n=352) + (n=352) + (n=352)
Trametinib Trametinib Trametinib
(n=352) (n=352) (n=352)
Median 13.8 7.5 13.8 7.9 13.8 8.5
(95% CI) (11.0, NR) (7.3, 9.3) (11.3, 17.7) (7.4, 9.3) (11.3, 18.6) (7.4, 9.3)
Primary analysis data cut-off: 17-Apr-2014, 3-year analysis data cut-off: 15-Feb-2016, 5-year analysis data cut-off: 8-Oct-2018
PFS = Progression Free Survival; NR = Not reached; NA=Not applicable
BRF117277 / DRB436B2204 (COMBI-MB) – Metastatic melanoma patients with brain

metastases
The efficacy and safety of Mekinist in combination with Tafinlar in patients with BRAF
mutant-positive melanoma that has metastasized to the brain was studied in a non-
randomized, open-label, multi-center, Phase II study (COMBI-MB study).
A total of 125 patients were enrolled into four cohorts:
• Cohort A: patients with BRAFV600E mutant melanoma with asymptomatic brain

metastases without prior local brain-directed therapy and ECOG performance status of
0 or 1.
• Cohort B: patients with BRAFV600E mutant melanoma with asymptomatic brain
metastases with prior local brain-directed therapy and ECOG performance status of 0
or1.
• Cohort C: patients with BRAFV600D/K/R mutant melanoma with asymptomatic brain
metastases, with or without prior local brain-directed therapy and ECOG performance
status of 0 or 1.
• Cohort D: patients with BRAFV600D/E/K/R mutant melanoma with symptomatic
brain metastases, with or without prior local brain-directed therapy and ECOG
performance status of 0 or 1 or 2.
The primary endpoint of the study was intracranial response in Cohort A, defined as the
percentage of patients with a confirmed intracranial response assessed by the investigator using
modified Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Efficacy
results are summarised in Table 12-5. Secondary endpoints were duration of intracranial
response, ORR, PFS and OS. Efficacy results are summarized in Table 12-7. Due to small
sample size reflected by wide 95% CIs, the results in cohorts B, C, and D should be interpreted
with caution”. BRAF V600K was the predominant mutation in cohort C and BRAF V600E was
the predominant mutation in cohort D; and there were no BRAF V600D mutations observed.
Table 12-7 COMBI-MB - Efficacy data by investigator assessment

All treated patients population
Endpoints/ assessment Cohort A Cohort B Cohort C Cohort D
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)
ORR, % (95% CI)
59% 56% 44% 65%
(47.3, 70.4) (29.9, 80.2) (19.8, 70.1) (38.3, 85.8)
PFS, 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)
OS, median, months (95% CI)
Median, months 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 Reported
• In cohort A, 3 patients were found to have the BRAF V600K mutation upon central
confirmation.
• In cohort C, 14 patients had the BRAF V600K mutation, and 2 patients had the BRAF V600R
mutation.
• In cohort D, 15 patients had the BRAF V600E mutation, 1 patient had the BRAF V600K
mutation and 1 patient had the BRAF V600R mutation.

Study BRF115532 / DRB436F2301 (COMBI-AD)
The efficacy and safety of Mekinist in combination with Tafinlar was studied in a Phase III,
multicenter, randomized, double-blind, placebo-controlled study in patients with Stage III
melanoma with a BRAF V600 mutation, following complete resection.
Patients were randomized 1:1 to receive either dabrafenib and trametinib combination therapy
(Mekinist 2 mg once daily and Tafinlar 150 mg twice daily) or two placebos for a period of
12 months. Enrollment required complete resection of melanoma with complete
lymphadenectomy within 12 weeks prior to randomization. Any prior systemic anticancer
treatment, including radiotherapy, was not allowed. Patients with a history of prior malignancy,
if disease free for at least 5 years, were eligible. Patients presenting with malignancies with
confirmed activating RAS mutations were not eligible. Patients were stratified by BRAF
mutation status (V600E or V600K) and stage of disease prior to surgery (by Stage III sub-stage,
indicating different levels of lymph node involvement and primary tumor size and ulceration).
The primary endpoint was investigator-assessed relapse-free survival (RFS), defined as the time
from randomization to disease recurrence or death from any cause. Radiological tumor
assessment was conducted every 3 months for the first two years and every 6 months thereafter,
until first relapse was observed. Secondary endpoints include overall survival (OS; key
secondary endpoint) and distant metastasis-free survival (DMFS).
A total of 870 patients were randomized 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 tumor ulceration. The majority of patients had a BRAF V600E
mutation (91%). At the time of the primary analysis, the median duration of follow-up (time
from randomization to last contact or death) was 2.83 years in the dabrafenib and trametinib
combination arm and 2.75 years in the placebo arm.

Results for the primary analysis of RFS are presented in Table 12-8. The study showed a
statistically significant difference for the primary outcome of RFS between treatment arms,
with an estimated 53% risk reduction in the dabrafenib and trametinib combination arm as
compared to the placebo arm (HR=0.47; 95% CI: 0.39, 0.58; p=1.53×10-14). Results were
consistent across subgroups, including stratification factors for disease stage and BRAF V600
mutation type. Median RFS was 16.6 months for the placebo arm, and was not reached for the
combination arm at the time of the primary analysis.
Table 12-8 COMBI-AD primary analysis – Relapse-free survival results

Dabrafenib + Trametinib Placebo
RFS parameter N=438 N=432
Number of events, n (%) 166 (38%) 248 (57%)
Recurrence 163 (37%) 247 (57%)
Relapsed with 103 (24%) 133 (31%)
distant metastasis
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] 1.53×10-14
1-year rate (95% CI) 0.88 (0.85, 0.91) 0.56 (0.51, 0.61)
2-year rate (95% CI) 0.67 (0.63, 0.72) 0.44 (0.40, 0.49)
3-year rate (95% CI) 0.58 (0.54, 0.64) 0.39 (0.35, 0.44)
[1] Hazard ratio is obtained from the stratified Pike model.
[2] P-value is obtained from the two-sided stratified log-rank test (stratification factors were disease stage – IIIA vs. IIIB vs.
IIIC – and BRAF V600 mutation type – V600E vs. V600K)
NE = not estimable
Based on updated data with an additional 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 12-4). The 5-year RFS rate was 52% (95% CI: 48,
58) in the combination arm compared to 36% (95% CI: 32, 41) in the placebo arm.

Figure 12-4 COMBI-AD - Relapse-free survival Kaplan-Meier curves (ITT Population)
Based on 153 events (60 (14%) in the combination arm and 93 (22%) in the placebo arm)
corresponding to a 26% information fraction of the total target of 597 OS events, the estimated
hazard ratio for OS was 0.57 (95% CI: 0.42, 0.79; p=0.0006). These results did not meet the
pre-specified boundary to claim statistical significance at this first OS interim analysis
(HR=0.50; p=0.000019). Survival estimates at 1 and 2 years from randomization were 97% and
91% in the combination arm and 94% and 83% in the placebo arm, respectively. The Kaplan-
Meier curve for this OS interim analysis is shown in Figure 12-5.

Figure 12-5 COMBI-AD – Overall survival Kaplan-Meier curves (ITT Population)
1. 0
0. 9
0. 8
0. 7
0. 6
0. 5
0. 4
0. 3
0. 2
0. 1
0. 0
Advanced NSCLC
Study E2201 (Study BRF113928)
The efficacy and safety of trametinib in combination with dabrafenib was studied in a Phase II,
three-cohort, multicentre, non-randomised and open-label study in which patients with stage IV
BRAF V600E mutant NSCLC were enrolled. The primary endpoint was the investigator-
assessed overall response rate (ORR) using the ‘Response Evaluation Criteria In Solid Tumors’
(RECIST 1.1 assessed by the investigator). Secondary endpoints included duration of response
(DoR), progression-free survival (PFS), overall survival (OS), safety and population
pharmacokinetics. ORR, DoR and PFS were also assessed by an Independent Review
Committee (IRC) as a sensitivity analysis.
Cohorts were enrolled sequentially:

• Cohort A: Monotherapy (dabrafenib 150 mg twice daily), 84 patients enrolled.
78 patients had previous systemic treatment for their metastatic disease (see package
insert for Tafinlar on results from Cohort A).
• Cohort B (n=57): Combination therapy (dabrafenib 150 mg twice daily and trametinib
2 mg once daily), 59 patients enrolled. 57 patients had one to three lines of previous
systemic treatment for their metastatic disease. Two patients did not have any previous
systemic treatment and were included in the analysis for patients enrolled in Cohort C.
• Cohort C (n=36): Combination therapy (dabrafenib 150 mg twice daily and trametinib
2 mg once daily), 34 patients. (note: the two patients from Cohort B that did not have any
previous systemic treatment were included in the analysis for patients enrolled in Cohort
C for a total of 36 patients). All patients received study medication as first-line treatment
for metastatic disease.

Among the total of 93 patients who were enrolled in the combination therapy in Cohorts B and
C, most patients were Caucasian (n = 79, 85%). There was a similar female to male ratio (54%
versus 46%). The median age was 64 years in patients who had at least one prior therapy and
68 years in patients who were treatment naïve for their advanced disease. Most patients (n=87,
94%) enrolled in the combination therapy treated Cohorts had an ECOG performance status of
0 or 1. Twenty-six (26) patients (28%) had never smoked. Ninety-one (91) patients (97.8%)
had a non-squamous histology. In the pre-treated population, 38 patients (67%) had one line of
systemic anti-cancer therapy for metastatic disease.
At the time of the primary analysis, the investigator-assessed ORR was 61.1% (95% CI, 43.5%,
76.9%) in the first-line population and 66.7% (95% CI, 52.9%, 78.6%) in the previously treated
population. These results met the statistical significance to reject the null hypothesis that the
ORR of trametinib in combination with dabrafenib for both NSCLC populations was less than
or equal to 30%. The ORR results assessed by IRC were consistent with the investigator
assessment (Table 12-9). The final analysis of efficacy performed 5 years after last subject first
dose is presented in Table 12-9.
Table 12-9 Efficacy Results in Patients with BRAF V600E NSCLC

Endpoint Analysis Combination Combination
First Line Second Line Plus
N=36 N=57
Overall confirmed response n By Investigator 23 (63.9%) 39 (68.4%)
(%) (46.2, 79.2) (54.8, 80.1)
(95% CI)
By IRC 36
23 (63.9%)
(63.2%)
(46.2, 79.2)
(49.3, 75.6)
Median DoR, months By Investigator 10.2 9.8
(95% CI) (8.3, 15.2) (6.9, 18.3)
By IRC 15.2 12.6
(7.8, 23.5) (5.8, 26.2)
Median PFS, months By Investigator 10.8 10.2
(95% CI) (7.0, 14.5) (6.9, 16.7)
By IRC 14.6 8.6
(7.0, 22.1) (5.2, 16.8)
Median OS, months - 17.3 18.2
(95% CI) (12.3, 40.2) (14.3, 28.6)

Study BRF117019 / CDRB436X2201
The efficacy and safety of Mekinist in combination with Tafinlar was studied in a Phase II,
nine-cohort, multicenter, non-randomized, open-label study in patients with rare cancers with
the BRAF V600E mutation, including locally advanced or metastatic anaplastic thyroid cancer
(ATC).
The study had pre-specified interim analyses that were performed approximately every
12 weeks. Patients received Mekinist 2 mg once daily and Tafinlar 150 mg twice daily. The
primary endpoint was the investigator-assessed overall response rate (ORR) using the
‘Response Evaluation Criteria In Solid Tumors’ (RECIST 1.1 assessed by the investigator).

Secondary endpoints included duration of response (DoR), progression-free survival (PFS),
overall survival (OS), and safety. ORR, DoR, and PFS were also assessed by an Independent
Review Committee (IRC).
Thirty-six patients were enrolled and were evaluable for response in the ATC cohort. The
median age was 71 years (range: 47 to 85); 44% were male, 50% white, 44% Asian; and 94%
had ECOG performance status of 0 or 1. Prior anti-cancer treatments included surgery (n=30,
83%), external beam radiotherapy (n=30, 83%), and systemic therapy (n=24, 67%) for ATC.
Central laboratory testing confirmed the BRAF V600E mutation in 23 patients (92%).
For the primary endpoint, the investigator-assessed ORR was 56% (95% CI: 38.1, 72.1) in the
ATC cohort. The ORR results assessed by IRC and investigator-assessment were consistent
(Table 12-8).
Responses were durable with a median DoR in the ATC cohort of 14.4 months (95% CI: 7.4,
43.6) by investigator assessment, and a median PFS of 6.7 months (95% CI: 4.7, 13.8).
For ATC subjects, the median OS was 14.5 months (95% CI: 6.8, 23.2). Kaplan-Meier estimate
of overall survival at 12 months for ATC patients was 51.7% (95% CI: 33.6, 67.1).
Table 12-10 Efficacy Results in Patients with BRAF V600E ATC

