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.

What is in this leaflet

Please read this leaflet carefully before you start using MEKINIST.

This leaflet answers some common questions about MEKINIST (trametinib). It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date Consumer Medicine Information from www.novartis.com.au.

The updates may contan important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking MEKINIST against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What MEKINIST is used for

MEKINIST tablets contain the active ingredient trametinib. MEKINIST belongs to a group of medicines called "selective MEK-inhibitors".

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.

MEKINIST is used to:

  • treat types of:
    - thyroid cancers called anaplastic thyroid cancer (ATC)
    - lung cancers called non-small cell lung cancer (NSCLC)
    - skin cancers called melanoma that have spread to other parts of the body or cannot be removed by surgery.
  • prevent melanoma from coming back after the melanoma has been removed by surgery.

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

Ask your doctor, pharmacist, or nurse if you have any questions about how MEKINIST works or why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

MEKINIST should not be used in children and adolescents, under the age of 18 years because it is not known whether it is safe and effective in this younger group of patients.

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

It is not addictive.

Before you take MEKINIST

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

When you must not take it

Do not take MEKINIST if:

  • you have an allergy to trametinib (active ingredient) or to any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include:
    - Shortness of breath
    - Wheezing or difficulty breathing
    - Swelling of the face, lips, tongue or other parts of the body
    - Rash, itching or hives on the skin

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. The expiry date refers to the last day of that month.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

If you are pregnant, or think you may become pregnant, ask your doctor, pharmacist or health care provider for advice before taking this medicine. Also, please read "Pregnancy".

Tell your doctor, healthcare provider, pharmacist, or nurse if you have allergies to any other medicines, foods, preservatives or dyes. They will want to know if you are prone to allergies.

Tell them if you have or have had any of the following medical conditions:

  • Heart problems
    Such as heart failure, so that you:
    - Are short of breath
    - Have difficulties breathing when lying down
    - Have swelling of the feet or legs or
    - Have problems with the way your heart beats.
    Your doctor should check your heart function before you start taking MEKINIST and during treatment.
  • Eye problems
    Including:
    - Sensation of flashing light, loss of vision (retinal detachment)
    - Blockage of the vein draining the eye (retinal vein occlusion) or
    - Swelling in the back of the eye which may be caused by fluid blockage (chorio-retinopathy). Your doctor may arrange for you to have an eye examination before you take MEKINIST and while you are taking it.
  • Lung or breathing problems
    Including:
    - Difficulty in breathing often accompanied by chest pain, fainting, rapid heart rate, bluish skin discoloration. Your doctor may arrange to check your lung function before you start taking MEKINIST
    - Interstitial lung disease (ILD) - the group of diseases that affect the tissues and space around the air sacs of the lungs or
    - Inflammation of the lung (pneumonitis).
  • Skin problems
    Including:
    - Rash or
    - Acne-like rash.

If you are taking the combination of MEKINIST and TAFINLAR

Tell your doctor if you have an eye problem called uveitis.

The symptoms of uveitis include:

  • Eye redness and irritation
  • Blurred vision
  • Eye pain
  • Increased sensitivity to light
  • Floating spots before the eyes.

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

If you are not sure whether you should start taking this medicine, talk to your doctor.

Pregnancy

Do not take MEKINIST if you are pregnant or if you think that you may be pregnant. MEKINIST can harm your unborn baby.

Ask your doctor, healthcare provider, pharmacist, or nurse for advice if you are planning to have a baby. Your doctor can discuss with you the risks and benefits involved.

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

If MEKINIST is taken in combination with TAFINLAR, non-hormonal contraception should be used. Birth control methods containing hormones (such as pills, injections, or patches) may not work as well while taking TAFINLAR.

You need to use another effective method of birth control so you don't become pregnant while taking MEKINIST is taken in combination with TAFINLAR.

Ask your doctor, healthcare provider, pharmacist, or nurse about options for effective birth control or for advice.

If you do become pregnant while you're taking MEKINIST tell your doctor or nurse immediately.

