Consumer medicine information

Mekinist

Trametinib

BRAND INFORMATION

Brand name

Mekinist

Active ingredient

Trametinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mekinist.

SUMMARY CMI

Mekinist®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using MEKINIST?

MEKINIST contains the active ingredient trametinib. In adult patients MEKINIST is used to treat certain types of skin cancer (melanoma), thyroid cancers and lung cancers; also used to prevent the melanoma coming back if removed by surgery. In children 1 year and older, MEKINIST is used to treat brain tumours, following other treatments.

For more information, see Section 1. Why am I using MEKINIST? in the full CMI.

2. What should I know before I use MEKINIST?

Do not use if you have ever had an allergic reaction to trametinib or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use MEKINIST? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MEKINIST and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MEKINIST?

  • MEKINIST should be taken on an empty stomach at least 1 hour BEFORE eating or 2 hours AFTER eating
  • In adults, the usual total dose of MEKINIST is one 2 mg tablet once a day, taken at the same time each day
  • MEKINIST tablet: Swallow the MEKINIST tablet whole with a full glass of water
  • In children, dosage is based on body weight.
  • MEKINIST powder is made into a solution and taken as a liquid oral solution only. Follow Instruction for Use in box.

More instructions can be found in Section 4. How do I use MEKINIST? in the full CMI.

5. What should I know while using MEKINIST?

Things you should do
  • Remind any doctor, dentist, nurse, or pharmacist you visit that you are using MEKINIST
  • Keep all your doctor's appointments so that your progress can be checked
Things you should not do
  • Do NOT take MEKINIST with food
  • Do NOT stop taking MEKINIST or change the dose unless your doctor tells you to
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how MEKINIST affects you
Drinking alcohol
  • Tell your doctor if you drink alcohol
Looking after your medicine
  • MEKINIST needs protection from light and moisture.
  • Keep MEKINIST tablets and powder in the refrigerator at between 2°C and 8°C.
  • Once MEKINIST powder has been made into a solution, the bottle must be kept below 25°C. Do not freeze.

For more information, see Section 5. What should I know while using MEKINIST? in the full CMI.

6. Are there any side effects?

Common side effects include cough, headache, fever, feeling tired/sick, diarrhoea, vomiting, rash, dry mouth, itching, hair loss/thinning, swelling, flu-like symptoms, joint or muscle pain, blurry vision, mouth sores, nose bleeds, bruising, cracked/dry/red or irritated skin, weakness. Severe side effects include severe tummy pain, blood in poo or vomit, severe cramps, slow or fast heart rate, difficulty breathing, wheezing, swelling of face, hands, lips or eyes, vision loss, sense of flashing lights, sudden bleeding. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring due to approval of an extension of indications. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

Mekinist® (MEH-kih-nist)

Active ingredient(s): trametinib dimethyl sulfoxide

Consumer Medicine Information (CMI)

This leaflet provides important information about using MEKINIST. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using MEKINIST.

Where to find information in this leaflet:

1. Why am I using MEKINIST?
2. What should I know before I use MEKINIST?
3. What if I am taking other medicines?
4. How do I use MEKINIST?
5. What should I know while using MEKINIST?
6. Are there any side effects?
7. Product details

1. Why am I using MEKINIST?

MEKINIST contains the active ingredient trametinib.

MEKINIST belongs to a group of medicines called "selective MEK-inhibitors".

MEKINIST is used to:

  • Treat adult patients with the following types of cancers that have spread to other parts of the body:
    - skin cancers called melanoma
    - thyroid cancers called anaplastic thyroid cancer (ATC)
    - lung cancers called non-small cell lung cancer (NSCLC)
  • Prevent melanoma from coming back after the melanoma has been removed by surgery in adult patients.
  • Treat children 1 year and older with a brain tumour (glioma), following other treatments.

These cancers have a change (mutation) in a gene called "BRAF" that may have caused the cancer to grow. MEKINIST targets proteins made from this changed gene and slows down or stops the growth of your cancer.

MEKINIST can be used by itself or in combination with another medicine called TAFINLAR (containing dabrafenib).

If you are taking these two medicines together, read the full TAFINLAR Consumer Medicine Information as well as this one carefully.

2. What should I know before I use MEKINIST?

Monitoring

Before you take MEKINIST, your doctor will take tumour tissue samples to check whether MEKINIST is suitable for you.

Your doctor should check your heart before you start taking MEKINIST and during treatment.

Your doctor may arrange for you to have an eye examination before you take MEKINIST and while you are taking it.

Warnings

Do not use MEKINIST if:

  • You are pregnant
  • You are allergic to "trametinib", or any of the ingredients listed at the end of this leaflet (symptoms of an allergic reaction can include difficulty breathing, wheezing, swelling of the face, lips or tongue and rash.
  • You are under 12 months of age. It is not known whether it is safe and effective in this younger group of patients.

Check with your doctor if you have:

  • Heart problems
  • Eye problems
  • Bleeding problems
  • Lung problems or difficulty breathing
  • Skin problems such as an acne-like rash
  • Liver problems
  • Gut problems

Pregnancy and breastfeeding

  • If you are pregnant or breast-feeding, think you may become pregnant or are planning to have a baby, ask your doctor, pharmacist, or health care provider for advice before taking this medicine.
  • If you do become pregnant while you are taking MEKINIST, tell your doctor immediately.
  • Your doctor will discuss with you the potential risk(s) of taking MEKINIST during pregnancy or breast-feeding. MEKINIST alone or in combination with TAFINLAR are not recommended during pregnancy or while breastfeeding and may harm your baby.

Birth control requirements

Women taking MEKINIST

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

If MEKINIST is taken in combination with TAFINLAR, non-hormonal contraception should also be used.

Birth control methods containing hormones (such as pills, injections, or patches) may not work as well while taking TAFINLAR.

Men taking MEKINIST

Male patients (including those who have had a vasectomy) with female partners who are or who may become pregnant should use condoms during sexual intercourse while on treatment and for at least 16 weeks after stopping MEKINIST.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins, or supplements that you buy without a prescription from your pharmacy, supermarket, or health food shop.

Some medicines may interfere with MEKINIST and affect how it works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MEKINIST.

4. How do I use MEKINIST?

How much to take

Adults

  • The usual dose of MEKINIST is one 2 mg tablet once a day.
  • Follow the instructions provided and use MEKINIST until your doctor tells you to stop.
  • Do not take more MEKINIST than your doctor has recommended.

Children (1 year and above)

  • The daily dose is based on the body weight and will be advised by their doctor.
  • Follow the instructions provided and give MEKINIST until their doctor tells you to stop.
  • Do not give more MEKINIST than their doctor has recommended.

When to take MEKINIST TABLETS

  • Take MEKINIST once a day. Take it at the same time each day.

How to take MEKINIST TABLETS

  • Take MEKINIST on an empty stomach.
  • Swallow the MEKINIST tablet whole with a full glass of water
  • MEKINIST should be taken either at least:
    - 1 hour BEFORE eating. After taking MEKINIST, wait at least one hour before eating
    OR
    - 2 hours AFTER eating. After eating, wait at least two hours before taking MEKINIST.

When to give MEKINIST FOR ORAL SOLUTION

  • Give MEKINIST once a day. Give it at the same time each day.

How to give MEKINIST for ORAL SOLUTION

MEKINIST powder needs to be prepared into a solution before it is given. Your pharmacist will prepare the oral solution for you. If you are given a MEKINIST bottle containing powder, do not give MEKINIST and contact your pharmacist.

Follow the Instruction for Use enclosed in the box on how to give MEKINIST oral solution. Talk to your doctor or pharmacist if you are not sure.

  • Give MEKINIST on an empty stomach.
  • MEKINIST should be given either at least:
    - 1 hour BEFORE eating. After giving MEKINIST, wait at least one hour before eating
    OR
    - 2 hours AFTER eating. After eating, wait at least two hours before giving MEKINIST.

If you forget to take MEKINIST

MEKINIST should be taken regularly at the same time each day. If the missed dose of MEKINIST is:

  • Less than 12 hours late, take it as soon as you remember.
  • More than 12 hours late, skip that dose and take your next dose at the usual time. Then go back to taking your medicine normally.

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

If you use too much MEKINIST

If you think that you have taken too much MEKINIST (or TAFINLAR if using them together), you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using MEKINIST?

Things you should do

  • Use contraception for both men and women to avoid pregnancy while taking MEKINIST and do this for 16 weeks after stopping MEKINIST
  • If taking MEKINIST and TAFINLAR together, non-hormonal contraception should also be used (e.g., condoms)
  • If you become pregnant while taking MEKINIST, tell your doctor immediately
  • Keep all your doctor's appointments so that your progress can be checked
  • Have the blood tests your doctor tells you to have
  • Have your eyes, liver, kidneys, blood pressure and heart checked regularly.

Call your doctor straight away if you:

  • Get a high fever (Signs of a fever may include a temperature of 38°C or more, severe chills, shivering, thirst, or dehydration, feeling dizzy, faint, or as if you're going to be sick).

Things you should not do

  • Do not stop using this medicine suddenly
  • Do not take MEKINIST with food.

Additional tests

  • Your doctor may do some blood tests such as checking blood cells (white blood cells, red blood cells and platelets), electrolytes (e.g., sodium and phosphorus) and sugar levels in your body from time to time to make sure MEKINIST is working and to prevent unwanted side effects. Your eyes, kidneys, liver, heart, blood pressure will also be checked regularly.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MEKINIST affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your tablets or the prepared solution in the bottle until it is time to take them.
  • Tablets: Do not remove the desiccant (material that keeps the medicine dry)
  • Keep your tablets and powder that has not been prepared in the refrigerator between 2°C and 8°C.
  • Once powder has been prepared into a solution, keep below 25°C. Do not freeze.
  • Once powder has been prepared into a solution, discard solution after a maximum of 35 days.