Endpoint Analysis By Investigator1 Analysis By IRC
ATC Cohort ATC Cohort
N= 36 N= 36
Overall confirmed response 20 (56%) 19 (53%)(35.5, 69.6)

n (%) (38.1, 72.1)
(95% CI)
Median DoR, months 14.4 13.6

(95% CI) (7.4, 43.6) (3.8, NE2)
Median PFS, months 6.7 5.5

(95% CI) (4.7, 13.8) (3.7, 12.9)
Median OS, months 14.5

(95% CI) (6.8, 23.2)
1
Data cut-off: 14-Sep-2020
2
NE: Not Estimable
Other studies
Pyrexia Management Analysis
Pyrexia is observed in patients treated with Mekinist and Tafinlar combination therapy. The
initial registration 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 Tafinlar in case of pyrexia. In
two subsequent studies in unresectable or metastatic melanoma (COMBI-i control arm, N=264)
and in the adjuvant melanoma setting (COMBI-Aplus, N=552), interruption of both Mekinist
and Tafilnar when patient’s temperature was ≥38oC (100.4°F) (COMBI-Aplus) or at the first
symptom of pyrexia (COMBI-i; COMBI-Aplus for recurrent pyrexia), resulted in improved
pyrexia-related outcomes without impacting efficacy:

• Unresectable or metastatic melanoma setting (COMBI-d/v vs COMBI-i):
o grade 3/4 pyrexia reduced from 6.6% to 3.4%
o hospitalization due to pyrexia reduced from 12.3% to 6.1%
o pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope,
severe chills) reduced from 6.4 % to 1.9%
o treatment discontinuation rates due to pyrexia were comparable, 1.1% versus 1.9%
• Adjuvant melanoma setting (COMBI-AD vs COMBI-Aplus):

o grade 3/4 pyrexia reduced from 5.7% to 4.3%
o hospitalization due to pyrexia reduced from 11.0% to 5.1%
o pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope,
severe chills) reduced from 6.0% to 2.2%
o treatment discontinuation due to pyrexia reduced from 6.2% to 2.5%
13 Non-clinical safety data

Carcinogenicity and mutagenicity
Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic
in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian
cells and micronuclei in the bone marrow of rats.
Reproductive toxicity
Embryofetal development and fertility
Trametinib may impair female fertility in humans. In adult and juvenile rat repeat-dose studies
with trametinib, alterations in follicular maturation, consisting of increases in cystic follicles
and decreases in cystic corpora lutea, were observed at ≥0.016 mg/kg/day (approximately 0.3
times the human clinical exposure based on AUC).
Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in
hallmarks of female sexual maturation (vaginal opening and increased incidence of prominent
terminal end buds within the mammary gland) and slight hypertrophy of the surface epithelium
of the uterus were observed. All of these effects were reversible following an off-treatment
period and attributable to pharmacology. However, in rat and dog toxicity studies up to
13 weeks in duration, there were no treatment effects observed in male reproductive tissues.
Juvenile animal studies
In a juvenile rat toxicity study, the principal toxicities in juvenile rats were on growth
(bodyweight and long bone length), adverse microscopic findings included changes in the bone,
mineralization and/or degeneration in various organs, primarily stomach at all doses. Adverse
findings at the higher doses included in eye, kidney, aortic arch and/or nasal cavity/sinuses,
heart, liver and in skin, and higher heart weights and the delay in a physical landmark of sexual
maturity in females (vaginal opening).
The majority of findings are reversible with the exception of the bone, serum phosphorus and
soft tissue mineralization which progressed/worsened during the off-drug period. Also, kidney
tubular basophilia and higher heart weights were still present at end of recovery period.
With the exception of corneal mineralization/dystrophy and increased heart weight, similar

effects have been observed in adult animals given trametinib. At the lowest combined dose
level evaluated, the systemic exposure is approximately 0.3 times the human exposure at
clinical dose of 2 mg/day based on AUC.
Safety pharmacology and repeat-dose toxicity
In mice, lower heart rate, heart weight and left ventricular function were observed without
cardiac histopathology after 3 weeks at ≥0.25 mg/kg/day trametinib (approximately 3 times
human clinical exposure based on AUC) for up to three weeks. In adult rats, myocardial
mineralisation and necrosis of multiple organs was associated with increased serum phosphorus
were seen at doses ≥1 mg/kg/day (approximately 12 times human clinical exposure based on
AUC) and was closely associated with necrosis in heart, liver and kidney and haemorrhage in
the lung at exposures comparable to the human clinical exposure. In rats, hypertrophy of the
physis and increased bone turnover were observed, but the physeal hypertrophy is not expected
to be clinically relevant for adult humans. In rats and dogs given trametinib at or below clinical
exposures, bone marrow necrosis, lymphoid atrophy in thymus and GALT and lymphoid
necrosis in lymph nodes, spleen and thymus were observed, which have the potential to impair
immune function. In juvenile rats, increased heart weight with no histopathology was observed
at 0.35 mg/kg/day (approximately twice the adult human clinical exposure based on AUC).
Trametinib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU)
assay at significantly higher concentrations than clinical exposures (IC50 at 2.92 µg/ml,
≥130 times the clinical exposure based on Cmax), indicating that there is low risk for
phototoxicity to patients taking trametinib.
In repeat-dose studies the effects seen after trametinib exposure are found mainly in the skin,
gastrointestinal tract, haematological system, bone and liver. Most of the findings are reversible
after drug-free recovery. In rats, hepatocellular necrosis and transaminase elevations were seen
after 8 weeks at ≥0.062 mg/kg/day (approximately 0.8 times human clinical exposure based on
AUC).
Non-fixed dose combination therapy
Trametinib in combination with dabrafenib: Dogs given trametinib and dabrafenib in

combination for 4 weeks demonstrated similar toxicities to those in comparable monotherapy
studies. Refer to the full package insert for Tafinlar.
14 Pharmaceutical information
Incompatibilities
Not applicable.
Special precautions for storage

See folding box.
Store in a refrigerator 2 to 8°C. Store in the original package to protect from light and moisture.
Keep the bottle tightly closed. Contains desiccant, do not remove or eat.
Mekinist should not be used after the date marked “EXP” on the pack.
Mekinist must be kept out of the reach and sight of children.

Instructions for use and handling
There are no special requirements for use or handling of this product.
Manufacturer:
See folding box.
Country Specific Package Leaflet

Information issued: Dec 2021.SIN
®
= Registered Trademark
Novartis Pharma AG, Basel, Switzerland

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1 Tradename

MEKINIST® 0.5 mg and 2 mg film-coated tablets.

2 Description and composition

Adjuvant treatment of melanoma

Mekinist Dec 2021.SIN Page 1 of 45

Advanced non-small cell lung cancer

Locally advanced or metastatic anaplastic thyroid cancer

4 Dosage regimen and administration

General target population

Recommended Dosage for the Adjuvant Treatment of Melanoma

Recommended Dosage for NSCLC

Recommended Dosage for ATC

Mekinist Dec 2021.SIN Page 2 of 45

Mekinist as monotherapy and in combination with Tafinlar

Table 4-1 Recommended dose level reductions

Mekinist Dec 2021.SIN Page 3 of 45

RAS-mutation-positive non-cutaneous malignancies

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

Mekinist Dec 2021.SIN Page 4 of 45

Table 4-3 Recommended dose modifications for trametinib for RPED

Interstitial lung disease (ILD)/Pneumonitis

Mekinist Dec 2021.SIN Page 5 of 45

Geriatric patients (65 years of age or above)

Pediatric patients (below 18 years)

6 Warnings and precautions

BRAF V600 testing

Trametinib monotherapy compared to BRAF inhibitors

Mekinist Dec 2021.SIN Page 6 of 45

Trametinib in combination with dabrafenib in patients with brain metastases

Cutaneous squamous cell carcinoma (cuSCC)

New primary melanoma

Mekinist Dec 2021.SIN Page 7 of 45

LVEF reduction/Left ventricular dysfunction

A cross-study comparison in 1,810 patients treated with combination therapy demonstrated a

Mekinist Dec 2021.SIN Page 8 of 45

Interstitial lung disease (ILD)/Pneumonitis

Mekinist Dec 2021.SIN Page 9 of 45

Severe cutaneous adverse reactions

Venous thromboembolism (VTE)

Mekinist Dec 2021.SIN Page 10 of 45

7 Adverse drug reactions

Summary of the safety profile

Tabulated summary of adverse reactions

Mekinist Dec 2021.SIN Page 11 of 45

Table 7-1 Adverse reactions reported in the integrated safety population of

Immune system disorders Common Hypersensitivitya

Mekinist Dec 2021.SIN Page 12 of 45

Table 7-2 Unresectable or metastatic melanoma and Advanced NSCLC Adverse

Mekinist Dec 2021.SIN Page 13 of 45

Mekinist Dec 2021.SIN Page 14 of 45

Description of selected adverse reactions

LVEF reduction/Left ventricular dysfunction

Mekinist Dec 2021.SIN Page 15 of 45

Interstitial lung disease (ILD)/Pneumonitis

Mekinist Dec 2021.SIN Page 16 of 45

In the integrated safety population of trametinib in combination with dabrafenib (n=641),

Adjuvant treatment of melanoma

Mekinist Dec 2021.SIN Page 17 of 45

Mekinist Dec 2021.SIN Page 18 of 45