Breast-feeding

If you are breast-feeding, or planning to breast-feed, you must tell your doctor. MEKINIST is not recommended while breast-feeding.

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

You and your doctor will decide whether you will take MEKINIST or breast-feed.

If you have not told your doctor about any of these things, tell them before you start taking MEKINIST.

Male patients

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

Taking other medicines

Tell your doctor, or healthcare provider, nurse, or pharmacist if you are taking, have recently taken, or might take any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

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

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take MEKINIST

Follow all directions given to you by your doctor, healthcare provider, or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How much to take

The usual dose of MEKINIST is one 2 mg tablet once a day.

Depending on how you respond to MEKINIST, your doctor may decide that you should take a lower dose or interrupt treatment temporarily.

Don't take more MEKINIST than your doctor has recommended.

If you are aged 65 years or more, you can use MEKINIST at the same dose as for other adults.

When to take it

Take MEKINIST once a day. Take it at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take MEKINIST on an empty stomach

It is important to take MEKINIST on an empty stomach. Food may affect the way the medicine is absorbed into your body.

Mekinist should either be taken 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.

How to take it

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

Taking MEKINIST together with TAFINLAR

Swallow the MEKINIST tablet and the TAFINLAR capsule, with a full glass of water.

Take MEKINIST in combination with TAFINLAR exactly as your doctor tells you.

Do not change your dose, or stop MEKINIST in combination with TAFINLAR unless your healthcare provider tells you.

Take your once daily dose of MEKINIST at the same time each day, with EITHER the morning dose or the evening dose of TAFINLAR.

Take the first dose of TAFINLAR in the morning, and take the second dose of TAFINLAR in the evening, approximately 12 hours later.

Do NOT take:

  • More than one dose of MEKINIST a day, or
  • The morning and evening doses of TAFINLAR at the same time.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This is a long term treatment, possibly lasting for months to years. Do not stop unless your doctor advises you to.

If you have any further questions about how long to take this medicine, ask your doctor or nurse.

If you forget to take it

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

MEKINIST taken alone

If the missed dose 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 as you would normally.

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

MEKINIST taken together with TAFINLAR

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 carry on taking MEKINIST at regular times as usual.

Do not make up for missed doses.

If the missed dose of TAFINLAR is:

  • Less than 6 hours late, take it as soon as you remember
  • More than 6 hours late, skip that dose and take the next dose at the usual time.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your doctor, nurse or pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that:

  • You may have taken too many MEKINIST tablets, or TAFINLAR capsules (if taking the combination), or if
  • Somebody else may have accidentally taken your medicine(s).

Do this even if there are no signs of discomfort or poisoning. You/they may need urgent medical attention.

Take the medication pack(s) with you.

If you stop taking MEKINIST

Do not stop taking your medicine unless your doctor tells you to stop taking MEKINIST. Stopping your treatment with MEKINIST may cause your condition to become worse.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or health care provider.

While you are using MEKINIST

Things you must do

If you are about to be started on any new medicine remind your doctor and pharmacist that you are taking MEKINIST.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked.

Monitoring during your treatment

Your doctor may do some tests from time to time to make sure that MEKINIST is working and to prevent unwanted side effects.

Your doctor may organize regular monitoring of your heart function during treatment with MEKINIST.

You may also have regular evaluations by an eye doctor (ophthalmologist) during treatment with this medicine.

During and after severe high fever events, some substances (enzymes) might be abnormally increased and your doctor will measure those and check that your kidneys are working properly.

Conditions you may need to look out for

Some people taking MEKINIST or MEKINIST and TAFINLAR together (combination treatment) develop other conditions which can be serious.

You need to know about important signs and symptoms to look out for while you're taking MEKINIST.

FEVER (HIGH TEMPERATURE)

Taking MEKINIST or the combination of MEKINIST with TAFINLAR may cause fever. Although, fever is more likely with the two medicines together.

Signs and symptoms of a fever may include:

  • Temperature of 38.5°C or more
  • Shivering
  • Thirst or dehydration
  • Feeling dizzy, faint, or as if you're going to be sick.