Whilst in use, the tablet bottle may be stored out of the refrigerator for a maximum of 30 days.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat, or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
MEKINIST alone
Hair problems
  • Loss or thinning of hair
Skin problems
  • Red, dry, itchy, pale, or irritated
  • Sensitive or chapped skin
  • Warts, tender bumps
Tummy problems
  • Vomiting, minor tummy pain
  • Constipation
General wellness
  • Lack of energy, feeling sick, headache, tiredness, bloating
  • Cough, sore throat
  • Changes to appetite
  • Excessive thirst, dry mouth
Kidney problems
  • More frequent wee
Limb problems
  • Nail disorders and pain
  • Swelling in the arms, legs, or other part of the body
MEKINIST and TAFINLAR together
Skin problems
  • Red, dry, itchy, pale, or irritated
  • Sunspots, skin tags, warts
  • Painful bumps or other changes
  • Sensitive skin
General wellness
  • Lack of energy, feeling sick, headache, feeling lightheaded
  • Cough, sore throat, runny nose
  • Changes to appetite
  • Irritability, excessive thirst/dry mouth
  • Night sweats, excessive sweating
  • Weight increased (in children)
General pain
  • Muscles, joints, hands, or feet, muscle spasm
Kidney problems
  • More frequent wee or urinary tract infection
Tummy problems
  • Vomiting, minor tummy pain
  • Constipation
Limb problems
  • Nail disorders and pain
  • Swelling in the arms, legs, or other part of the body
Speak to your doctor if you have any of these less serious side effects and they worry you.
If these side effects become severe, please tell your doctor, pharmacist, or healthcare provider.

Serious side effects

Serious side effectsWhat to do
MEKINIST alone
Tummy problems
  • Severe tummy pain, blood in poo or vomit, severe cramps
Kidney problems
  • Less wee when going to the toilet than expected
Signs of allergic reaction
  • Trouble breathing/swallowing, swelling of face, throat or tongue, itchy rash, wheezing.
Eye problems
  • Loss of or blurred vision, flashing light sensation, eye swelling
Heart problems
  • Slow/fast heart rate
  • Irregular heartbeat
Breathing problems
  • Painful or troubled breathing, feeling breathless or tired
MEKINIST and TAFINLAR together
Signs of infection
  • Fever, chills, sore throat
Bleeding problems
  • Bloody poo or vomit, coughing up blood, nosebleeds
  • Sudden bleeding/bruising
Kidney problems
  • Less wee when going to the toilet
  • Unexplained drowsiness, confusion, or feeling sick
  • Red-brown wee or pain when going to the toilet
  • Fluid buildup (e.g., swollen legs)
Skin problems
  • Severe rash, blisters on the eyes or lips, peeling.
  • Swollen lymph nodes
  • Unusual skin changes or changes in colour of moles
Tummy problems
  • Severe, sudden tummy pain or cramps
Eye problems
  • Loss of or blurred vision, flashing light sensation, red eyes
Heart problems
  • Tightness in chest, fast heart rate, flushing or bluish skin
  • Slow heart rate
  • Irregular heartbeat
Breathing problems
  • Painful or troubled breathing
  • Chest pain
Signs of allergic reaction
  • Trouble breathing/swallowing, dizziness, swelling of face, throat or tongue, itchy rash, wheezing.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What MEKINIST contains

Active ingredient
(main ingredient)		Trametinib dimethyl sulfoxide
Other ingredients - tablets
(inactive ingredients)		Mannitol (E421)
Microcrystalline cellulose (E460(i))
Hypromellose (E464)
Croscarmellose sodium
Magnesium stearate (vegetable source) (E572)
Sodium lauryl sulphate (E487)
Colloidal anhydrous silica
Titanium dioxide (E171)
Polyethylene glycol
0.5 mg tablets only
Iron oxide yellow CI 77492 (E172).
2 mg tablets only
Polysorbate 80 (E433)
Iron oxide red CI 77491 (E172)
Other ingredients - powder for oral solution (inactive ingredients)Sucralose
Citric acid monohydrate
Dibasic sodium phosphate
Sulfobutyl betadex sodium
Potassium sorbate
Methyl hydroxybenzoate
Flavour strawberry
Potential allergensMEKINIST tablets & powder do not contain lactose, gluten, tartrazine, or any other azo dyes.
Powder: Contains sucrose

Do not take this medicine if you are allergic to any of these ingredients.

What MEKINIST looks like

MEKINIST tablets are supplied in two strengths and are available in plastic bottles containing 30 tablets. The bottle has a child resistant closure and contains a desiccant. MEKINIST is also available as a powder (to be made into a solution) which is supplied in a glass bottle with a child resistant closure.

0.5 mg tablets

Yellow, modified oval, biconvex, film-coated tablets with 'GS' debossed on one face and 'TFC' on the opposite face (AUST R 205917).

2 mg tablets

Pink, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'HMJ' on the opposite face (AUST R 205919).

4.7 mg powder for oral solution

White or almost white powder.

(AUST R 397190).

Who distributes MEKINIST:

MEKINIST is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road, Macquarie Park NSW 2113 Australia
Telephone 1 800 671 203
www.novartis.com.au

® Registered Trademark

This leaflet was prepared in December 2023.

Internal document code

(mek291123c based on PI mek291123i)

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Mekinist

Active ingredient

Trametinib

Schedule

S4

 

1 Name of Medicine

Trametinib.

2 Qualitative and Quantitative Composition

Active substance.

Mekinist 0.5 mg film coated tablet.

Each film coated tablet contains trametinib dimethyl sulfoxide equivalent to trametinib 500 micrograms.

Mekinist 2 mg film coated tablet.

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

Mekinist 0.05 mg/mL powder for oral solution.

Each bottle contains 5.3 mg trametinib dimethylsulfoxide equivalent to 4.7 mg of trametinib. Each mL of the constituted solution contains 0.05 mg of trametinib.

Excipients.

For the list of excipients, see Section 6.1 List of Excipients.

Excipients with known effect.

Mekinist powder for oral solution contains sucralose.

Note.

Trametinib tablets and powder for oral solution are not fully interchangeable.

3 Pharmaceutical Form

Mekinist 0.5 mg film coated tablet.

Yellow, modified oval, biconvex, film-coated tablets with 'GS' debossed on one face and 'TFC' on the opposing face; or
Yellow, ovaloid, biconvex, unscored, film-coated tablets with Novartis logo on one side and TT on the other side.

Mekinist 2 mg film coated tablet.

Pink, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'HMJ' on the opposing face; or
Pink, round, biconvex, unscored, film-coated tablets with Novartis logo on one side and LL on the other side.

Mekinist 0.05 mg/mL powder for oral solution.

White or almost white powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Unresectable or metastatic melanoma.

Mekinist in combination with dabrafenib is indicated for the treatment of patients with BRAF V600 mutation positive unresectable Stage III or metastatic (Stage IV) melanoma.
Mekinist as a monotherapy is indicated for the treatment of patients with BRAF V600 mutation positive unresectable Stage III or metastatic (Stage IV) melanoma and in whom either there is intolerance to BRAF inhibitors or BRAF inhibitors cannot be used.
Mekinist as monotherapy has not demonstrated clinical activity in patients who have progressed on BRAF inhibitor therapy (see Section 5.1, Clinical trials).

Adjuvant treatment of melanoma.

Mekinist in combination with dabrafenib is indicated for the adjuvant treatment of patients with melanoma with a BRAF V600 mutation and involvement of the lymph node(s), following complete resection.

Anaplastic thyroid cancer (ATC).

Mekinist 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.

Non-small cell lung cancer (NSCLC).

Mekinist in combination with dabrafenib is indicated for the treatment of patients with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation.

Low-grade glioma.

Mekinist in combination with dabrafenib is indicated for the treatment of paediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy (see Section 5.1, Clinical trials).

High-grade glioma.

Mekinist in combination with dabrafenib is indicated for the treatment of paediatric patients 1 year of age and older with high-grade glioma (HGG) with a BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options (see Section 5.1, Clinical trials).

4.2 Dose and Method of Administration

Treatment with Mekinist should be initiated by a physician experienced in the use of anticancer therapies.
Confirmation of the BRAF V600 mutation, using an approved/ validated test, is required for the selection of patients appropriate for Mekinist monotherapy and Mekinist in combination with dabrafenib (see Section 5.1, Clinical trials).
For dabrafenib dosing instructions, when Mekinist is used in combination with dabrafenib, refer to the full dabrafenib (Tafinlar) product information.
The efficacy and safety of Mekinist have not been established in patients with wild-type BRAF tumours (see Section 5.1, Clinical trials). Mekinist should not be used in patients with BRAF wild-type tumours (see Section 4.4 Special Warnings and Precautions for Use).

Note.

Trametinib tablets and powder for oral solution are not fully bioequivalent/interchangeable; caution is advised when consideration is given to changing formulations due to any difficulty in swallowing solid forms and frequent switching between formulations is discouraged.

Duration of treatment.

The recommended duration of treatment for patients with unresectable or metastatic melanoma, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity.
In the adjuvant melanoma setting, the treatment duration is limited to a maximum of 1 year.
The recommended duration of treatment for paediatric patients with glioma is until disease progression or until unacceptable toxicity. There are limited data in patients older than 18 years of age with glioma who require first systemic therapy. Therefore, continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician.