Tell your doctor, or nurse immediately if you get a temperature of 38.5°C or above while you are taking this medicine. They will carry out tests to find out if there are other causes for the fever and treat the problem with other medicines.

If your temperature is between 38.5°C and 40°C inclusive Your MEKINIST treatment may continue. If you are taking MEKINIST or MEKINIST and TAFINLAR together you may be asked to interrupt TAFINLAR treatment. If your fever is controlled, your doctor may recommend that you resume TAFINLAR treatments either at the same dose or a lower dose.

If your temperature is above 40°C You may be asked to interrupt treatment when you are taking MEKINIST or MEKINIST and TAFINLAR together. If your fever is controlled, your doctor may recommend that you resume both treatments at a lower dose, or that you receive only MEKINIST treatment.

If the fever is very severe or keeps returning, your doctor may recommend that you stop taking TAFINLAR and only receive treatment with MEKINIST.

Things you must not do

Do NOT take MEKINIST with food. See "Take MEKINIST on an empty stomach."

Do NOT take MEKINIST to treat any other complaints unless your doctor tells you to. This medicine has been prescribed for only you.

Do NOT give your medicine to anyone else, even if they have the same condition as you. It may harm them, even if the signs of illness are the same as yours.

Do NOT stop taking your medicine or lower the dosage without first checking with your doctor. This may cause your condition to become worse.

Things to be careful of

Be careful when driving or operating machinery until you know how MEKINIST affects you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking MEKINIST.

Like all medicines, MEKINIST can cause side effects but not everybody gets them. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Possible Serious Side Effects - when taking MEKINIST alone

STOP taking MEKINIST and tell your doctor, nurse, or pharmacist IMMEDIATELY if you get any of the following symptoms (either for the first time or if they get worse) during treatment with MEKINIST:

  • Headaches, dizziness, or weakness, coughing up of blood or blood clots, vomit containing blood or that looks like "coffee grounds", bleeding from nose, red or black stools that look like tar (signs of haemorrhage)
  • Difficulty in breathing or swallowing, dizziness, swelling of the face lips, tongue or throat, severe itching of the skin, with a red rash or raised bumps (signs of hypersensitivity reaction)
  • Thirst, low urine output, weight loss, dry flushed skin, irritability (signs of dehydration)
  • Loss of vision (sign of visual impairment)
  • Fatigue, feeling full or bloated, heart palpitations, loss of appetite, nausea, reduced ability to exercise, shortness of breath, swelling (signs of left ventricular dysfunction)
  • Slow heart-beat (sign of bradycardia)
  • Cough, difficult or painful breathing, wheezing, pain in chest when breathing, fever (signs of pneumonitis)
  • Swelling in the eye by fluid leakage causing a blurred vision (signs of chorioretinopathy)
  • Sensation of flashing light, loss of vision (signs of retinal detachment)
  • Breathlessness, difficulty breathing when lying down, swelling of the feet or legs (as signs of the heart muscle not pumping blood as well as it should and signs of cardiac failure)
  • Severe stomach pain, nausea, and vomiting of blood, black or bloody stools (signs of gastrointestinal perforation in the stomach, small intestine, or bowel)
  • Cramping diarrhoea with or without blood in stool, abdominal pain as signs of an inflammation of the inner lining of the colon (colitis)
  • Blurring or loss of vision that is usually sudden in onset caused by blockage of small veins that carry blood away from the back of the eye (signs of retinal vein occlusion)
  • Abnormal breakdown of muscle, causing pain, fever, red-brown urine (signs of rhabdomyolysis.