Recommended dosage.

Mekinist is available in two dosage forms, film coated tablets and powder for oral solution.

Adult patients.

The recommended dose of Mekinist, used as monotherapy or in combination with dabrafenib, is 2 mg given orally once daily independent of body weight.

Dose modifications.

Mekinist as monotherapy and in combination with dabrafenib. The management of adverse events/ adverse drug reactions may require treatment interruption, dose reduction, or treatment discontinuation.
Recommended dose level reductions are provided in Table 1. Doses below 1 mg once daily are not recommended, whether used as monotherapy or in combination with dabrafenib.
The recommended dose modification schedule is provided in Tables 2 and 3. 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.
If treatment related toxicities occur when Mekinist is used in combination with dabrafenib, then both treatments should be simultaneously dose reduced, interrupted or discontinued, with the exceptions shown below.

Exception where dose modification is necessary for only dabrafenib.

New primary non-cutaneous malignancies; pyrexia.
For dose modification guidelines, refer to the dabrafenib product information.

Exceptions where dose modifications are necessary for only Mekinist.

LVEF reduction; RVO and RPED; ILD/ pneumonitis.
Detailed dosing modifications for selected adverse reactions.

New primary malignancies.

For new primary cutaneous malignancies no dose modifications are required.
For new primary non-cutaneous malignancies no dose modifications are required for Mekinist. If used in combination with dabrafenib, permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies.

Haemorrhagic events.

Permanently discontinue Mekinist, and also permanently discontinue dabrafenib if administered in combination, for all Grade 4 haemorrhagic events and for any Grade 3 haemorrhagic events that do not improve.
Withhold Mekinist for up to 3 weeks for Grade 3 haemorrhagic events; if improved resume at a lower dose level.
Withhold dabrafenib for Grade 3 haemorrhagic events; if improved resume at a lower dose level.

Pyrexia management.

Therapy should be interrupted (Mekinist when used as monotherapy, and both Mekinist and Tafinlar when used in combination) if the patient's temperature is ≥ 38°C or at the first symptom of pyrexia/pyrexia syndrome. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia/pyrexia syndrome. 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 4.4 Special Warnings and Precautions for Use).
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. See Table 3.
Monitor serum creatinine and other evidence of renal function during and following severe events of pyrexia.

Left ventricular ejection fraction (LVEF) reduction/ left ventricular dysfunction management.

Mekinist should be interrupted in patients who have an asymptomatic, absolute decrease of ≥ 10% in LVEF compared to baseline and the ejection fraction is below the institution's lower limit of normal (LLN) (see Section 4.4 Special Warnings and Precautions for Use). If Mekinist is being used in combination with dabrafenib then therapy with dabrafenib may be continued at the same dose. If the LVEF recovers, treatment with Mekinist may be restarted, but reduce dose by one dose level with careful monitoring.
Permanently discontinue Mekinist with Grade 3 or 4 left ventricular cardiac dysfunction or if LVEF-reduction does not recover. If Mekinist is being used in combination with dabrafenib then therapy with dabrafenib should be withheld and resumed at the same dose upon recovery of cardiac function.

RVO and RPED management.

If patients report new visual disturbances such as diminished central vision, blurry vision, or loss of vision at any time while on Mekinist therapy, a prompt ophthalmological assessment is recommended.
In patients who are diagnosed with RVO, treatment with Mekinist, whether given as monotherapy or in combination with dabrafenib, should be permanently discontinued (see Section 4.4 Special Warnings and Precautions for Use). Dabrafenib treatment can continue at the same dose.
If RPED is diagnosed, follow the dose modification schedule (intolerable) in Table 4 for Mekinist and, if Mekinist is being used in combination with dabrafenib, continue dabrafenib at the same dose (see Section 4.4 Special Warnings and Precautions for Use).

Interstitial lung disease (ILD)/ pneumonitis.

Withhold Mekinist 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 Mekinist for patients diagnosed with treatment-related ILD or pneumonitis. If Mekinist is used in combination with dabrafenib, do not modify the dose of dabrafenib.

Serious skin toxicity.

For dosing instructions for intolerable or severe skin toxicity for Mekinist and Mekinist in combination with dabrafenib see Table 5. Dose reduction, interruption or discontinuation should be applied to both treatments.
The following rash management guidance should be considered whether Mekinist is given as monotherapy or in combination with dabrafenib, and if dose reduction, interruption or discontinuation is necessary it should be applied to both treatments.
Treatment of rash has not been formally studied and should be based on rash severity. The following guidelines were used in clinical studies with Mekinist as monotherapy or in combination with dabrafenib and can be used to manage rash (see Table 6).
Paediatric patients.

Film-coated tablets.

The recommended dosage for Mekinist tablets in paediatric patients who weigh at least 26 kg, is based on body weight (Table 7). A recommended dose for patients who weigh less than 26 kg has not been established.
Recommended dose level reductions for Mekinist tablets in paediatric patients are provided in Table 8.

Powder for oral solution.

The recommended dosage and dose level reductions for Mekinist powder for oral solution are based on body weight (Table 9).

Special populations.

Paediatric use.

The safety and efficacy of Mekinist in combination with dabrafenib have not been established in paediatric patients younger than 1 year of age with LGG/HGG with BRAF V600E mutation. The safety and effectiveness of Mekinist as a single agent in paediatric patients has not been established.

Use in the elderly.

No dose adjustments are required in patients over 65 years (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dosage adjustment 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 5.2 Pharmacokinetic Properties). There are no clinical data with Mekinist in patients with severe renal impairment; therefore, the potential need for starting dose adjustment cannot be determined. Mekinist should be used with caution in patients with severe renal impairment.

Hepatic impairment.

No dosage adjustment is required in patients with mild hepatic impairment.
Available data in patients with moderate or severe hepatic impairment from a clinical pharmacology study indicate a limited impact on Mekinist exposure (see Section 5.2 Pharmacokinetic Properties). Trametinib should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with dabrafenib.

Administration.

Mekinist should be administered for twelve (12) months only in the adjuvant treatment of melanoma.
Mekinist should be taken without food, at least 1 hour before or 2 hours after a meal (see Section 5.2 Pharmacokinetic Properties).
When Mekinist and dabrafenib are taken in combination, the dose of Mekinist should be taken at the same time each day with either the morning or evening dose of dabrafenib.
If a dose of Mekinist is missed, only take the dose if it is more than 12 hours until the next scheduled dose.

Powder for oral solution.

Mekinist powder for oral solution is reconstituted before use with water. To prepare Mekinist for oral solution, tap the bottle to loosen powder. When prepared in a pharmacy, add 90 mL distilled or purified water to the powder in the bottle and invert or gently shake the bottle with re-attached cap for up to 5 minutes until powder is fully dissolved yielding a clear solution. Separate the dosing adapter from the oral syringe. Insert dosing adapter into bottle neck after reconstitution of the solution. Write the discard after date. Refer to the Instruction for use for detailed reconstitution instructions. Discard any unused solution 35 days after reconstitution. Administer Mekinist for oral solution from oral dosing syringe or feeding tube.
When using Mekinist powder for oral solution, physicians should review and discuss with the patient or caregiver(s) the Consumer Medicine Information and instructions for mixing and administering Mekinist. Physicians should confirm that the patients or caregiver(s) understand how to mix Mekinist powder for oral solution with water and administer the correct daily dose.

4.3 Contraindications

Mekinist is contraindicated in patients with known hypersensitivity to the active substance trametinib dimethyl sulfoxide or any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

BRAF V600 testing.

Confirmation of BRAF V600 mutation using an approved/ validated test is required for selection of patients appropriate for Mekinist monotherapy and in combination with dabrafenib. Patients enrolled in the melanoma clinical studies were required to have BRAF V600 mutation status measured. The safety and efficacy of Mekinist have not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation.

New primary melanoma.

New primary malignancies can occur when Mekinist is used in combination with dabrafenib and with dabrafenib as a single agent [refer to Product Information for dabrafenib (Tafinlar)]. Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms (refer to the Product Information for dabrafenib).

Non-cutaneous secondary/ recurrent malignancies.

In patients receiving Mekinist in combination with dabrafenib, four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. If used in combination with dabrafenib, no dose modification is required for Mekinist in patients who develop non-cutaneous malignancies. Permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies (see Section 4.2 Dose and Method of Administration).

Haemorrhage.

Haemorrhagic events, including major haemorrhagic events have occurred in patients taking Mekinist as monotherapy and in combination with dabrafenib (see Section 4.8 Adverse Effects (Undesirable Effects)). If patients develop symptoms of hemorrhage they should immediately seek medical care.
Six (6) out of 559 unresectable or metastatic melanoma patients (1.1%) receiving Mekinist in combination with dabrafenib in phase III trials had fatal intracranial haemorrhagic events. Three cases were from study MEK115306 (COMBI-d) and three cases were from study MEK116513 (COMBI-v). No fatal hemorrhagic events occurred in the Phase III study in the adjuvant treatment of melanoma (0/438). 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.
In Study BRF113220, treatment with Mekinist in combination with dabrafenib resulted in an increased incidence and severity of any haemorrhagic event: 16% (9/55) of patients treated with Mekinist in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. The major haemorrhagic events of intracranial or gastric haemorrhage occurred in 5% (3/55) of patients treated with Mekinist in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Intracranial haemorrhage was fatal in two (4%) patients receiving the combination of Mekinist and dabrafenib.
Permanently discontinue Mekinist, and also permanently discontinue dabrafenib if administered in combination, for all Grade 4 haemorrhagic events and for any Grade 3 haemorrhagic events that do not improve. Withhold Mekinist for up to three weeks for Grade 3 haemorrhagic events; if improved resume at a lower dose level. Withhold dabrafenib for Grade 3 haemorrhagic events; if improved resume at a lower dose level (see Section 4.2 Dose and Method of Administration).