Very common side effects - MEKINIST alone

Tell your doctor or pharmacist if you notice any of the following (that may affect more than 1 in 10 people):

  • Headache, dizziness, or other signs of high blood pressure
  • Cough
  • Short of breath, difficulty breathing
  • Diarrhoea
  • An increase in the volume, wateriness, or frequency of bowel movements (diarrhoea)
  • Unpleasant feeling of needing to vomit, or unwillingness to eat (nausea)
  • Uncomfortable, involuntary, forceful, throwing up of food (vomiting)
  • Difficult or infrequent bowel movements (constipation)
  • Stomach ache or abdominal pain
  • Dry mouth
  • Skin rash
  • Rash, dry skin, acne-like problem (dermatitis acneiform)
  • Dry skin
  • Itching
  • Unusual hair loss or thinning (alopecia)
  • Feeling tired, weak or having lack of energy (fatigue)
  • Swollen hands, ankles, or feet (peripheral oedema)
  • Fever, temperature of 38.5°C or higher.

Common side effects - MEKINIST alone

Tell your doctor or pharmacist if you notice any of the following that may affect up to 1 in 10 people.

  • Inflammation of hair follicles in the skin that causes itching (folliculitis)
  • Nail disorders such as nail bed changes, nail pain, infection and swelling of the cuticles (paronychia)
  • Hot, tender and red skin, sometimes with fever, chills, and inflammation caused by infection (cellulitis)
  • Skin rash with pus-filled blisters (pustular rash)
  • Tiredness, fatigue, pale skin (anaemia)
  • Eyesight problems (blurred vision)
  • Swelling of the eyelids and swelling around the eye (periorbital oedema)
  • Tiredness, chest discomfort, light headedness pain, palpitations (ejection fraction decreased)
  • Hard and painful swelling in the arms, legs, or other parts of the body (lymphoedema)
  • Nose bleeds (epistaxis)
  • Mouth sores, mouth ulcers, inflammation of gums (stomatitis)
  • Skin chapped
  • Skin reddening (erythema)
  • Skin effects such as rash, wart-like growths, or redness and/or swelling and possibly peeling on the palms, fingers, and soles of the feet which may be accompanied by tingling sensation and burning pain (palmar-plantar erythrodysesthesia syndrome)
  • Skin fissures
  • Swelling of the face (face oedema)
  • Pain, mouth sores, redness and swelling of airways or food pipe (mucosal inflammation)
  • Unusual weakness (asthenia).

Common side effects that may show up in your test results

  • Blood alkaline phosphatase (ALP) increased (bone function),
  • Some elevated liver function enzymes (ALT and AST)
  • Abnormal kidney blood test result as a sign of impaired muscle health (blood creatine phosphokinase increased).

Uncommon side effects - MEKINIST

Tell your doctor or pharmacist if you notice any of the following (that may affect up to 1 in 100 people).

  • Blurred vision as a sign of swelling of the optic disk (papilloedema)
  • Cough, difficulty breathing, painful breathing (ILD).

Possible side effects - when taking MEKINIST with TAFINLAR

Refer to the TAFINLAR Consumer Medicine Information for possible side effects and important signs and symptoms to look out for, such as fever, skin problems and eye problems.

When you take MEKINIST and TAFINLAR together you may get any of the side effects in the previous lists, although the frequency may change (increase or decrease).

STOP taking MEKINIST and tell your doctor, nurse, or pharmacist IMMEDIATELY if you get any of the following symptoms (either for the first time or if they get worse) during treatment with Mekinist.