Cardiac effects.

QT prolongation.

Initially, the QT prolongation potential of trametinib was assessed as part of the first time in human study MEK111054 to determine the relationship between the independently manually-read QTc interval and plasma concentrations of trametinib using a nonlinear mixed effects model. Data were available in 50 patients with a total of 498 matched QTc values. Based on the concentration-QTc analysis, trametinib showed no apparent potential to alter the QTc interval. At the mean Cmax value observed at the recommended dose of 2 mg once daily, the median increase in QTc is 2.2 msec (90% CI: 0.2, 4.0).
In BRF113220, QTcF prolongation to > 500 msec occurred in 4% (2/55) of patients treated with Mekinist in combination with dabrafenib and in 2% (1/53) of patients treated with dabrafenib as a single agent. The QTcF was increased more than 60 millisecond (msec) from baseline in 13% (7/55) of patients treated with Mekinist in combination with dabrafenib and 2% (1/53) of patients treated with dabrafenib as a single agent.
To confirm the lack of effect on QTc, the QT prolongation potential of Mekinist was further assessed in a dedicated, stand-alone Phase I study MEK114655 in 35 patients with solid tumors. Patients received 3 mg matched placebo on study day 1 followed by a 2 mg once daily dose of trametinib and 2 tablets of 0.5 mg matched placebo on study days 2 to 14. On study day 15, all patients received a single dose of 3 mg Mekinist (supratherapeutic dose). The study showed no potential for Mekinist to alter the QTcF interval after repeat dose administration of 2 mg trametinib, including at the supratherapeutic dose of 3 mg on day 15. At a dose 1.5 times the maximum recommended dose, Mekinist does not prolong the QT interval to any clinically relevant extent.

Bradycardia.

A dedicated cardiac study in solid tumour patients (n = 30) confirmed early exploratory analyses in showing statistically significant changes in both PR interval (mean 21.68 msec increase, normal = 120 to 200) and heart rate (mean 8.12 bpm decrease) with trametinib versus placebo. The clinical significance of this small increase in PR interval is unclear, however in a large ongoing trial (n = 704), heart rate decrease to < 60 bpm has been recorded in 23% of 348 patients on trametinib and dabrafenib combined therapy compared to 12% of patients in the vemurafenib monotherapy control arm.

LVEF reduction/ left ventricular dysfunction.

Mekinist has been reported to decrease LVEF (see Section 4.8 Adverse Effects (Undesirable Effects)). Mekinist should be used with caution in patients with conditions that could impair left ventricular function. In clinical trials, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure, and LVEF decrease in patients treated with Mekinist (as monotherapy or in combination with dabrafenib) was between two to five months. LVEF should be evaluated in all patients prior to initiation of treatment with Mekinist with a recommendation of periodic follow-up within eight weeks of initiating therapy, as clinically appropriate. LVEF should continue to be evaluated during treatment with Mekinist as clinically appropriate (see Section 4.2 Dose and Method of Administration).
Across clinical trials of Mekinist at the recommended dose (N = 329), 11% of patients developed evidence of cardiomyopathy (decrease in left ventricular ejection fraction, or LVEF, below institutional lower limits of normal with an absolute decrease in LVEF ≥ 10% below baseline) and 5% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥ 20% below baseline.
LVEF should be evaluated by echocardiogram or multigated acquisition (MUGA) scan in all patients prior to initiation of treatment with Mekinist, one month after initiation of therapy, and then at approximately three monthly intervals while on treatment.
Mekinist should be interrupted in patients who have an asymptomatic, absolute decrease of ≥ 10% in LVEF compared to baseline and the ejection fraction is below the institution's lower limit of normal (LLN). If Mekinist is being used in combination with dabrafenib then therapy with dabrafenib may be continued at the same dose. If the LVEF recovers, treatment with Mekinist may be restarted, but the dose should be reduced by one dose level with careful monitoring.
With Grade 3 or 4 left ventricular cardiac dysfunction or if LVEF does not recover Mekinist should be permanently discontinued. If Mekinist is being used in combination with dabrafenib, therapy with dabrafenib should be withheld and resumed at the same dose upon recovery of cardiac function (see Section 4.2 Dose and Method of Administration).

Visual impairment.

A thorough ophthalmological evaluation should be performed at baseline and during treatment with Mekinist, if clinically warranted. 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, follow the dose modification schedule (intolerable) (see Section 4.2 Dose and Method of Administration). The data from clinical trials demonstrates that when all reported ocular events are pooled, there was a higher reported rate in the patients treated with combination therapy than monotherapy (20% vs 13%, respectively). The median exposure time for combination therapy was substantially longer than Mekinist monotherapy (6.41 vs. 3.84 months, respectively).
Disorders associated with visual disturbance, including retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO), have been observed with Mekinist 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 Mekinist (see Section 4.8 Adverse Effects (Undesirable Effects)). If patients report new visual disturbances such as diminished central vision, blurry vision, or loss of vision at any time while on Mekinist therapy, a prompt ophthalmological assessment is recommended.

Retinal pigment epithelial detachment (RPED).

Retinal pigment epithelial detachments (RPED) can occur during treatment with Mekinist. Across all clinical trials of Mekinist, the incidence of RPED was 0.8% (14/1749). Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range: 3 to 71 days) following the interruption of dosing with Mekinist, although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.
If RPED is diagnosed, follow the dose modification schedule (intolerable) in Table 4 (see Section 4.2 Dose and Method of Administration).

Retinal vein occlusion (RVO).

Mekinist is not recommended in patients with a history of RVO. Across all clinical trials of Mekinist, the incidence of RVO was 0.2% (4/1749). In patients who experience RVO, treatment with trametinib should be permanently discontinued.
RVO may lead to macular oedema, decreased visual function, neovascularisation, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue Mekinist in patients with documented RVO.

Interstitial lung disease (ILD)/ pneumonitis.

Any diagnosis of ILD or pneumonitis warrants immediate discontinuation of Mekinist.
In a Phase 3 trial, 2% (5/211) of patients treated with Mekinist 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).
Withhold Mekinist in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue Mekinist for patients diagnosed with treatment-related ILD or pneumonitis. If Mekinist is used in combination with dabrafenib, do not modify the dose of dabrafenib.

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 dabrafenib. 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 dabrafenib should be withdrawn.

Venous thromboembolism (VTE).

VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), can occur with Mekinist monotherapy and when Mekinist is used in combination with dabrafenib. If patients develop symptoms of VTE they should immediately seek medical care (see Section 4.8).

Pyrexia and serious non-infectious febrile events.

Pyrexia was reported in the clinical trials with Mekinist. The incidence and severity of pyrexia are increased when Mekinist is used in combination with dabrafenib (see Section 4.8 Adverse Effects (Undesirable Effects)). In patients with unresectable or metastatic melanoma who received the combination dose of dabrafenib 150 mg twice daily and Mekinist 2 mg once daily and 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 3 or more events. Pyrexia may be accompanied by severe rigors, dehydration, and hypotension, which in some cases can lead to acute renal insufficiency. Monitor serum creatinine and other evidence of renal function during and following severe events of pyrexia. Renal failure was reported in 7% of patients who received the combination dose of dabrafenib 150 mg twice daily and Mekinist 2 mg once daily, a higher frequency than observed in dabrafenib monotherapy patients (< 1%), and was often seen in the context of pyrexia and dehydration.
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.
Therapy with Mekinist (Mekinist when used in monotherapy, or both Mekinist and Tafinlar when used in combination) should be interrupted if the patient's temperature is ≥ 38.0°C or at the first symptom of pyrexia/pyrexia syndrome. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia/pyrexia syndrome. 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 4.4 Special Warnings and Precautions for Use).
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.
For management of pyrexia see Section 4.2 Dose and Method of Administration.
For management of pyrexia, also see Section 4.2 Dose and Method of Administration, Pyrexia management and the Product Information for dabrafenib (Tafinlar).

Serious skin toxicity.

Serious skin toxicity can occur when Mekinist is administered as a single agent or when used in combination with dabrafenib. Serious skin toxicity can also occur with dabrafenib as a single agent (refer to Product Information for dabrafenib).
In MEK114267, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients treated with Mekinist and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with Mekinist. Skin toxicity requiring hospitalisation occurred in 6% of patients treated with Mekinist, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalisation for severe skin toxicity or infections of the skin. The median time to onset of skin toxicity in patients treated with Mekinist was 15 days (range: 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range: 1 to 282 days). Reductions in the dose of Mekinist were required in 12% and permanent discontinuation of Mekinist was required in 1% of patients with skin toxicity.
In BRF113220, the incidence of any skin toxicity was similar for patients receiving Mekinist in combination with dabrafenib (65% [36/55]) compared with patients receiving dabrafenib as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with Mekinist in combination with dabrafenib was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of Mekinist or dabrafenib for skin toxicity.
Across clinical trials of Mekinist administered in combination with dabrafenib (n = 202), severe skin toxicity and secondary infection of the skin requiring hospitalisation occurred in 2.5% (5/202) of patients treated with Mekinist in combination with dabrafenib.
Withhold Mekinist, and dabrafenib if used in combination, for intolerable or severe skin toxicity until further assessment (see Section 4.2 Dose and Method of Administration). Mekinist and dabrafenib may be resumed at a lower dose level in patients with improvement or recovery from skin toxicity within three weeks.

Rash.

In clinical studies with Mekinist, rash has been observed in about 60% of patients as monotherapy and 30% in combination with dabrafenib (see Section 4.2 Dose and Method of Administration). The majority of these cases were grade 1 or 2 and did not require any dose interruptions or dose reductions.

Hepatic events.

Hepatic adverse events have been reported in clinical trials with Mekinist as monotherapy and in combination with dabrafenib. It is recommended that patients receiving treatment with Mekinist monotherapy or in combination with dabrafenib have liver function monitored every four weeks for 6 months after treatment initiation with Mekinist (see Section 4.8 Adverse Effects (Undesirable Effects)).

Colitis and gastrointestinal perforation.

Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking Mekinist as monotherapy and in combination with Tafinlar (see Section 4.8 Adverse Effects (Undesirable Effects)). Treatment with Mekinist monotherapy or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including a 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.

Haemophagocytic lymphohistiocytosis (HLH).

In post-marketing experience, HLH has been observed with Mekinist in combination with Tafinlar. If HLH is suspected, treatment should be interrupted. If HLH is confirmed, treatment should be discontinued and appropriate management of HLH should be initiated.

Hypertension.

Elevations in blood pressure have been reported in association with dabrafenib in combination with trametinib, in patients with or without pre-existing hypertension (see Section 4.8 Adverse Effects (Undesirable Effects)). Also refer to the Tafinlar Product Information for additional information.

Rhabdomyolysis.

Rhabdomyolysis has been reported in patients taking Tafinlar in combination with Mekinist (see Section 4.8 Adverse Effects (Undesirable Effects)). Also refer to the Tafinlar Product Information for additional information.

Use in the elderly.

No initial dose adjustments are required in patients over 65 years of age (see Section 5.2 Pharmacokinetic Properties).
More frequent dose adjustments may be required in patients over 65 years of age (see Section 4.8 Adverse Effects (Undesirable Effects)). Across clinical trials of Mekinist administered in combination with dabrafenib (n = 202), adverse events resulting in dose interruption were reported for 71% of those aged ≥ 65 years as compared to 60% of those < 65 years, while adverse events resulting in dose reduction occurred in 64% of those aged ≥ 65 years as compared to 44% of those < 65 years.
Clinical trials of Mekinist administered as a single agent or in combination with dabrafenib did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In MEK114267, 49 patients (23%) were 65 years of age and older, and 9 patients (4%) were 75 years of age and older. Across clinical trials of Mekinist administered in combination with dabrafenib (n = 202), 42 patients (21%) were 65 years of age and older, and 12 patients (6%) were 75 years of age and older.

Paediatric use.

The safety and efficacy of Mekinist in combination with dabrafenib have not been yet established in paediatric patients younger than 1 year of age with LGG/HGG with BRAF V600E mutation. For information of paediatric patients aged 1 to 18 years, see Section 4.1; Section 4.2; Section 4.8; Section 5.1; Section 5.2. The safety and effectiveness of Mekinist as a single agent in paediatric patients have not been established.

Effects on laboratory tests.

Treatment-emergent laboratory abnormalities may include any of the following serum elevations: gamma-glutamyltransferase (GGT), alkaline phosphatase (AP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose, and kidney function results. Also see Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Trametinib 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 (see Section 5.2 Pharmacokinetic Properties).
Based on in vitro data, Mekinist is unlikely to significantly affect the pharmacokinetics of other medicinal products via interactions with CYP enzymes (see Section 5.2 Pharmacokinetic Properties) or transporters.

Trametinib in combination with dabrafenib.

Repeat dose administration of once daily Mekinist 2 mg had no effect on the single dose Cmax and AUC of dabrafenib, a CYP2C8/ CYP3A4 substrate. Co-administration of repeat dosing of dabrafenib 150 mg twice daily and Mekinist 2 mg once daily resulted in an increase of 16% and 23% for dabrafenib Cmax and AUC respectively. A small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was estimated when Mekinist is administered in combination with dabrafenib using a population PK analysis. These changes in dabrafenib or trametinib Cmax and AUC are considered not clinically relevant.
See Product Information for dabrafenib (Tafinlar) for guidelines on drug interactions associated with dabrafenib monotherapy.

Effects of other drugs on trametinib.

In vitro and in vivo data suggest that the PK of Mekinist 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: organic anion transporting polypeptides (OATP) 1B1, 1B3, 2B1, organic cation transporter (OCT) 1, breast cancer resistance protein (BCRP), 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. Following concomitant administration of trametinib and dabrafenib, a CYP3A4 inducer, repeat-dose Cmax and AUC of trametinib were generally consistent with the exposure observed in monotherapy, although a small decrease in bioavailability was estimated as discussed in the 'Combination of Mekinist with dabrafenib' in the previous paragraph.

Effects of Mekinist on drug metabolising enzymes and transporters.

In vitro and in vivo data suggest that trametinib is unlikely to affect the PK of other drugs. 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, OATP1B1, OATP1B3, MATE1, Pgp and BCRP. However, based on the low dose and low clinical trametinib systemic exposure relative to the in vitro potency of inhibition or induction, trametinib is not considered to be an in vivo inhibitor or inducer of these enzymes or transporters.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Infertility.

There is no information on the effect of Mekinist on human fertility. In animals, no fertility studies have been performed, but an increase in ovarian cystic follicles and decrease in corpora lutea were seen in female rats at ≥ 0.016 mg/kg/day (0.3 times the clinical exposure based on AUC). Mekinist may impair female fertility in humans. However, in rat and dog toxicity studies up to 13 weeks in duration, there were no treatment-related effects observed on male reproductive tissues.

Males taking Mekinist in combination with dabrafenib.

Male fertility studies in animals with the trametinib/dabrafenib combination have not been conducted. Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. See Product Information for dabrafenib for more detail.
(Category D)
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.
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 effective alternate method of contraception, such as barrier methods, 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.
 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 of the potential risk 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.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Mekinist on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of Mekinist. The clinical status of the patient and the adverse event profile of Mekinist should be borne in mind when considering the patient's ability to perform tasks that require judgment, motor and cognitive skills.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions are listed in this section by MedDRA system organ class. Within each system organ class, the adverse events are ranked by frequency, with the most frequent adverse events first. Within each frequency grouping, adverse events are presented in order of decreasing seriousness. The following convention (CIOMS III) has been utilised for the classification of frequency: Very common: ≥ 1 in 10; Common: ≥ 1 in 100 and < 1 in 10; Uncommon: ≥ 1 in 1,000 and < 1 in 100; Rare: ≥ 1/10,000 and < 1/1,000; Very rare: < 1/10,000.

Summary of the safety profile.

Unresectable or metastatic melanoma.

Mekinist monotherapy.

The safety of Mekinist monotherapy has been evaluated in an integrated population of 329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with Mekinist 2 mg orally once daily in studies MEK114267, MEK113583, and MEK111054. Of these patients, 211 patients were treated with Mekinist for BRAF mutant melanoma in the randomised open label study MEK114267 (see Section 5.1, Clinical trials). The most common adverse reactions (≥ 20%) for Mekinist include rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis acneiform. In clinical trials with Mekinist, adverse reactions of diarrhoea and rash were managed with appropriate supportive care (see Section 4.2 Dose and Method of Administration).
Table 10 and Table 11 respectively lists the adverse events reported in patients receiving Mekinist monotherapy.

Mekinist and dabrafenib combination therapy.

The safety of trametinib and dabrafenib combination therapy has been evaluated in two randomised Phase III studies and one small phase II study of patients with BRAF mutant unresectable or metastatic melanoma treated with trametinib 2 mg orally once daily and dabrafenib 150 mg orally twice daily (see Section 5.1, Clinical trials). The most common adverse reactions (≥ 20%) for trametinib and dabrafenib combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhoea, rash, arthralgia, hypertension, vomiting, peripheral oedema and cough.
Table 12 lists adverse reactions when Mekinist was used in combination with dabrafenib from the randomised double-blind Phase III study MEK115306 (N = 209), and integrated safety data from MEK115306 (N = 209) and from the randomised open-label Phase III study MEK116513 (N = 350).
See Table 13.

Metastatic melanoma patients with brain metastases.

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 (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Adjuvant treatment of melanoma.

Mekinist in combination with dabrafenib.

The safety of Mekinist in combination with Tafinlar was evaluated in a Phase III, randomised, 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 5.1, Clinical trials).
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, diarrhoea, vomiting, and arthralgia.
Table 14 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.
See Table 15.
Locally advanced or metastatic anaplastic thyroid cancer.

Mekinist in combination with Tafinlar.

The efficacy and safety of Mekinist in combination with Tafinlar was studied in a Phase II, nine-cohort, multicentre, non-randomised, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (see Section 5.1, Clinical trials).
The 'All Treated Patients (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 16 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.
Advanced non-small cell lung cancer.

Mekinist in combination with Tafinlar.

The safety of Mekinist in combination with Tafinlar was evaluated in a Phase II, multicenter, multi-cohort, non-randomised, open-label study of patients with BRAF V600E mutation positive metastatic NSCLC (see Section 5.1, Clinical trials).
In the Mekinist 2 mg orally once daily and Tafinlar 150 mg orally twice daily arms (Cohorts B and C) the most common adverse events (≥ 20%) reported for Mekinist and Tafinlar combination therapy were pyrexia, nausea, vomiting, peripheral edema, diarrhea, decreased appetite, asthenia, dry skin, chills, cough, fatigue, rash, and dyspnea.
Table 17 lists the adverse drug reactions for Mekinist in combination with Tafinlar occurring at an incidence ≥ 10% for all adverse drug reactions or at an incidence ≥ 2% for Grade 3 and Grade 4 adverse drug reactions or events which are medically significant in Cohorts B and C of study BRF113928.