  • Fever, chills, sore throat or mouth ulcers due to infections as signs of a low level of a type of white blood cells (signs of neutropenia)
  • Generalized swelling (oedema includes generalized and peripheral oedema)
  • Tiredness, fatigue, pale skin (anaemia)
  • Fever, chills, sore throat or mouth ulcers due to infections as signs of a low level of white blood cells (leukopenia)
  • Abnormal growth of cancerous cells of the skin (signs of cutaneous squamous cell carcinoma (cuSCC) including SCC of the skin, SCC in situ (Bowen’s disease), keratoacanthoma)
  • Spontaneous bleeding or bruising (signs of thrombocytopenia)
  • Sensation of flashing light, loss of vision (signs of retinal detachment)
  • Acute severe upper stomach pain (sign of pancreatitis acute)
  • Severely decreased urine output (signs of renal failure)
  • Difficulty breathing, chest pain, fainting, rapid heart rate, bluish skin discoloration (signs of pulmonary embolism)
  • High or low urine output, drowsiness, confusion, or nausea as signs of an inflamed kidney (tubulointerstitial nephritis)
  • Abnormal breakdown of muscle, causing pain, fever, red-brown urine (signs of rhabdomyolysis)
  • Painful red eye (sign of uveitis).
  • Change in size or colour of a mole or a new skin lesion (new primary melanoma)
  • Severe upper stomach pain (sign of pancreatitis)
  • High or low urine output, drowsiness, confusion, or nausea as signs of an inflamed kidney (nephritis)
  • Severely decreased urine output (sign of acute renal failure)
  • Serious skin reactions such as rash, red skin, blistering of the lips, eyes or mouth, skin peeling, with or without fever, which may be possible signs of Stevens-Johnson syndrome.
  • Serious skin reactions such as widespread rash, fever, and enlarged lymph nodes (which may be signs of drug reaction with eosinophilia and systemic symptoms [DRESS]).
  • Chest pain, sudden shortness of breath, trouble breathing, pain in your legs with or without swelling, swelling in your arms and legs, or a cool, pale arm or leg. These may be symptoms of a blood clot.

Very common side effects when taking MEKINIST with TAFINLAR

Tell your doctor or pharmacist if you notice any of the following (that may affect more than 1 in 10 people).

  • Urinary tract infection
  • Sore throat and runny nose (nasopharyngitis)
  • Decreased appetite
  • Tiredness, confusion, muscle twitching, convulsions (hyponatremia)
  • Headache
  • Dizziness
  • Skin reddening (erythema)
  • Thickening of the outer layers of the skin (hyperkeratosis also including actinic keratosis (thick scaly crusty skin), seborrheic keratosis (waxy, "pasted-on-the-skin" skin growths) and keratosis pilaris (rough, slightly red bumps on light skin and brown bumps on darker skin))
  • Muscle spasms
  • Joint pain (arthralgia)
  • Muscle pain (myalgia)
  • Pain in the hands or feet (pain in extremity)
  • Excessive thirst, high urine output, dark urine, increase appetite with weight loss, dry flushed skin, irritability as signs of high level of sugar (glucose) in the blood (signs of hyperglycaemia)
  • Dizziness, light-headedness (hypotension)
  • Feeling weak, sick, and tired (fatigue including asthenia and malaise)
  • Chills
  • Tiredness, chills, sore throat, joints or muscles aching (influenza-like illness)

Very common side effects that may show up in your test results

  • High levels of the following enzymes:
    - blood alkaline phosphatase (AP) increased
    - alanine aminotransferase (ALT) increased (liver function)
    - aspartate aminotransferase (AST) increased (liver function).

Common side effects when taking MEKINIST with TAFINLAR

  • Warts (papilloma including skin papilloma)
  • Skin tags (acrochordon)
  • Low phosphorus in the blood (hypophosphatemia)
  • Night sweats
  • Skin lesion
  • Skin fissures
  • Excessive sweating (hyperhidrosis)
  • Tender or painful bumps below the surface of the skin (panniculitis)
  • Increased sensitivity of the skin to sun (photosensitivity).

Common side effects that may show up in your test results

  • Abnormal liver blood tests (gamma-glutamyltransferase increased)

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using MEKINIST

Storage

Keep MEKINIST tablets in the refrigerator at between 2°C and 8°C, where children cannot see or reach it. Whilst in use, the bottle may be stored out of the refrigerator for a maximum of 30 days. Keep it where children cannot reach it. A locked cupboard at least one and half metres above the ground is a good place to store medicines.

Do NOT store MEKINIST or any other medicine:

  • In the bathroom or near a sink.
  • On a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep the tablets in the bottle until it is time to take a dose.

Do not remove the desiccant. Keep the bottle tightly closed between doses. MEKINIST needs protection from light and moisture. If you take the tablets out of the bottle or remove the desiccant, they may not keep well.

Disposal

If the packaging is torn or shows signs of tampering when you received it, return it to the pharmacist.