Post-marketing experience and pooled clinical trials.

The following adverse reactions have been derived from post-marketing experience including spontaneous case reports with Mekinist monotherapy and in combination with Tafinlar (Table 18). Because post-marketing adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency. Where applicable, these frequencies have been calculated from the pooled clinical trials across indications. Adverse reactions are listed according to system organ classes in MedDRA.

Special populations.

Paediatric patients.

Mekinist in combination with Tafinlar.

The safety of Mekinist in combination with Tafinlar was studied in 171 paediatric patients across two studies (G2201 and X2101) with BRAF V600E mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (22.8%) patients were 2 to < 6 years of age, 54 (31.6%) patients were 6 to < 12 years of age, and 74 (43.3%) patients were 12 to < 18 years of age.
The overall safety profile in the paediatric population was similar to the safety profile observed in adults. The most frequently reported adverse drug reactions (≥ 20%) were pyrexia, rash, headache, vomiting, dry skin, fatigue, diarrhoea, haemorrhage, neutropenia, nausea, dermatitis acneiform, abdominal pain, and cough.
An adverse drug reaction of weight increased was identified in the paediatric safety pool with a frequency of 15.2% (very common). Fifty-one out of 171 patients (29.8%) had an increase from baseline of ≥ 2 BMI-for-age-percentile categories.
Adverse drug reactions occurring at a higher frequency category in paediatric patients compared to adult patients were neutropenia, dermatitis acneiform, paronychia, anaemia, leukopenia (very common); bradycardia, dermatitis exfoliative generalised, hypersensitivity and pancreatitis (common). See Table 19.
Use in the elderly. Across clinical trials of Mekinist administered in combination with dabrafenib (n = 202), adverse events resulting in dose interruption were reported for 71% of those aged ≥ 65 years as compared to 60% of those < 65 years, while adverse events resulting in dose reduction occurred in 64% of those aged ≥ 65 years as compared to 44% of those < 65 years. Patients ≥ 65 years were more likely to experience SAEs, fatal SAEs and AEs leading to permanent discontinuation of study drug, dose reduction and dose interruption than those < 65 years.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-adverse-events.

4.9 Overdose

Symptoms and signs.

There were no cases of Mekinist dose above 4 mg once daily reported from the clinical trials. Doses of 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.

Treatment.

There is no specific treatment for an overdose of Mekinist. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Haemodialysis is not expected to enhance the elimination as Mekinist is highly bound to plasma proteins.
For information on the management of overdose contact the Poisons Information Centre on telephone number 13 11 26.

5 Pharmacological Properties

Pharmacotherapeutic group: Mitogen-activated protein kinase (MEK) inhibitor.
Anatomical Therapeutic Chemical (ATC) code: L01EE01.

5.1 Pharmacodynamic Properties

Mechanism of action.

Trametinib monotherapy.

Trametinib (Mekinist) is a reversible allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and 2 (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 activates MEK and stimulates tumour cell growth. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity. Trametinib inhibits growth of BRAF V600 mutant melanoma, ATC and non-small cell lung cancer (NSCLC) cell lines in vitro and demonstrates anti-tumour effects in BRAF V600 mutant melanoma xenograft models.

Trametinib in combination with dabrafenib.

Dabrafenib is an ATP-competitive inhibitor of BRAF V600 mutant kinases and wild type BRAF and CRAF kinases. Mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumour cell growth. Dabrafenib and trametinib inhibit two critical kinases in this pathway, BRAF and MEK, and the combination provides concomitant inhibition of the pathway. Combination of dabrafenib with trametinib is synergistic 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.

Pharmacodynamic effects.

In patients with BRAF mutant melanoma, administration of trametinib resulted in dose dependent changes in tumour biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). The mean trametinib concentrations observed following repeat dose administration of 2 mg once daily exceeds the preclinical target concentration over the 24 hour dosing interval, thereby providing sustained inhibition of the MEK pathway.

Determination of BRAF mutation status.

In the Phase II and III clinical trials for metastatic melanoma, screening for eligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conducted on the most recent tumour sample available. Primary tumour or tumour from a metastatic site was tested with an investigational use only assay (IUO) developed by Response Genetics Inc. (RGI). The RGI IUO is an allele-specific polymerase chain reaction (PCR) assay performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue. The assay was specifically designed to differentiate between the V600E and V600K mutations. Only patients with BRAF V600E or V600K mutation positive tumours were eligible for study participation.
In the Phase III clinical trial for adjuvant melanoma, screening for eligibility required central testing for BRAF V600 mutation with the bioMerieux THxID BRAF assay. Only patients with BRAF V600E or V600K mutation positive tumours were eligible for study participation.
In the Phase II clinical trial for NSCLC, patients determined to be BRAF V600E positive by the local laboratory tests were enrolled in the study and tumour tissue samples were required for central confirmation by the Oncomine Dx Target Test by Thermo Fisher Scientific.
In the Phase II trial for rare cancers, including anaplastic thyroid cancer, patients determined to be BRAF V600E positive by the local laboratory tests were enrolled in the study and tumour tissue samples were required for central confirmation by the bioMerieux THxID BRAF assay.

Clinical trials.

Unresectable or metastatic melanoma.

Mekinist monotherapy.

Open label studies. MEK114267.

The efficacy and safety of Mekinist in patients with BRAF mutant unresectable or metastatic melanoma (V600E and V600K) were evaluated in a randomised open label study (MEK114267). 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 tumour 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 randomised 2:1 to receive Mekinist 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 Mekinist 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 progression-free survival 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 Mekinist arm after independent confirmation of progression. Fifty-one (47%) patients with confirmed disease progression in the chemotherapy arm, crossed over to receive Mekinist.
Baseline characteristics were balanced between treatment groups in the primary efficacy population and the ITT population. In the ITT population, the majority of patients were male (54%) and all were Caucasian (100%). The median age was 54 years (22% were ≥ 65 years), most patients (64%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 11 patients (3%) had a history of brain metastases. Most patients (87%) in the ITT population had BRAF V600E mutation and 12% of patients had a BRAF V600K mutation. Most patients (66%) received no prior chemotherapy for advanced or metastatic disease.
The efficacy results in the primary efficacy population were consistent with those in the ITT population; therefore, only the efficacy data for the ITT population are presented in Table 20 and Figure 1.
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).
At the time of the data cut off, 51 patients (47%) on the chemotherapy arm had crossed over to the Mekinist arm after disease progression. These patients are included in the OS analysis. ITT = Intent to treat; PFS = Progression-free survival; CI = Confidence interval.

MEK113583 - phase II BRAF inhibitor pre-treatment study.

In a single arm, multi-centre, Phase II study, MEK113583 evaluated the ORR, safety and PK following once daily oral dosing of Mekinist 2 mg in patients with BRAF V600E, V600K, or V600D mutation-positive metastatic melanoma, previously treated with or without a BRAF inhibitor (BRAFi). Patients were enrolled into two separate cohorts, defined by therapy received prior to Mekinist. Cohort A patients (n = 40) had received prior treatment with a BRAFi. Cohort B patients (n = 57) were BRAFi-naïve and had received at least one prior chemotherapy or immunotherapy. Mekinist did not demonstrate clinical activity in Cohort A (patients who progressed on a prior BRAFi therapy) (see Section 4.2 Dose and Method of Administration).
Mekinist in combination with dabrafenib. The efficacy and safety of the recommended dose of Mekinist (2 mg once daily) in combination with dabrafenib (150 mg twice daily) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation was studied in Phase I/II study BRF113220 and two pivotal phase III studies, MEK116513 and MEK115306.

Randomised open label studies. BRF113220 (phase I/II studies).

In this open label study, the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of Mekinist and dabrafenib combination therapy were evaluated in patients with BRAF V600E, V600K, or V600D mutation-positive metastatic melanoma. This study had four parts, A-D:
Part A was a drug/ drug interaction (DDI) study to determine the effect of repeat doses of Mekinist on the PK of a single dose of dabrafenib and its metabolites (n = 8);
Part B was a dose escalation and expansion study to determine optimal doses and safety of Mekinist when administered in combination with dabrafenib (n = 135);
Part C was an open-label, randomised phase II study to determine the efficacy, safety, and tolerability of Mekinist and dabrafenib in patients with BRAF mutant metastatic melanoma (n = 162); and
Part D was a PK and safety evaluation of the combination of Mekinist and dabrafenib capsules (n = 110).
The determination of BRAF mutation positive status was required and established by institutional laboratory for all patients enrolled in Parts A-D.

Prior BRAFi therapy.

There are limited data in patients taking the combination of Tafinlar with trametinib who have progressed on a prior BRAF inhibitor.
Part B of open-label study BRF113220 included a cohort of 26 patients that had progressed on a BRAFi. The combination of 150 mg Tafinlar with 2 mg trametinib demonstrated limited clinical activity in patients who had progressed on a BRAFi. The investigator-assessed ORR was 15% (95% CI: 4.4, 34.9) and the median PFS was 3.6 months (95% CI: 1.9, 5.2). Similar results were seen in the 43 patients who crossed over from Tafinlar monotherapy to the combination of 150 mg Tafinlar plus 2 mg trametinib in Part C of this study. In these patients a 9% (95% CI: 2.6, 22.1) ORR was observed with a median PFS of 3.6 months (95% CI: 1.8, 3.9).

Part C.