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Do not throw MEKINIST in the general household rubbish or flush it down the toilet. It may end up in landfill or enter waterways affecting the environment or marine life.

Do not keep old medicines because you think you may need them in the future. Keeping any unwanted or expired medications runs the risk of unintentional poisonings.

Product description

What MEKINIST tablets look 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 also contains a desiccant.

0.5 mg tablets
Yellow, modified oval, biconvex, film-coated tablets with 'GS' debossed on one face and 'TFC' on the opposite face.

2 mg tablets
Pink, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'HMJ' on the opposite face.

Ingredients

Each MEKINIST tablet contains trametinib dimethyl sulfoxide, equivalent to 0.5 mg or 2 mg per tablet as the active ingredient.

The tablets also contain the following 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 tablet only

The 0.5 mg tablet also contains:

  • Iron oxide yellow CI 77492 (E172).

2 mg tablet only

The 2 mg tablet also contains:

  • Polysorbate 80 (E433)
  • Iron oxide red CI 77491 (E172)

MEKINIST tablets do not contain lactose, sucrose, gluten, tartrazine, or any other azo dyes.

Sponsor

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

Australian Registration Numbers:

  • AUST R 205917: MEKINIST trametinib 0.5 mg (as dimethyl sulfoxide) tablet
  • AUST R 205919: MEKINIST trametinib 2 mg (as dimethyl sulfoxide) tablet

This leaflet was prepared in December 2019.

Internal document code
(mek021219c based on PI mek021219i)

Published by MIMS February 2020

BRAND INFORMATION

Brand name

Mekinist

Active ingredient

Trametinib

Schedule

S4

 

1 Name of Medicine

Trametinib.

6.7 Physicochemical Properties

Chemical structure.


CAS 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.

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.

Excipients.

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

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.

Mekinist 2 mg film coated tablet.

Pink, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'HMJ' on the opposing face.

5 Pharmacological Properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor.
Anatomical Therapeutic Chemical (ATC) code: L01XE25.

5.1 Pharmacodynamic Properties

Mechanism of action.

Trametinib monotherapy (melanoma, ATC and NSCLC).

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 (melanoma, ATC, and NSCLC).

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 16 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, randomized, 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 randomized 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 OS analysis for Study MEK116513 was conducted when 222 total deaths (77% of the required events for the final analysis) occurred. The Independent Data Monitoring Committee (IDMC) recommended stopping the study since the OS results crossed the pre-specified efficacy boundary. As a consequence the interim OS summary was considered as the final comparative OS analysis.
The OS analysis was based on 222/704 (32%) deaths in the study [Mekinist and dabrafenib combination therapy: 100 deaths (28%) and vemurafenib monotherapy: 122 deaths (35%)]. The median follow-up time on study treatment was 11 months for the combination arm and 9 months in the vemurafenib arm. Study MEK116513 showed a statistically significant 31% reduction in the risk of death for trametinib and dabrafenib combination therapy compared with vemurafenib monotherapy (HR = 0.69, 95% CI: 0.53, 0.89; p = 0.005). The median OS was not yet reached for the combination arm, and was 17.2 months for vemurafenib monotherapy. The results of the secondary efficacy endpoints for PFS, ORR and DoR are summarized in Table 17.
Extended follow-up found the 36-month OS estimate to be 45% for patients who received Mekinist in combination with Tafinlar and 31% for patients who received vemurafenib monotherapy.

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

This Phase III, randomized, 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 randomized 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.
At the time of final OS analysis, a total of 222 deaths (52.5%) [Mekinist and dabrafenib combination therapy: 99 deaths (47%), dabrafenib monotherapy: 123 deaths (58%)] out of the randomized (or ITT) population were reported. The median follow-up time on study treatment was 20 months in the combination therapy arm and 16 months in the dabrafenib monotherapy arm. Study MEK115306 showed a statistically significant 29% reduction in the risk of death for the combination therapy arm compared with the dabrafenib monotherapy arm (HR = 0.71, 95% CI: 0.55, 0.92; p = 0.011). The median OS was 25.1 months for the combination therapy arm and 18.7 months for the dabrafenib monotherapy arm. The 12 month (74%) and 24 month (51.4%) OS estimates for the combination were also greater than those for dabrafenib monotherapy (67.6% and 42.1%, respectively). Efficacy Results of PFS, ORR and Duration of Response are summarized in Table 18.
Extended follow-up found the 36-month OS estimate to be 44% for patients who received Mekinist in combination with Tafinlar and 32% for patients who received Tafinlar monotherapy.

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, randomized, double blind, placebo-controlled study in patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
Patients were randomized 1:1 to receive either dabrafenib and trametinib combination therapy (Mekinist 2 mg once daily and Tafinlar 150 mg twice daily) or two placebos for a period of 12 months. Enrolment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. Any prior systemic anticancer treatment, including radiotherapy, was not allowed. Patients with a history of prior malignancy, if disease free for at least 5 years, were eligible. Patients presenting with malignancies with confirmed activating RAS mutations were not eligible. Patients were stratified by BRAF mutation status (V600E or V600K) and stage of disease prior to surgery (by Stage III sub-stage, indicating different levels of lymph node involvement and primary tumour size and ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Radiological 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 randomized to the combination therapy (n=438) and placebo (n=432) arms. Most patients were Caucasian (99%) and male (55%), with a median age of 51 years (18% were ≥ 65 years). The study included patients with all sub-stages of Stage III disease prior to resection; 18% of these patients had lymph node involvement only identifiable by microscope and no primary tumour ulceration. The majority of patients had a BRAF V600E mutation (91%). The median duration of follow-up (time from randomization to last contact or death) was 2.83 years in the dabrafenib and trametinib combination arm and 2.75 years in the placebo arm.
Results for the primary analysis of RFS are presented in Figure 4 and in Table 19. The study showed a statistically significant difference for the primary outcome of RFS between treatment arms, with an estimated 53% risk reduction in the dabrafenib and trametinib combination arm as compared to the placebo arm (HR=0.47; 95% CI: 0.39, 0.58; p=1.53×10-14). Results were consistent across subgroups, including stratification factors for disease stage and BRAF V600 mutation type. Median RFS was 16.6 months for the placebo arm, and has not yet been reached for the combination 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 randomization were 97% and 91% in the combination arm and 94% and 83% in the placebo arm, respectively. The Kaplan-Meier curve for this OS interim analysis is shown in Figure 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-randomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic anaplastic thyroid cancer (ATC).
The study had pre-specified interim analyses that were performed approximately every 12 weeks. 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).
In the ATC cohort, patients received Mekinist 2 mg once daily and dabrafenib 150 mg twice daily. At the time of efficacy analysis, the ATC cohort had 26 patients enrolled, of which 23 patients were evaluable for response. There were 20 ATC patients who had a minimum of 6 months of follow-up after the first scheduled post-baseline assessment or discontinued study treatment prior to that.
Among the 26 patients enrolled, 13 (50%) were Caucasian and 12 (46%) were Asian. The female to male ratio was 1:1. The median age was 70 years. All patients (n=26, 100%) had an ECOG performance status of 0 or 1. Fourteen patients (54%) had a prior history of differentiated thyroid cancer. Prior anti-cancer treatments included surgery (n=24, 92%), external beam radiotherapy (n=21, 81%), and systemic therapy (n=14, 54%) for ATC. Central laboratory testing confirmed the BRAF V600E mutation in 23 patients (88%).
For the primary endpoint, the investigator-assessed ORR was 70% (95% CI: 47.1, 86.8) in the ATC cohort. The ORR results assessed by IRC and investigator-assessment were consistent (Table 20).
Responses were durable with a median DoR in the ATC cohort of 12.1 months (95% CI: 3.3, NE) by investigator assessment, and a median PFS of 13.8 months (95% CI: 4.7, NE).
For ATC patients, the median OS was not yet reached at the time of data cut-off. Kaplan-Meier estimate of overall survival at 12 months for ATC patients was 63.8% (95% CI: 36.3, 82.0).

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-randomized, 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.
For the primary endpoint, 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 21).
The response was durable with median DoR in the previously treated population reaching 9.8 months (95% CI, 6.9, 16.0) by investigator assessment. For the first-line population, the median DoR and PFS could not yet be estimated (Table 21) and 68% of patients with confirmed response were still ongoing in follow-up for duration of response.

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 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 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.

The pharmacokinetics of trametinib were characterised in 64 patients enrolled in clinical trials with trametinib who had mild hepatic impairment (defined by National Cancer Institute classification) using a population pharmacokinetic analysis. Trametinib oral clearance and thus exposure to trametinib was not significantly different in these patients relative to patients with normal hepatic function. No data are available in patients with moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration).

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.

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

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.

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.

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 tumours. 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, neovascularization, 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 Adverse Effects (Undesirable Effects)).

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.
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 hospitalization 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 hospitalization 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 hospitalization 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.

Brain metastases.

The safety and efficacy of the combination of Tafinlar and Mekinist has not been evaluated in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain.

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.

Paediatric use.

The safety and efficacy of Mekinist has not been yet established in children and adolescents (< 18 years).

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.

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 (P-gp), 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, P-gp 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 using Mekinist during treatment and for four months 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 hormonal contraceptives and an 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 excreted in 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.

4.8 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 a randomized open label study (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 7 and Table 8 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 randomized 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 9 lists adverse reactions when Mekinist was used in combination with dabrafenib from the randomized double blind Phase III study MEK115306 (N = 209), and integrated safety data from MEK115306 (N = 209) and from the randomized open label Phase III study MEK116513 (N = 350).
See Table 10.

Adjuvant treatment of melanoma.

Mekinist in combination with dabrafenib.

The safety of Mekinist in combination with Tafinlar was evaluated in a Phase III, randomized, double-blind study of Mekinist in combination with Tafinlar versus two placebos in the adjuvant treatment of Stage III BRAF V600 mutation-positive melanoma after surgical resection (see Section 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 11 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 12.

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-randomized, 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 13 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-randomized, 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 14 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 in combination with Tafinlar (Table 15). 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.

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.

4.2 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.

Adult dose.

Recommended dosage for unresectable or metastatic melanoma.

The recommended dose of Mekinist, used as monotherapy or in combination with dabrafenib, is 2 mg given orally once daily with a full glass of water.

Recommended dosage for the adjuvant treatment of melanoma.

The recommended dosage of Mekenist is 2 mg given orally once daily in combination with dabrafenib, until disease recurrence or unacceptable toxicity for up to 1 year.

Recommended dosage for NSCLC and ATC.

The recommended dose of Mekinist, used in combination with dabrafenib, is 2 mg given orally once daily with a full glass of water.

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 (see Table 1 and Table 2).
Dose adjustment for Mekinist below 1 mg QD is not recommended, whether used as monotherapy or in combination with dabrafenib.
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.

Pyrexia may occur with Mekinist monotherapy and with dabrafenib combination therapy. Initiate treatment with anti-pyretics such as ibuprofen (preferred) or paracetamol. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patients should be evaluated for signs and symptoms of infection (see Section 4.4 Special Warnings and Precautions for Use). Follow the management given in 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).

Special populations.

Paediatric use.

The safety and efficacy of Mekinist has not been yet established in children and adolescents (< 18 years).

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. In a population pharmacokinetic analysis, Mekinist oral clearance and thus exposure was not significantly different in patients with mild hepatic impairment compared to patients with normal hepatic function (see Section 5.2 Pharmacokinetic Properties).
There are no clinical data in patients with moderate or severe hepatic impairment; therefore, the potential need for starting dose adjustment cannot be determined. Mekinist should be used with caution in patients with moderate or severe hepatic impairment.

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.

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.

4.9 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.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

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).

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

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.

6.5 Nature and Contents of Container

Mekinist tablets are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures and desiccant, containing 7* or 30 tablets.
* 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.

Summary Table of Changes