Part C of this open-label randomised three-arm phase II study assessed the safety and efficacy of dabrafenib at 150 mg given twice daily in combination with two different doses of Mekinist (1 mg once daily and 2 mg once daily) relative to dabrafenib alone (150 mg twice daily) in 162 patients. The primary efficacy endpoints were PFS, ORR, and DoR. Patients on the dabrafenib monotherapy arm were permitted to cross-over to the full-dose combination arm (150 mg dabrafenib plus 2 mg Mekinist) upon progression. A total of 43 patients (81%) in the dabrafenib monotherapy arm with disease progression crossed over to receive the Mekinist 2 mg and dabrafenib 150 mg combination.
Baseline characteristics were balanced between treatment groups. Most patients (85%) in all treatment arms had BRAF V600E mutation and 15% of patients had BRAF V600K. Investigator assessed median PFS for dabrafenib 150 mg twice daily plus Mekinist 2 mg once daily was 9.4 months (95% CI: 8.6, 16.7) compared to 5.8 months (95% CI: 4.6, 7.4 months) for dabrafenib 150 mg twice daily monotherapy. The hazard ratio was 0.39 (95% CI 0.25, 0.62, p < 0.0001). Overall response rate for dabrafenib 150 mg twice daily plus Mekinist 2 mg once daily was 76% (95% CI: 62.4, 86.5, p = 0.0264) compared to 54% (95% CI: 39.6, 67.4) for dabrafenib 150 mg twice daily monotherapy.
The investigator-assessed ORR, DoR, and PFS were consistent in the subgroup of patients with BRAF V600E and BRAF V600K mutation positive melanoma receiving 2 mg Mekinist plus 150 mg dabrafenib combination.
A retrospective blinded independent committee review (BICR) was conducted and obtained the following results:
61% ORR (95% CI: 46.9%, 74.1%; p = 0.1486) for the 150 mg dabrafenib plus 2 mg Mekinist combination;
39% ORR (95% CI: 25.9, 53.1; p = 0.5008) for the 150 mg dabrafenib plus 1 mg Mekinist combination; and
46% ORR (95% CI: 32.6%, 60.4%) for the dabrafenib monotherapy group.
Median PFS was 9.2 months (95% CI: 7.6, NR; p = 0.0121) for patients treated with 150 mg dabrafenib plus 2 mg Mekinist combination therapy;
median PFS was 8.3 months (95% CI: 5.6, 11.3; p = 0.1721) for patients treated with 150 mg dabrafenib plus 1 mg Mekinist combination therapy; and
median PFS was 7.3 months (95% CI: 5.5, 9.4) for patients treated with dabrafenib monotherapy.

Randomised open label study in BRAFi-treatment-naïve patients, MEK116513 (COMBI-v, phase III study).

Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing trametinib and dabrafenib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of the study was OS (see Figure 2), and the key secondary endpoint was PFS. Other secondary objectives included ORR, DoR, and safety. Patients were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ ULN) and BRAF mutation (V600E versus V600K).
Seven hundred and four (704) patients were randomised 1:1 to either the combination therapy arm (trametinib 2 mg once daily and dabrafenib 150 mg twice daily) or the vemurafenib monotherapy arm (960 mg twice daily). Most patients were white (> 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 patients had LDH ≤ ULN (67%), ECOG performance status of 0 (70%), and visceral disease (78%) at baseline. Overall, 54% of patients had < 3 disease sites at baseline. The majority of patients had a BRAF V600E mutation (89%).
The final OS analysis 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% (95% CI: 30.5, 40.9) for the combination versus 23% (95% CI: 18.1, 27.4) for vemurafenib monotherapy (Table 21, Figure 2). The Kaplan-Meier OS curve appears to stabilise from 3 years to 5 years (see Figure 2).
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 21).

Randomised double-blind study in BRAFi-treatment-naïve patients. MEK115306 (COMBI-d, phase III study).

This Phase III, randomised, double-blind study comparing the combination of dabrafenib and Mekinist to dabrafenib and placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of the study was investigator assessed PFS with a key secondary endpoint of OS (Figure 3). Patients were stratified by lactate dehydrogenase (LDH) level (> ULN versus ≤ ULN) and BRAF mutation (V600E versus V600K).
Four hundred and twenty three (423) patients were randomised 1:1 to either the combination therapy arm (dabrafenib 150 mg twice daily and Mekinist 2 mg once daily) (N = 211) or dabrafenib monotherapy arm (150 mg twice daily) (N = 212). Baseline characteristics were balanced between treatment groups. Males constituted 53% of patients and the median age was 56 years; Majority of patients had an ECOG performance score of 0 (72%) and had Stage IVM1c disease (66%). Most patients had the BRAF V600E mutation (85%); the remaining 15% of patients had the BRAF V600K mutation. Patients with brain metastases were not included in the trial.
The final OS analysis 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 for dabrafenib monotherapy (25.8 months versus 18.7 months) with 5 year survival rates of 32% (95% CI: 25.1, 38.3) for the combination versus 27% (95% CI: 20.7, 33.0) for dabrafenib monotherapy (Table 22, Figure 3). The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 3).
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 22).

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 metastasised to the brain was studied in a non-randomised open-label, multi-centre 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 or 1.
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 23. Secondary endpoints were duration of intracranial response, ORR, PFS and OS. Efficacy results are summarised in Table 23.

Adjuvant treatment of melanoma.

Mekinist in combination with dabrafenib.

Randomised double-blind study. Study BRF115532/ DRB436F2301 (COMBI-AD).

The efficacy and safety of Mekinist in combination with Tafinlar was studied in a Phase III, multicentre, randomised, double blind, placebo-controlled study in patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
Patients were randomised 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. Enrolment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomisation. 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 tumour size and ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), defined as the time from randomisation to disease recurrence or death from any cause. Radiological tumour assessment was conducted every 3 months for the first two years and every 6 months thereafter, until first relapse was observed. Secondary endpoints include overall survival (OS; key secondary endpoint) and distant metastasis-free survival (DMFS).
A total of 870 patients were randomised to the combination therapy (n = 438) and placebo (n = 432) arms. Most patients were Caucasian (99%) and male (55%), with a median age of 51 years (18% were ≥ 65 years). The study included patients with all sub-stages of Stage III disease prior to resection; 18% of these patients had lymph node involvement only identifiable by microscope and no primary tumour ulceration. The majority of patients had a BRAF V600E mutation (91%). At the time of primary analysis, the median duration of follow-up (time from randomisation to last contact or death) was 2.83 years in the dabrafenib and trametinib combination arm and 2.75 years in the placebo arm.
Results for the primary analysis of RFS are presented in Table 24. 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 x 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. See Figure 4.
Based on updated data with an additional 29 months of follow-up compared to the primary analysis (minimum follow-up of 59 months), the RFS benefit was maintained with an estimated HR of 0.51 (95% CI: (0.42, 0.61) (Figure 4). The 5-year RFS rate was 52% (95% CI: 48, 58) in the combination arm compared to 36% (95% CI: 32, 41) in the placebo arm.
Based on 153 events (60 (14%) in the combination arm and 93 (22%) in the placebo arm) corresponding to a 26% information fraction of the total target of 597 OS events, the estimated hazard ratio for OS was 0.57 (95% CI: 0.42, 0.79; p = 0.0006). These results did not meet the pre-specified boundary to claim statistical significance at this first OS interim analysis (HR = 0.50; p = 0.000019). Survival estimates at 1 and 2 years from randomisation were 97% and 91% in the combination arm and 94% and 83% in the placebo arm, respectively. The Kaplan-Meier curve for this OS interim analysis is shown in Figure 5.

Locally advanced or metastatic anaplastic thyroid cancer.

Mekinist in combination with dabrafenib.

Non-randomised open label study. Study BRF117019 (CDRB436X2201).

The efficacy and safety of Mekinist in combination with dabrafenib was studied in a Phase II, nine-cohort, multicentre, non-randomised, 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 ORR using the 'Response Evaluation Criteria In Solid Tumors' (RECIST 1.1 assessed by the investigator). Secondary endpoints included DoR, PFS, 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 33 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 25).
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 patients, 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).

Advanced NSCLC.

Mekinist in combination with dabrafenib.

Non-randomised open label studies. BRF113928 (Study E2201).

The efficacy and safety of Mekinist in combination with dabrafenib was studied in a Phase II, three-cohort, multicentre, non-randomised, open-label study enrolling patients with Stage IV BRAF V600E mutant NSCLC.
The primary endpoint was the investigator-assessed ORR using the 'Response Evaluation Criteria In Solid Tumors' (RECIST 1.1 assessed by the investigator). Secondary endpoints included DoR, PFS, OS, safety and population pharmacokinetics. ORR, DoR and PFS were also assessed by an Independent Review Committee (IRC) as a sensitivity analysis.
Cohorts were enrolled sequentially:
Cohort A: Monotherapy (dabrafenib 150 mg twice daily): 84 patients enrolled. 78 patients had previous systemic treatment for their metastatic disease (see Product information for dabrafenib on results from Cohort A).
Cohort B (n = 57): Combination therapy (Mekinist 2 mg once daily and dabrafenib 150 mg twice daily): 59 patients enrolled. 57 patients had previously received one to three lines of 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 (Mekinist 2 mg once daily and dabrafenib 150 mg twice daily): 34 patients enrolled (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 Caucasians (n = 79, 85%). There was a similar female to male ratio (54% vs 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 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 Mekinist 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 26). The final analysis of efficacy performed 5 years after last subject first dose is presented in Table 26.

Low-grade glioma (LGG) and high-grade glioma (HGG).

Study DRB436G2201.

The clinical efficacy and safety of Mekinist plus Tafinlar combination therapy in paediatric patients aged 1 to < 18 years of age with BRAF V600E mutation-positive glioma was evaluated in the multi-centre, open-label, phase II clinical trial CDRB436G2201. Patients with low-grade glioma (WHO grades 1 and 2) who required first systemic therapy were randomized in a 2:1 ratio to trametinib plus dabrafenib (D+T) or carboplatin plus vincristine (C+V), and patients with relapsed or refractory high-grade glioma (WHO grades 3 and 4) were enrolled into a single arm trametinib plus dabrafenib cohort.
BRAF mutation status was identified prospectively via a local test, or a central laboratory real-time polymerase chain reaction (PCR) test when a local test was not available. In addition, retrospective testing of available tumour samples by the central laboratory was performed to confirm the BRAF V600E mutation.
Tafinlar and Mekinist dosing was age and weight dependent, with Tafinlar dosed orally at 2.625 mg/kg twice daily for ages < 12 years and 2.25 mg/kg twice daily for ages 12 years and older; Mekinist was dosed orally at 0.032 mg/kg once daily for ages < 6 years and 0.025 mg/kg once daily for ages 6 years and older. Tafinlar doses were capped at 150 mg twice daily and Mekinist doses at 2 mg once daily. Carboplatin and vincristine were dosed based on age and body surface area at doses 175 mg/m2 and 1.5 mg/m2, respectively as one 10-week induction course followed by eight 6-week cycles of maintenance therapy.
The primary efficacy endpoint in both cohorts was overall response rate (ORR, sum of confirmed complete/CR and partial responses/PR) by independent review based on RANO criteria (RANO 2017 for LGG, and RANO 2010 for HGG). The primary analysis was performed when all patients in both cohorts had completed at least 32 weeks of therapy.

BRAF mutation-positive low-grade glioma (WHO grades 1 and 2).

In the low-grade glioma (LGG) cohort of study G2201, 110 patients were randomized to D+T (n=73) or C+V (n=37). Median age was 9.5 years, with 34 patients (30.9%) aged 12 months to < 6 years, 36 patients (32.7%) aged 6 to < 12 years and 40 patients (36.4%) aged 12 to < 18 years; 60% were female. The ORR in the D+T arm (46.6%) showed a statistically significant improvement over C+V arm (10.8%), with an odds ratio of 7.19 and 1-sided p-Value < 0.001 (Table 27). The subsequent hierarchical testing also demonstrated improved progression-free survival (PFS) over chemotherapy, with an estimated 69% risk reduction in progression/death (HR 0.31; 1-sided log-rank p-Value < 0.001).
See Figure 6.

BRAF mutation-positive high-grade glioma (WHO grades 3 and 4).

In the single-arm high-grade glioma (HGG) cohort of study G2201, 41 patients with relapsed or refractory HGG were enrolled and treated with Mekinist plus Tafinlar for a median duration of 72.7 weeks. Median age was 13.0 years, with 5 patients (12.2%) aged 12 months to < 6 years, 10 patients (24.4%) aged 6 to < 12 years and 26 patients (63.4%) aged 12 to < 18 years; 56% were female.
The ORR in this cohort was 56.1% (23/41). The Kaplan-Meier percent progression free estimate at 6 months was 66.8% (95% CI: 49.6 to 79.2%), the median progression-free survival was 9.0 months (95% CI: 5.3 to 24.0), and the median overall survival was 32.8 months (95% CI: 19.2, NE), with 27 subjects censored at the time of the primary analysis.

Other studies.

Pyrexia management analysis.

Study CPDR001F2301 (COMBI-i) and study CDRB436F2410 (COMBI-Aplus).

Pyrexia is observed in patients treated with trametinib and dabrafenib 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 dabrafenib in case of pyrexia (fever ≥ 38.5°C). 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 medicinal products when patient's temperature is ≥ 38°C (COMBI-Aplus) or at the first symptom of pyrexia (COMBI-i; COMBI-Aplus for recurrent pyrexia) was advised. In COMBI-i and COMBI-Aplus there was a lower incidence of grade 3/4 pyrexia, complicated pyrexia, hospitalisation due to serious pyrexia adverse events of special interest (AESIs), the time spent in pyrexia AESIs, and permanent discontinuations from both medicinal products due to pyrexia AESIs (the latter in the adjuvant setting only) compared to COMBI-d, COMBI-v and COMBI-AD. The COMBI-Aplus study met its primary endpoint with a composite rate of 8.0% (95% CI: 5.9, 10.6) for grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent treatment discontinuation due to pyrexia compared to 20.0% (95% CI: 16.3, 24.1) for the historical control (COMBI-AD).

5.2 Pharmacokinetic Properties

Absorption.

Trametinib is absorbed orally with median time to achieve peak concentrations of 1.5 hours post-dose. The mean absolute bioavailability of a single 2 mg tablet dose is 72% relative to an intravenous (IV) microdose. The increase in exposure (Cmax and AUC) was dose-proportional following repeat dosing. Following administration of 2 mg daily, geometric mean Cmax, AUC(0-t) and predose concentration were 22.2 nanogram/mL, 370 nanogram*hr/mL and 12.1 nanogram/mL, respectively with a low peak:trough ratio (1.8). Inter-patient variability was low (< 28%).

Effect of food on trametinib.

Administration of a single dose of trametinib tablet 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 4.2 Dose and Method of Administration). Trametinib tablets and powder for oral solution are immediate-release formulations that are expected to have similar food effects on PK.

Trametinib in combination with dabrafenib.

Co-administration of repeat dosing of dabrafenib 150 mg twice daily and trametinib 2 mg once daily resulted in an increase of 16% and 23% for dabrafenib Cmax and AUC, respectively. A small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was estimated when trametinib is administered in combination with dabrafenib using a population pharmacokinetic analysis.

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.

Metabolism.

In vitro and in vivo studies demonstrated that trametinib is metabolised predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, and may also be mediated by other hydrolytic enzymes.
Following a single dose of [14C]-trametinib, about 50% of circulating radioactivity is represented as parent. However, based on metabolite profiling after repeat dosing of trametinib, ≥ 75% of drug related material in plasma is parent.

Excretion.

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 5.3 days (range 3.4-9.0) after single dose administration. Steady-state is generally 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. Faecal excretion is the major route of elimination after [14C]-trametinib oral dose, accounting for > 80% of excreted radioactivity recovered while urinary excretion accounted for < 19% of excreted radioactivity recovered. Less than 0.1% of the excreted dose was recovered as parent in urine.

Special patient 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 4.2 Dose and Method of Administration).

Use in the elderly.

Based on the population pharmacokinetics analysis, age had no relevant clinical effect on trametinib pharmacokinetics.

Paediatric use.

The pharmacokinetics of trametinib in glioma and other solid tumours were evaluated in 244 paediatric patients (1 to < 18 years old) following single or repeat weight-adjusted dosing. Pharmacokinetic characteristics (drug absorption rate and drug clearance) of trametinib in paediatric patients are comparable to those of adults. Weight was found to influence trametinib oral clearance. The pharmacokinetic exposures of trametinib at the recommended weight-adjusted dosage in paediatric patients were within range of those observed in adults.

Race/ ethnicity.

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

5.3 Preclinical Safety Data

Genotoxicity.

Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells and micronuclei in the bone marrow of rats.

Carcinogenicity.

Carcinogenicity studies with Mekinist have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Film-coated tablets.

The core tablets contain mannitol, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate (vegetable source), sodium lauryl sulphate, anhydrous colloidal silica. The film coating contains hypromellose, titanium dioxide, macrogol, iron oxide yellow (0.5 mg tablet only), polysorbate 80, and iron oxide red (2 mg tablet only).

Powder for oral solution.

Sulfobutyl betadex sodium, sucralose, citric acid monohydrate, dibasic sodium phosphate, potassium sorbate, methyl hydroxybenzoate, flavour strawberry (Proprietary Ingredient No. 144653).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Film-coated tablets.

Store 2°C to 8°C. (Refrigerate.)
Store Mekinist tablets in the original package to protect from light and moisture. Keep the bottle tightly closed. Do not remove the desiccant.
In-use stability has been demonstrated for 1 month when stored up to 30°C.

Powder for oral solution.

Store in a refrigerator at 2°C to 8°C until reconstitution.
Store in the original package to protect from light and moisture. Keep the bottle tightly closed.
After reconstitution, store the reconstituted solution below 25°C and do not freeze. Discard any unused solution 35 days after reconstitution.

6.5 Nature and Contents of Container

Mekinist film-coated tablets are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures and desiccant, containing 7* or 30 tablets.
Mekinist powder for oral solution is supplied in 180 mL amber glass (type III) bottle with child-resistant, high-density polyethylene/polypropylene (HDPE/PP) closure, press-in bottle adaptor and dosing syringe, containing 5.3 mg powder.
* Not all pack sizes, may be distributed in Australia.

6.6 Special Precautions for Disposal

Any unused product should not be disposed of in household waste or wastewater. Return it to a pharmacist for safe disposal.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

Chemical Abstracts Service (CAS) registry number: 1187431-43-1.
Chemical name: N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl) amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl} phenyl)acetamide.
Molecular formula: C26H23FIN5O4.C2H6OS.
Molecular weight: 693.5.
Trametinib dimethyl sulfoxide is a polycyclic, nitrogen-containing heterocycle also possessing aromatic halide and amide functionality, and is a dimethyl sulfoxide solvate. Trametinib dimethyl sulfoxide is a white to almost white powder. It is almost insoluble in water. The calculated partition coefficient of trametinib dimethyl sulfoxide is 4.99.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes