Consumer medicine information

Tafinlar

Dabrafenib

BRAND INFORMATION

Brand name

Tafinlar

Active ingredient

Dabrafenib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tafinlar.

SUMMARY CMI

TAFINLAR®

Consumer Medicine Information (CMI) summary

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

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

1. Why am I using TAFINLAR?

TAFINLAR contains the active ingredient dabrafenib. In adult patients TAFINLAR is used to treat certain types of skin cancer (melanoma), thyroid cancers and lung cancers; prevent the melanoma coming back if removed by surgery. In children 1 year and older, TAFINLAR is used to treat brain tumours, following other treatments. For more information, see Section 1. Why am I using TAFINLAR? in the full CMI.

2. What should I know before I use TAFINLAR?

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

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

3. What if I am taking other medicines?

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

4. How do I use TAFINLAR?

  • TAFINLAR should be taken at least 1 hour BEFORE eating or 2 hours AFTER eating.
  • In adults, the usual total dose of TAFINLAR is 150 mg twice each day (each dose being 12 hours apart).
  • TAFINLAR capsules: Take each 150 mg dose on an empty stomach, either as two 75 mg capsules or three 50 mg capsules: one after the other swallowed whole with a full glass of water
  • In children, dosage is based on body weight, and is taken twice each day.
  • TAFINLAR dispersible tablets are to be taken as a liquid oral solution only. Follow the Instructions for Use in the pack.

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

5. What should I know while using TAFINLAR?

Things you should do
  • Remind any doctor, dentist, nurse, or pharmacist you visit that you are using TAFINLAR
  • Keep all your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do NOT take TAFINLAR with food.
  • Do NOT stop using TAFINLAR suddenly or change the dose instructed by your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how TAFINLAR affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your medicine in the bottle until it is time to use them.
  • Keep capsules and dispersible tablets in a cool dry place where the temperature stays below 30°C.
  • Once tablets are dispersed in water, use within 30 minutes.

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

6. Are there any side effects?

Common side effects include feeling sick, vomiting, headache, changes to appetite, lack of energy, joint pain, hair loss, skin changes including redness, dryness, itching, raised bumps, rash, waxy feel. Serious side effects include difficulty breathing or wheezing, trouble swallowing, swollen hands, feet, or face; chest pain, severe tummy pain, less wee than normal, changes to colour of moles, fever, unexplained bleeding, vision changes. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

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



FULL CMI

TAFINLAR® (Taf-in-lar)

Active ingredient(s): [dabrafenib (as mesilate)] (da-braf-e-nib mee-sill-ate)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using TAFINLAR?

TAFINLAR contains the active ingredient dabrafenib.

TAFINLAR belongs to a group of medicines called "selective BRAF-inhibitors."

TAFINLAR is used to:

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

These cancers have changes (mutations) in a gene called "BRAF" that may have caused your cancer to grow. TAFINLAR slows down or stops the growth of your cancer.

TAFINLAR can be used by itself or together with another medicine called MEKINIST (containing trametinib).

If you are taking these medicines together, please read the MEKINIST Consumer Medicine Information as well as this one carefully.

2. What should I know before I use TAFINLAR?

Monitoring

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

Your doctor may also take blood samples to monitor your liver while you are taking TAFINLAR.

Warnings

Do not use TAFINLAR if:

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

Check with your doctor if you have:

  • Liver problems
  • Kidney problems
  • Diabetes or high levels of sugar in your blood
  • Heart problems
  • Eye problems
  • Lung or breathing problems
  • Skin problems

Pregnancy and breastfeeding

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

Birth control requirements

Women taking TAFINLAR

If you are a woman who could become pregnant, you must use good birth control while you are taking TAFINLAR and for:

  • at least two weeks after you stop taking it
    OR
  • at least 16 weeks following the last dose of MEKINIST (when taking in combination with TAFINLAR)

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

  • You need to use another good method of birth control, so you don't become pregnant while you are taking TAFINLAR.
  • Ask your doctor, healthcare provider, pharmacist, or nurse about options for good birth control or for advice.

Men taking TAFINLAR

You may have a lower sperm count while you are taking TAFINLAR. Your sperm count may not return to normal levels after you stop taking TAFINLAR.

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 taking TAFINLAR and for at least 2 weeks after stopping TAFINLAR.

If taking TAFINLAR in combination with MEKINIST, male patients should use condoms during sexual intercourse while on TAFINLAR and for at least 16 weeks after stopping both TAFINLAR and MEKINIST.

If you have any further questions on the effect of this medicine on sperm count, ask your doctor or nurse.

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

3. What if I am taking other medicines?

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

Some medicines may interfere with TAFINLAR and affect how it works such as:

  • Birth control medicines that use hormones
  • Warfarin (a medicine used to thin blood and prevent clots)
  • Medicines to treat fungal infections (such as ketoconazole, itraconazole, voriconazole, posaconazole)
  • Antibiotics such as clarithromycin, telithromycin or rifampicin
  • Medicines that cause a low immune system
  • Medicines that decrease the amount of stomach acid in your stomach (for example: omeprazole, esomeprazole, rabeprazole, pantoprazole, lansoprazole, ranitidine, cimetidine, famotidine, nizatidine or common antacids.
  • Medicines that lower fats in the body such as gemfibrozil
  • Medicines that decrease swelling such as dexamethasone
  • Medicines used to treat HIV such as ritonavir, saquinavir and atazanavir
  • Medicines used to treat seizures phenytoin, phenobarbital, or carbamazepine
  • Some anti-depressant medicines such as nefazodone and the herbal St John's wort (Hypericum perforatum)
  • Medicines used to treat high levels of cholesterol such as rosuvastatin.

4. How do I use TAFINLAR?

How much to take

Adults

  • The usual total dose of TAFINLAR is 150 mg twice each day.
  • Follow the instructions provided and use TAFINLAR until your doctor tells you to stop.

You must take 2 TAFINLAR doses each day.

Take each 150 mg dose on an empty stomach as either:

  • Two 75 mg capsules, or
  • Three 50 mg capsules.

Children (1 year and above)

  • The daily dose is based on the body weight and will be determined by their doctor.
  • Follow the instructions provided and use TAFINLAR until your doctor tells you to stop.

Do not take more TAFINLAR than your doctor has recommended.

When to take TAFINLAR

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

Take the morning and evening doses at about the same time each day.

How to take TAFINLAR CAPSULES

Swallow each capsule whole, with a full glass of water. Take the capsules, one after the other, unless your doctor has advised a lower dose.

Take TAFINLAR on an empty stomach

TAFINLAR should be taken either at least:

  • 1 hour BEFORE eating
    If taking TAFINLAR BEFORE something to eat or drink, take it and then wait at least 1 (one) hour before having any food or drink
    OR
  • 2 hours AFTER eating

If taking TAFINLAR AFTER eating a meal or having a drink, wait at least two (2) hours before taking TAFINLAR.

How to take TAFINLAR DISPERSIBLE TABLETS

TAFINLAR dispersible tablets are to be taken as a liquid oral suspension only and should not be swallowed whole, chewed, or crushed.

If you are taking TAFINLAR dispersible tablets, please follow Instructions for Use in the carton on how to prepare and take TAFINLAR dispersible tablets. Talk to your doctor or pharmacist if you are not sure.

Give TAFINLAR on an empty stomach

TAFINLAR should be given either at least:

  • 1 hour BEFORE eating
    If taking TAFINLAR BEFORE something to eat or drink, give it and then wait at least 1 (one) hour before having any food or drink
    OR
  • 2 hours AFTER eating

If giving TAFINLAR AFTER eating a meal or having a drink, wait at least two (2) hours before giving TAFINLAR

If you forget to use TAFINLAR

TAFINLAR should be used regularly at the same time each day. 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 your next dose at the usual time.

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

If you use too much

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

You should immediately:

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

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

5. What should I know while using TAFINLAR?

Things you should do

  • Use additional contraception for both men and women to avoid pregnancy while taking TAFINLAR and do this for 2 weeks after stopping TAFINLAR or 16 weeks after stopping MEKINIST and TAFINLAR (if using both medicines together)
  • If you become pregnant while taking TAFINLAR, tell your doctor immediately
  • Keep all your doctor's appointments so that your progress can be checked
  • Have the blood tests your doctor tells you to have
  • Have your eyes checked regularly.

Call your doctor straight away if you:

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

Things you should not do

  • Do not stop taking this medicine suddenly.
  • Do not take TAFINLAR with food.

Additional Tests

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

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your capsules and dispersible tablets in the bottle until it is time to take them
  • Store below 30°C (capsules). Store below 25°C (dispersible tablets).
  • Do not remove the desiccant from the capsule bottle or canisters from the dispersible tablet bottle (material that keeps the medicine dry).
  • Once dispersible tablets are dispersed, solution should be drunk within 30 minutes.

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

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

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

Serious side effects

Serious side effectsWhat to do
TAFINLAR alone
Skin problems
  • Unusual growth of skin cells
  • Sore skin that doesn't heal
  • Change in colour or size of mole
Tummy problems
  • Severe tummy pain
Kidney problems
  • Changes to the amount of wee when going to the toilet
  • Unexplained drowsiness, confusion, or feeling sick
Signs of allergic reaction
  • Trouble breathing/swallowing, dizziness, swelling of face, throat or tongue, itchy rash, wheezing.
TAFINLAR and MEKINIST together
Signs of infection
  • Fever, chills, sore throat, painful bumps in your mouth (ulcers)
Bleeding problems
  • Bloody poo or vomit, coughing up blood, nosebleeds
  • Sudden bleeding/bruising
Kidney problems
  • Less wee when going to the toilet
  • Unexplained drowsiness, confusion, or feeling sick
  • Red-brown wee or pain when going to the toilet
  • Fluid build up eg swlloen legs
Skin problems
  • Severe rash, blisters on the eyes or lips, peeling.
  • Swollen lymph nodes
Tummy problems
  • Severe, sudden tummy pain or cramps
Eye problems
  • Loss of or blurred vision, flashing light sensation, red eyes
Heart problems
  • Tightness in chest, fastheart rate, flushing or bluish skin
  • Slow heart rate
  • Irregular heartbeat
Breathing problems
  • Painful or troubled breathing
Signs of allergic reaction
  • Trouble breathing/swallowing, dizziness, swelling of face, throat or tongue, itchy rash, wheezing.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What TAFINLAR contains

Active ingredient
(main ingredient)		Dabrafenib (as mesilate)
Other ingredients - capsules
(inactive ingredients)		Cellulose - microcrystalline (E460)
Magnesium stearate (E572)
Silica - colloidal anhydrous
Iron oxide red (E172)
Titanium dioxide (E171)
Hypromellose (E464)
Iron oxide black (E172)
Shellac
Butan-1-ol
Isopropyl alcohol
Propylene glycol (E1520)
Ammonium hydroxide (E527)
Potential allergensThis medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.
Other ingredients - dispersible tablets
(inactive ingredients)		Mannitol
Microcrystalline cellulose
Crospovidone
Hypromellose
Acesulfame potassium
agnesium stearate
Colloidal anhydrous silica
Artificial berry flavour
Potential allergensThis medicine does not contain lactose, gluten, tartrazine or any other azo dyes.

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

What TAFINLAR looks like

TAFINLAR capsules are available in plastic bottles containing 120 capsules. The bottle has a child resistant closure.

TAFINLAR dispersible tablets are available in plastic bottles containing 210 dispersible tablets. The bottle has a child resistant closure.

TAFINLAR 50 mg capsules: AUST R 200922

TAFINLAR 50 mg capsules are opaque, hard capsules composed of a dark red body and dark red cap containing a white to slightly coloured solid. The capsule shells are printed with GS TEW and 50 mg.

TAFINLAR 75 mg capsules: AUST R 200936

TAFINLAR 75 mg capsules are opaque, hard capsules composed of a dark pink body and dark pink cap containing a white to slightly coloured solid. The capsule shells are printed with GS LHF and 75 mg.

TAFINLAR 10 mg dispersible tablets: AUST R 397093

TAFINLAR 10 mg dispersible tablets are white to slightly yellow, round, biconvex tablets marked "D" on one side and "NVR" on the other.

Who distributes TAFINLAR

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

® Registered Trademark

This leaflet was prepared in December 2023.

Internal document code: taf291123c based on PI taf291123i.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Tafinlar

Active ingredient

Dabrafenib

Schedule

S4

 

1 Name of Medicine

Dabrafenib.

2 Qualitative and Quantitative Composition

Active substance.

Tafinlar 50 mg capsules. Each hard capsule contains dabrafenib mesilate equivalent to 50 mg of dabrafenib.
Tafinlar 75 mg capsules. Each hard capsule contains dabrafenib mesilate equivalent to 75 mg of dabrafenib.
Tafinlar 10 mg dispersible tablets. Each dispersible tablet contains dabrafenib mesilate equivalent to 10 mg of dabrafenib.

Note.

Dabrafenib capsules and dispersible tablets are not interchangeable.

Excipients.

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

3 Pharmaceutical Form

Tafinlar 50 mg capsules.

Opaque, size 2 hard capsule composed of a dark red body and dark red cap containing a white to slightly coloured solid. The capsule shells are imprinted with GS TEW and 50 mg.

Tafinlar 75 mg capsules.

Opaque, size 1 hard capsule composed of a dark pink body and dark pink cap containing a white to slightly coloured solid. The capsule shells are imprinted with GS LHF and 75 mg.

Tafinlar 10 mg dispersible tablets.

White to slightly-yellow, round biconvex 6 mm tablet debossed with "D" on one side and "NVR" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Unresectable or metastatic melanoma.

Tafinlar in combination with trametinib is indicated for the treatment of patients with BRAF V600 mutation positive unresectable Stage III or metastatic (Stage IV) melanoma.
Tafinlar as monotherapy is indicated for the treatment of patients with BRAF V600 mutation positive unresectable Stage III or metastatic (Stage IV) melanoma.

Adjuvant treatment of melanoma.

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

Anaplastic thyroid cancer (ATC).

Tafinlar in combination with trametinib 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).

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

Low-grade glioma.

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

High-grade glioma.

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

4.2 Dose and Method of Administration

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

Note.

Dabrafenib capsules and dispersible tablets are not fully bioequivalent/interchangeable. Caution is advised when consideration is given to changing formulations due to any difficulty in swallowing solid forms, and frequent switching between formulations is discouraged.

Duration of treatment.

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

Recommended dosage.

Tafinlar is available in two dosage forms, capsules (for use in adult patients and in paediatric patients who weigh at least 26 kg) and dispersible tablets (for use in patients 1 year of age and older).
The recommended dose of Tafinlar in adult patients is Tafinlar 150 mg (two 75 mg capsules) taken twice daily (corresponding to a total daily dose of 300 mg), independent of body weight. Dose level reductions are shown, see Table 1.
The recommended dose and dose level reductions of Tafinlar capsules in paediatric patients who weigh at least 26 kg, is based on body weight (see Table 2). A recommended dose of Tafinlar capsules for patients who weigh less than 26 kg has not been established.
The recommended dosage and dose level reductions for Tafinlar dispersible tablets are based on body weight (see Table 3).

Dose modifications.

Monotherapy and in combination with Mekinist.

The management of adverse reactions when Tafinlar is used as monotherapy or in combination with Mekinist (trametinib) may require treatment interruption, dose reduction, or treatment discontinuation (see Table 1, Table 2 and Table 3). Also refer to the full trametinib product information for dosing instructions and modifications.
Recommended dose level reductions are provided in Table 1. Doses below 50 mg twice daily are not recommended.
Dose modifications are not recommended for Tafinlar, when administered with trametinib, for the following adverse reactions of trametinib: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease (ILD)/pneumonitis, and uncomplicated venous thromboembolism. For pyrexia management guidance see section below titled "pyrexia management".
The recommended dose modification schedule is provided in Table 4. 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 Tafinlar dose should not exceed the recommended starting dose.

Detailed dosing modifications for selected adverse reactions.

New primary cutaneous malignancies.

No Tafinlar dose modifications are required.

New primary noncutaneous malignancies.

Permanently discontinue Tafinlar in patients who develop RAS mutation-positive non-cutaneous malignancies.

Pyrexia management.

Follow the dose modifications in Table 5. Therapy should be interrupted (Tafinlar when used as monotherapy, and both Tafinlar and Mekinist when used in combination) if the patient's temperature is ≥ 38.0°C, or at the first symptom of pyrexia/pyrexia syndrome. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia/pyrexia syndrome. 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). Tafinlar when used as monotherapy, or both Tafinlar and Mekinist when used in combination, should be restarted if patient is symptom free for at least 24 hours either (1) at the same dose level, or (2) reduced by one dose level, if pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient (see Table 5). Monitor serum creatinine and other evidence of renal function during and following severe events of pyrexia.
If treatment related toxicities occur when Tafinlar is used in combination with Mekinist then both treatments should be simultaneously dose reduced, interrupted or discontinued with the following exceptions.

Uveitis management.

No dose modifications are required as long as effective local therapies can control ocular inflammation.

Interstitial lung disease (ILD)/pneumonitis.

Do not modify the dose of Tafinlar.
When receiving Tafinlar in combination with Mekinist, 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.

Serious skin toxicity.

For dosing modifications in intolerable or severe skin toxicity see Table 5.
Rash management should be considered whether Tafinlar is given as monotherapy or in combination with Mekinist, 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.

Special populations.

Paediatric use.

The safety and efficacy of Tafinlar in combination with trametinib have not been established in paediatric patients younger than 1 year of age with LGG/HGG with BRAF V600E mutation. Studies in juvenile animals have shown effects of Tafinlar which had not been observed in adult animals (see Section 4.4 Special Warnings and Precautions for Use). The safety and effectiveness of Tafinlar as a single agent in paediatric patients have not been established.

Use in the elderly.

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

Renal impairment.

No dose adjustment is required for patients with renal impairment. Based on the population pharmacokinetic analysis, mild and moderate renal impairment had no significant effect on Tafinlar oral clearance or on the concentrations of its metabolites (see Section 5.2 Pharmacokinetic Properties). There are no clinical data in patients with severe renal impairment and the potential need for dose adjustment cannot be determined. Tafinlar should be used with caution in patients with severe renal impairment.

Hepatic impairment.

No dose adjustment is required for patients with mild hepatic impairment. Based on the population pharmacokinetic analysis, mild hepatic impairment had no significant effect on Tafinlar oral clearance or on the concentrations of its metabolites (see Section 5.2 Pharmacokinetic Properties). There are no clinical data in patients with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined. Hepatic metabolism and biliary secretion are the primary routes of elimination of Tafinlar and its metabolites and patients with moderate to severe hepatic impairment may have increased exposure. Tafinlar should be used with caution in patients with moderate or severe hepatic impairment.

Administration.

Tafinlar should be taken either at least one hour before, or at least two hours after a meal due to the effect of food on Tafinlar absorption, leaving an interval of approximately 12 hours between doses. Tafinlar should be taken at similar times every day.
If a patient vomits after taking Tafinlar, the patient should not retake the dose and should take the next scheduled dose.

Hard capsules.

Tafinlar hard capsules should be swallowed whole with a glass of water. Do not open, crush, or break Tafinlar capsules.

Dispersible tablets.

Tafinlar dispersible tablets are to be taken as a suspension only and should not be swallowed whole, chewed, or crushed.
The oral suspension is prepared with approximately 5 mL of water for 1 to 4 tablets, and approximately 10 mL of water for 5 to 15 tablets in a provided dosing cup (refer to the Instruction for use for reconstitution instructions). Tafinlar dispersible tablet suspension can be administered using three different methods: via drinking the suspension from the dosing cup; swallowing the suspension received from an oral syringe filled with the suspension withdrawn from the dosing cup or receiving the suspension via a feeding tube. Care should be taken to ensure the entire dose is administered. It may take 3 minutes (or more) to fully dissolve the tablets. Once they are dissolved, the suspension should be cloudy white.
Administer the suspension immediately after preparation from cup, oral dosing syringe or feeding tube. Discard suspension if not administered within 30 minutes after preparation in line with local regulations and restart from the beginning.

Combination therapy.

When Tafinlar and Mekinist are taken in combination, take the once-daily dose of Mekinist at the same time each day with either the morning dose or the evening dose of Tafinlar.

Missed dose.

If a dose is missed, it should not be taken if it is less than 6 hours until the next dose.

4.3 Contraindications

Tafinlar is contraindicated in patients with hypersensitivity to the active substance dabrafenib mesilate or any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

BRAF V600 testing.

Before taking Tafinlar, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test.
The efficacy and safety of Tafinlar have not been established in patients with wild-type BRAF melanoma, and therefore Tafinlar should not be used in patients with BRAF wild-type melanoma (see Section 5.1, Clinical trials). Further around 40% of BRAF wild-type metastatic melanomas have oncogenic NRAS mutations which may result in paradoxical activation of MAP-kinase signalling in the presence of BRAF inhibitors such as Tafinlar and may lead to accelerated tumour growth.

Pyrexia and serious non-infectious febrile events.

Pyrexia was reported in clinical trials with Tafinlar monotherapy and in combination with Mekinist (see Section 4.8 Adverse Effects (Undesirable Effects)). In a Phase III clinical trial in patients with unresectable or metastatic melanoma, the incidence and severity of pyrexia were increased when Tafinlar was used in combination with Mekinist (57% [119/209], 7% Grade 3) as compared to Tafinlar monotherapy (33% [69/211], 2% Grade 3). In a Phase III trial in the adjuvant treatment of melanoma, the incidence and severity of pyrexia were higher in the Tafinlar in combination with Mekinist arm (67% [292/435]; 6% Grade 3/4) as compared to the placebo arm (15% [66/432]; < 1% Grade 3). In a Phase II trial in patients with rare cancers including ATC, the incidence and severity of pyrexia was 35% (35/100), 4% Grade 3 or 4 across all cohorts. In a Phase II trial in patients with NSCLC the incidence and severity of pyrexia were increased slightly when Tafinlar was used in combination with Mekinist (55% [51/93], 5% Grade 3) as compared to Tafinlar monotherapy (37% [31/84], 2% Grade 3). In patients with unresectable or metastatic melanoma who received the combination dose of Tafinlar 150 mg twice daily and Mekinist 2 mg once daily developed pyrexia. Approximately one-third of the patients receiving combination therapy who experienced pyrexia had three or more events.
Monitor serum creatinine and other evidence of renal function during and following severe episodes of pyrexia (also see Section 4.4 Special Warnings and Precautions for Use, Renal failure).
In 1% of patients in clinical trials, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.
A cross-study comparison in 1,810 patients treated with combination therapy demonstrated a reduction in the incidence of high-grade pyrexia and other pyrexia-related adverse outcomes when both Tafinlar and Mekinist were interrupted, compared to when only Tafinlar was interrupted.
Therapy with Tafinlar (Tafinlar when used in monotherapy, or both Tafinlar and Mekinist when used in combination) should be interrupted if the patient's temperature is ≥ 38.0°C or at the first symptom of pyrexia/pyrexia syndrome. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia/pyrexia syndrome. Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. Patients should be evaluated for signs and symptoms of infection (see Section 4.4 Special Warnings and Precautions for Use).
Tafinlar (or both Tafinlar and Mekinist when used in combination should be restarted if patient is symptom free for at least 24 hours either (1) at the same dose level, or (2) reduced by one dose level, if pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure. The use of oral corticosteroids should be considered in those instances in which antipyretics are insufficient.
For management of pyrexia also see Section 4.2 Dose and Method of Administration.

Renal failure.

Renal failure has been identified in < 1% of patients treated with Tafinlar as monotherapy. Renal failure was reported in 7% of patients who received the combination dose of Tafinlar 150 mg twice daily and Mekinist 2 mg once daily, a higher frequency than observed in Tafinlar monotherapy patients (< 1%). Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported. Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, Tafinlar may need to be interrupted as clinically appropriate. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.

Cutaneous squamous cell carcinoma (cuSCC).

Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with Tafinlar as monotherapy and in combination with Mekinist (see Section 4.8 Adverse Effects (Undesirable Effects)). In a Phase III study in patients with unresectable or metastatic melanoma, 10% (22/211) of patients receiving Tafinlar as monotherapy developed cuSCC with a median time to onset of the first occurrence of approximately 8 weeks. In patients who received Tafinlar with Mekinist, 3% (6/209) of patients developed cuSCC and, events occurred later, with the median time to onset of the first occurrence of 20 to 32 weeks. More than 90% of patients on Tafinlar who developed cuSCC, continued on treatment without dose modification. In a Phase III trial in the adjuvant treatment of melanoma, 1% (6/435) of patients receiving Tafinlar in combination with Mekinist as compared to 1% (5/432) of patients receiving placebo developed cuSCC. The median time to onset of the first occurrence of cuSCC in the combination arm was approximately 18 weeks.
Skin examination for cuSCC should be performed prior to initiation of Tafinlar and every month throughout treatment with Tafinlar and for up to six months after treatment. Monitoring should continue every two or three months for six months following discontinuation of Tafinlar or until initiation of another anti-neoplastic therapy.
Cases of cuSCC should be managed by dermatological excision and Tafinlar treatment should be continued without any dose adjustment. Patients should be instructed to immediately inform their physician if new lesions develop.

New primary melanoma.

New primary melanomas have been reported in patients treated with Tafinlar. In clinical trials in unresectable or metastatic melanoma, these cases were identified within the first five months of therapy, were managed with excision, and did not require treatment modification. In the Phase III clinical trial in the adjuvant treatment of melanoma, new primary melanomas occurred in < 1% (1/435) of patients receiving the combination of Tafinlar and Mekinist as opposed to 1% (6/432) of patients receiving placebo. Monitoring for skin lesions should occur as described for cuSCC.

Non-cutaneous malignancies.

In vitro experiments have demonstrated paradoxical activation of MAP-kinase signalling in BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors. This may lead to an increased risk of non-cutaneous malignancies with Tafinlar exposure, when RAS mutations are present. RAS-associated malignancies have been reported in clinical trials, both with another BRAF inhibitor (chronic myelomonocytic leukaemia and non-cutaneous SCC of the head and neck) as well as with Tafinlar monotherapy (pancreatic adenocarcinoma, bile duct adenocarcinoma) and with Tafinlar in combination with the MEK inhibitor Mekinist (colorectal cancer, pancreatic cancer). In the Phase III trial in the adjuvant treatment of melanoma comparing combination of Tafinlar and Mekinist to placebo, non-cutaneous secondary malignancies or recurrent malignancies were observed in 1% (5/435) of patients receiving active therapy compared to 1% (3/432) of patients receiving placebo.
Prior to initiation of treatment, patients should undergo a head and neck examination with minimally visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen computerised tomography (CT) scan. During treatment, patients should be monitored as clinically appropriate which may include a head and neck examination every 3 months and a chest/abdomen CT scan every 6 months. Anal examinations and pelvic examinations (for women) are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts should be performed as clinically indicated. (See Section 4.2 Dose and Method of Administration.)
Carefully consider benefits and risks before administering Tafinlar to patients with a prior or concurrent cancer associated with RAS mutations. No dose modification of Mekinist is required when taken in combination with Tafinlar.
Following discontinuation of Tafinlar, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.

Serious skin toxicity.

Serious skin toxicity can occur with Tafinlar. Across clinical trials of Tafinlar administered with Mekinist (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients. Withhold Tafinlar for intolerable or severe skin toxicity. Tafinlar may be resumed at the next lower dose level in patients with improvement or recovery from skin toxicity within three weeks (see Section 4.2 Dose and Method of Administration).

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 Tafinlar in combination with trametinib. 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, Tafinlar and trametinib should be withdrawn.

Haemophagocytic lymphohistiocytosis (HLH).

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

Visual impairment.

Treatment with Tafinlar as monotherapy and in combination with Mekinist has been associated with ophthalmologic reactions, including uveitis, iridocyclitis, and iritis. Monitor patients routinely for visual signs and symptoms (such as, change in vision, photophobia and eye pain) during therapy. (Also see Section 4.2 Dose and Method of Administration.)

Uveitis.

If uveitis does not respond to local ocular therapy, withhold Tafinlar until resolution of ocular inflammation and then restart Tafinlar reduced by one dose level. (See Section 4.2 Dose and Method of Administration.)
No dose modification of Mekinist is required when taken in combination with Tafinlar following diagnosis of uveitis.

Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED).

RPED and RVO may occur with dabrafenib in combination with Mekinist (trametinib). No dose modification of Tafinlar is required when taken in combination with trametinib following diagnosis of RVO or RPED.
Please refer to the Mekinist Product Information.

Pancreatitis.

Pancreatitis has been reported in < 1% of Tafinlar-treated patients in unresectable or metastatic melanoma clinical trials. One of the events occurred on the first day of dosing of a melanoma patient and recurred following re-challenge at a reduced dose. In the adjuvant treatment of melanoma trial, pancreatitis was reported in 1% of patients receiving Tafinlar in combination with Mekinist, and in < 1% of patients receiving placebo.
Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting Tafinlar after an episode of pancreatitis.

Hyperglycaemia.

Hyperglycaemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycaemic agent therapy can occur with Tafinlar. In the pivotal study, five of 12 patients with a history of diabetes required more intensive hypoglycaemic therapy while taking Tafinlar. The incidence of Grade 3 hyperglycaemia based on laboratory values was 6% (12/187) in patients treated with Tafinlar compared to none of the dacarbazine-treated patients. Monitor serum glucose levels as clinically appropriate during treatment with Tafinlar in patients with pre-existing diabetes or hyperglycaemia. Advise patients to report symptoms of severe hyperglycaemia such as excessive thirst or any increase in the volume or frequency of urination.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Tafinlar, which contains a sulphonamide moiety, confers a potential risk of haemolytic anaemia in patients with G6PD deficiency. Monitor patients with G6PD deficiency for signs of haemolytic anaemia while taking Tafinlar.

Tafinlar in combination with Mekinist (trametinib).

When Tafinlar is given in combination with trametinib, please refer to the full trametinib Product Information, prior to initiation of combination treatment.

Haemorrhage.

Haemorrhagic events, including major haemorrhagic events have occurred in patients taking trametinib in combination with Tafinlar. If patients develop symptoms of haemorrhage, they should immediately seek medical care.
Six (6) out of 559 unresectable or metastatic melanoma patients (1.1%) receiving dabrafenib in combination with trametinib in a phase III trial had fatal intracranial haemorrhagic events. Three cases were from study MEK115306 (COMBI-d) and three cases were from study MEK116513 (COMBI-v). No fatal haemorrhagic events occurred in the Phase III study in the adjuvant treatment of melanoma (0/438). Two out of 93 patients (2%) receiving Tafinlar in combination with Mekinist in a Phase II trial in patients with metastatic NSCLC had fatal intracranial haemorrhagic events. If patients develop symptoms of haemorrhage they should immediately seek medical care.
In Study BRF113220, treatment with Tafinlar in combination with trametinib resulted in an increased incidence and severity of any haemorrhagic event: 16% (9/55) of patients treated with trametinib in combination with Tafinlar compared with 2% (1/53) of patients treated with Tafinlar 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 Tafinlar 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 Tafinlar.

Cardiac effects.

LVEF reduction/left ventricular dysfunction.

Cardiomyopathy can occur with Tafinlar (see Section 4.8 Adverse Effects (Undesirable Effects)). In MEK115306 (COMBI-d), all patients were required to have an echocardiogram at baseline to document normal left ventricular ejection fraction (LVEF) and serial echocardiograms at Week 4, Week 12, and every 12 weeks thereafter. Cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional lower limit of normal, occurred in 6% (12/206) of patients receiving Tafinlar with Mekinist and 2.9% (6/207) of patients receiving single-agent Tafinlar. The median time to onset of cardiomyopathy on the Tafinlar plus Mekinist arm was 8.2 months (range: 28 days to 24.9 months), and was 4.4 months (range: 28 days to 19.1 months) on the Tafinlar arm.
Cardiomyopathy was identified within the first month of initiation of Tafinlar with Mekinist in 2 of 12 patients, and in 2 of 6 patients receiving single-agent Tafinlar in MEK115306. Development of cardiomyopathy in patients receiving Tafinlar and trametinib resulted in dose interruption of Tafinlar (4.4%) or discontinuation of Tafinlar (1.0%). In patients receiving single-agent Tafinlar, development of cardiomyopathy resulted in dose interruption (2.4%), dose reduction (0.5%), or discontinuation (1.0%). Cardiomyopathy resolved in 10 of 12 patients receiving Tafinlar with trametinib, and in 3 of 6 patients receiving single-agent Tafinlar.
Assess LVEF by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of Tafinlar with Mekinist, one month after initiation of Tafinlar, and then at 2- to 3-month intervals while on treatment. Withhold Tafinlar for symptomatic cardiomyopathy or asymptomatic LV dysfunction of > 20% from baseline that is below institutional lower limit of normal (LLN). Resume Tafinlar at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤ 10% compared to baseline (see Section 4.2 Dose and Method of Administration).

QT prolongation.

Worst-case QTc prolongation of > 60 millisecond (ms) was observed in 3% of Tafinlar-treated patients (one > 500 ms in the integrated safety population). In the Phase III study MEK115306, no patients treated with trametinib in combination with dabrafenib had worst-case QTcB prolongation to > 500 ms; QTcB was increased more than 60 ms from baseline in 1% (3/209) of patients. In the Phase III study MEK116513 four patients (1%) treated with Mekinist in combination with Tafinlar had a QTcB Grade 3 increase (> 500 ms). Two of these patients had a QTcB Grade 3 increase (> 500 ms) that was also an increase > 60 ms from baseline. The potential effect of Tafinlar on QT prolongation was assessed in a dedicated multiple dose QT study. A supra therapeutic dose of 300 mg Tafinlar twice daily was administered in 32 patients with BRAF V600 mutation positive tumours. No clinically relevant effect of Tafinlar or its metabolites on the QTc interval was observed.

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 ms increase, normal = 120 to 200) and heart rate (mean 8.12 bpm decrease) with Mekinist 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 Mekinist and Tafinlar combined therapy compared to 12% of patients in the vemurafenib monotherapy control arm.

Hepatic events.

Hepatic adverse events have been reported in clinical trials with dabrafenib in combination with trametinib (see Section 4.8 Adverse Effects (Undesirable Effects)). It is recommended that patients receiving treatment with dabrafenib in combination with trametinib have liver function monitored every four weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically indicated. Refer to the trametinib Product Information for additional information.

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 Mekinist Product Information for additional information.

Interstitial lung disease (ILD)/pneumonitis.

Cases of pneumonitis or ILD have been reported in clinical trials with Tafinlar in combination with Mekinist. Refer to the trametinib Product Information for additional information. If Tafinlar is being used in combination with Mekinist, then therapy with Tafinlar may be continued at the same dose.

Rash.

Rash has been observed in about 25% of patients in clinical studies when Tafinlar is used in combination with Mekinist. Also refer to the Mekinist 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 Mekinist Product Information for additional information.

Venous thromboembolism (VTE).

VTE, including pulmonary embolism or deep vein thrombosis (DVT) can occur when Tafinlar is used in combination with Mekinist. If patients develop symptoms of VTE, including PE or DVT such as shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. Permanently discontinue Mekinist and Tafinlar for life-threatening pulmonary embolism.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Renal failure; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties.

Paediatric use.

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

Effects on laboratory tests.

Treatment-emergent laboratory abnormalities may include any of the following: hyperglycaemia, hyperbilirubinemia, increased GGT, increased ALP, increased ALT, increased AST, increased CPK, hypophosphatemia, hyponatremia, serum albumin abnormalities, anaemia, neutropenia, thrombocytopenia, leukopenia, and lymphocytopenia. See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro evaluation of drug interaction potential.

Effect of other medicines on Tafinlar. Tafinlar is a substrate of metabolising enzymes CYP2C8 and CYP3A4, while active metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are likely to increase or decrease, respectively, Tafinlar concentrations. Alternative agents should be considered during administration with dabrafenib when possible. Use caution if strong inhibitors (e.g. ketoconazole, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir, gemfibrozil) are coadministered with Tafinlar. Avoid coadministration of Tafinlar with potent inducers of CYP2C8 or CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort (Hypericum perforatum)).

Ketoconazole.

Co-administration of ketoconazole (a CYP3A4 inhibitor) 400 mg once daily with Tafinlar 75 mg twice daily, increased the AUC of dabrafenib by 71%. Pharmacokinetic data showed an increase in repeat dose dabrafenib Cmax (33%) and AUC (71%) with ketoconazole, and increases of 82% and 68%, respectively in hydroxy- and desmethyl-dabrafenib AUC with ketoconazole. A 16% decrease in AUC was noted for carboxy-dabrafenib.

Gemfibrozil.

Coadministration of Tafinlar 75 mg twice daily and gemfibrozil (a CYP2C8 inhibitor) 600 mg twice daily resulted in an increase in repeat-dose Tafinlar AUC (47%) and no clinically relevant changes were noted in the AUC of the metabolites.

Drugs that affect gastric pH.

Dabrafenib solubility is pH dependent with decreased solubility at higher pH. Medicinal products that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor agonists, and antacids) may decrease the solubility of Tafinlar and reduce its bioavailability. However, no clinical study has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of Tafinlar. Due to the theoretical risk that pH-elevating agents may decrease oral bioavailability and exposure to Tafinlar, medicinal products that increase gastric pH should be used with caution when co-administered with Tafinlar. The effect of these medicines on efficacy of Tafinlar is unknown.
Effect of Tafinlar on other medicines. Dabrafenib is an inducer of metabolising enzymes CYP3A4 and CYP2C9 and may induce other enzymes including CYP2B6, CYP2C8, CYP2C19, UDP glucuronosyl transferase (UGT) and transporters (e.g. P-glycoprotein [P-gp]).
Co-administration of Tafinlar and medicinal products which are affected by the induction of these enzymes or transporters such as hormonal contraceptives (see Section 4.6 Fertility, Pregnancy and Lactation), warfarin, dexamethasone, antiretroviral agents, or immunosuppressants may result in decreased concentrations and loss of efficacy. Concomitant use of Tafinlar with these medicinal products should generally be avoided if monitoring for efficacy and dose adjustment is not possible. If co-administration of these medications is necessary with Tafinlar, monitor patients for any potential loss of efficacy or consider substitutions of these medicinal products.
Onset of induction is likely to occur after 3 days of repeat dosing with Tafinlar. Transient inhibition of CYP3A4 may be observed during the first few days of treatment. Upon discontinuation of Tafinlar, concentrations of sensitive CYP3A4 substrates may increase and patients should be monitored for toxicity and dosage of these agents may need to be adjusted.

Midazolam.

The single dose AUC of midazolam (CYP3A4 substrate) was decreased by 74% with co-administration of Tafinlar.

Warfarin.

The single dose AUC of and S-warfarin (CYP2C9 substrate) was decreased by 37% with co-administration of Tafinlar. Exercise caution and additional INR (International Normalized Ratio) monitoring is recommended when Tafinlar is used concomitantly with warfarin, and at discontinuation of Tafinlar.

Digoxin.

Concomitant administration of Tafinlar with digoxin may result in decreased digoxin exposure. Caution should be exercised and additional monitoring of digoxin is recommended when digoxin (a transporter substrate) is used concomitantly with Tafinlar and at discontinuation of Tafinlar.
Effects of dabrafenib on substance transport systems. Dabrafenib is an in vitro inhibitor of human organic anion transporting polypeptide (OATP) 1B1 (OATP1B1) and OATP1B3 and clinical relevance cannot be excluded. Therefore caution is recommended at co-administration of Tafinlar and OATP1B1 or OATP1B3 substrates such as statins.
Although Tafinlar and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of human organic anion transporter (OAT) 1 and OAT3 in vitro, the risk of a drug-drug interaction is minimal based on clinical exposure. Tafinlar and desmethyl-dabrafenib were also shown to be moderate inhibitors of human breast cancer resistance protein (BCRP) and the human renal uptake transporter organic cation transporter 2 (OCT2); however, based on clinical exposure, the risk of a drug-drug interaction is minimal. Neither Tafinlar nor its 3 metabolites were demonstrated to be inhibitors of P-gp in vitro.

Combination of Tafinlar with Mekinist.

Co-administration of repeat dosing Tafinlar 150 mg twice daily and Mekinist 2 mg once daily resulted in no clinically meaningful changes in Tafinlar or trametinib Cmax and AUC (see Section 5.2 Pharmacokinetic Properties).
See Product Information for Mekinist for guidelines on drug interactions associated with Tafinlar combination therapy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Infertility.

There are no data in humans. Tafinlar may impair male and female fertility as adverse effects on male and female reproductive organs have been seen in animals. Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible.
In combined female fertility, early embryonic and embryofetal development studies in rats numbers of ovarian corpora lutea were reduced in pregnant females at 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC), but there were no effects on estrous cycle, mating or fertility.

Males taking Tafinlar in combination with Mekinist.

Male fertility studies with Tafinlar have not been conducted. However, in repeat dose studies, testicular degeneration/ depletion or spermatid retention was seen in mice, rats and dogs (≥ 0.2 times the human clinical exposure based on AUC). Testicular changes in rats and dogs were still present following a 4 week recovery period.
(Category D)
Tafinlar can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of Tafinlar in pregnant women. Reproductive studies in rats have shown embryofetal development toxicity, including teratogenic effects. In adult female rats dosed with dabrafenib before mating and during gestation embryofetal toxicities included embryo-lethality, variation in thymic shape, and fetal ventricular septal defects at 300 mg/kg/day, and delayed skeletal development and reduced fetal body weight at ≥ 20 mg/kg/day (≥ 0.5 times human clinical exposure based on AUC).
Tafinlar should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus.
Contraception.

Females.

Females of reproductive potential should be advised that animal studies have been performed showing Tafinlar to be harmful to the developing fetus. Sexually active females of reproductive potential are recommended to use effective methods of contraception when taking Tafinlar and for at least two weeks following discontinuation of Tafinlar. If taking Tafinlar in combination with Mekinist, sexually-active females of reproductive potential are recommended to use effective contraception and for at least 16 weeks after stopping treatment.
Tafinlar may decrease the efficacy of oral or any other systemic hormonal contraceptives and an alternate method of contraception (methods that result in less than 1% pregnancy rates) should be used during treatment and for at least two weeks after stopping treatment with Tafinlar (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If Tafinlar is used during pregnancy, or if the patient becomes pregnant while taking Tafinlar, the patient should be informed of the potential hazard to the foetus.

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 Tafinlar monotherapy and for at least 2 weeks after stopping treatment with Tafinlar. If taking Tafinlar in combination with Mekinist, male patients should use condoms during sexual intercourse, and for at least 16 weeks after stopping treatment.
 There are no data on the effect of Tafinlar on the breast-fed child, or on the effect of Tafinlar on milk production. Because many drugs are transferred into human milk and because of the potential for adverse reactions in nursing infants from Tafinlar, a nursing woman should be advised on the potential risks to the child. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for Tafinlar and any potential adverse effects on the breast-fed child from Tafinlar or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions are listed in this section by MedDRA body 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.

Tafinlar monotherapy.

Safety data were integrated from five clinical monotherapy studies BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK-2), BRF113220, and BRF112680 and included 578 patients with BRAF V600 mutant unresectable or melanoma. Approximately 30% of patients received treatment with Tafinlar for more than 6 months.
In the integrated Tafinlar safety population, the most common (≥ 15%) adverse reactions were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, skin papilloma, alopecia, rash and vomiting. See Table 6.
Table 7 lists the very common (≥ 10% of patients) adverse events reported in the Phase III randomised, open-label study [BREAK-3].
See Table 8.

Post-marketing experience and pooled clinical trials.

The following adverse reactions have been derived from post-marketing experience including spontaneous case reports with Tafinlar in combination with trametinib. 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 ADR frequencies have been calculated from the pooled clinical trials across indications. Adverse reactions are listed according to system organ classes in MedDRA. See Table 9.
Description of selected adverse reactions.

Pyrexia.

Fever has been reported in clinical trials with Tafinlar as monotherapy and in combination with trametinib. The incidence and severity of pyrexia are increased with the combination therapy. In 1% of patients in clinical trials, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency or pre-renal origin in patients with normal baseline renal function. The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care (see Section 4.2 Dose and Method of Administration).

Cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinomas (including those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 9% (52/578) of patients treated with Tafinlar monotherapy in the integrated safety population and 3% of patients treated with Tafinlar in combination with Mekinist in MEK115306. With Tafinlar monotherapy, approximately 70% of events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. In patients who received the combination dose of Tafinlar in combination with Mekinist, events occurred later with the median time to onset of 22 weeks. Ninety-six percent of patients on Tafinlar monotherapy in the integrated safety population and all patients on combination therapy in the Phase III studies who developed cuSCC continued on treatment without dose modification.

New primary melanoma.

New primary melanomas have been reported in clinical trials with Tafinlar. Cases were managed with excision and did not require treatment modification (see Section 4.4 Special Warnings and Precautions for Use).

Non-cutaneous malignancy.

Activation of MAP-kinase signalling in BRAF wild type cells which are exposed to BRAF inhibitors may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (see Section 4.4 Special Warnings and Precautions for Use). In clinical trials non-cutaneous malignancies were reported in 1% (6/586) of patients with Tafinlar monotherapy, and 1% (3/209) of patients in study MEK115306 and < 1% (3/350) of patients in study MEK116513 with Tafinlar in combination with Mekinist. Cases of RAS-driven malignancies have been seen with Tafinlar. Patients should be monitored as clinically appropriate.
Tafinlar and trametinib combination therapy. In addition to adverse reactions observed with monotherapy treatments (Table 10 and Table 11), the safety of Tafinlar and Mekinist combination therapy has been evaluated in two randomised Phase III studies and one small phase II study of patients with BRAF mutant unresectable or metastatic melanoma treated with Tafinlar 150 mg orally twice daily and Mekinist 2 mg orally once daily (see Section 5.1, Clinical trials). The following tables list adverse reactions which are specific to Tafinlar in combination with Mekinist.
In Table 13, there were 55 patients in the study and hence the frequencies of uncommon or rare events could not be calculated.
The most common adverse reactions (≥ 20%) for Tafinlar and Mekinist combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhoea, rash, arthralgia, hypertension, vomiting, peripheral oedema, and cough. See Tables 10, 11, 12, and 13.

Metastatic melanoma patients with brain metastases.

The safety profile observed in study BRF117277/DRB436B2204 (COMBI-MB) in metastatic melanoma patients with brain metastases is consistent with the safety profile of Tafinlar in combination with Mekinist in unresectable or metastatic melanoma (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Adjuvant treatment of melanoma.

Tafinlar in combination with Mekinist.

The safety of Tafinlar in combination with Mekinist was evaluated in a Phase III, randomised, double-blind study of Tafinlar in combination with Mekinist versus two placebos in the adjuvant treatment of Stage III BRAF V600 mutation-positive melanoma after surgical resection (see Section 5.1 Pharmacodynamic Properties).
In the Tafinlar 150 mg twice daily and Mekinist 2 mg once daily arm, the most common adverse reactions (≥ 20%) were pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.
Table 14 lists the adverse drug reactions in study BRF115532 (COMBI-AD) occurring at an incidence ≥ 10% for all grade adverse reactions or at an incidence ≥ 2% for Grade 3 and Grade 4 adverse drugs reactions or adverse events that are medically significant in the Tafinlar in combination with Mekinist arm.
See Tables 14 and 15.

Locally advanced or metastatic anaplastic thyroid cancer (ATC).

Tafinlar in combination with Mekinist.

The efficacy and safety of Tafinlar in combination with Mekinist was studied in a Phase II, nine-cohort, multicentre, non-randomised, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (see Section 5.1, Clinical trials).
The 'All Treated Patients (ATS)' population was the primary safety population for the study and includes all patients who received at least one dose of Tafinlar or Mekinist 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 Tafinlar in combination with Mekinist in the ATS population were fatigue, pyrexia, rash, nausea, chills, vomiting, cough, and headache.
Table 16 lists the adverse drug reactions for Tafinlar in combination with Mekinist 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.

Tafinlar monotherapy.

The safety of Tafinlar monotherapy was evaluated in a Phase II, multicentre, multi-cohort, non-randomised, open-label study of patients with BRAF V600E mutation positive metastatic NSCLC (see Section 5.1, Clinical trials).
In the Tafinlar 150 mg twice daily (N=84) monotherapy arm (Cohort A) the most common adverse drug reactions (≥ 20%) were pyrexia, asthenia, fatigue, hyperkeratosis, cough, skin papilloma, dry skin, palmar-plantar erythrodysesthesia syndrome, alopecia, nausea, and dyspnea.

Tafinlar in combination with Mekinist.

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

Paediatric use.

Tafinlar in combination with Mekinist.

The safety of Tafinlar in combination with Mekinist was studied in 171 paediatric patients across two studies (G2201 and X2101) with BRAF V600E mutation-positive advanced solid tumours, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (22.8%) patients were 2 to < 6 years of age, 54 (31.6%) patients were 6 to < 12 years of age, and 74 (43.3%) patients were 12 to < 18 years of age.
The overall safety profile in the paediatric population was similar to the safety profile observed in adults. The most frequently reported adverse drug reactions (≥ 20%) were pyrexia, rash, headache, vomiting, dry skin, fatigue, diarrhoea, haemorrhage, neutropenia, nausea, dermatitis acneiform, abdominal pain, and cough.
An adverse drug reaction of weight increased was identified in the paediatric safety pool with a frequency of 15.2% (very common). Fifty-one out of 171 patients (29.8%) had an increase from baseline of ≥ 2 BMI-for-age percentile categories.
Adverse drug reactions occurring at a higher frequency category in paediatric patients compared to adult patients were neutropenia, dermatitis acneiform, paronychia, anaemia, leukopenia (very common); bradycardia, dermatitis exfoliative generalised, hypersensitivity and pancreatitis (common). See Table 18.
In juvenile toxicity studies in rats, effects on growth (shorter long bone length), renal toxicity (tubular deposits, increased incidence of cortical cysts and tubular basophilia and reversible increases in urea and/or creatinine concentrations), thymus toxicity (lymphoid apoptosis) and testicular toxicity (degeneration and tubular dilation) were observed.

Use in the elderly.

No initial dose adjustment is required in patients over 65 years of age (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
For clinical trials of Tafinlar monotherapy, compared with younger patients (< 65 years of age), more patients over 65 years old had adverse reactions that lead to study drug dose reductions (22% versus 12%) or interruptions (39% versus 27%). In addition, older patients experienced more serious adverse reactions compared to younger patients (41% versus 22%). No overall differences in efficacy were observed between these patients and younger patients.
Across clinical trials of Tafinlar administered in combination with Mekinist (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 of age.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

There is currently very limited experience with overdosage with Tafinlar. The maximum dose of Tafinlar administered during clinical trials was 600 mg (300 mg twice daily).

Treatment.

There is no specific antidote for overdosage of Tafinlar. Patients who develop adverse reactions should receive appropriate symptomatic treatment. In case of suspected overdose, Tafinlar should be withheld and supportive care instituted. For information on the management of overdose contact the Poison Information Centre on 13 11 26.

5 Pharmacological Properties

Pharmacotherapeutic group: B-Raf serine-threonine kinase (BRAF) inhibitors.
Anatomical Therapeutic Chemical (ATC Code): L01EC02.

5.1 Pharmacodynamic Properties

Mechanism of action.

Tafinlar monotherapy.

The active ingredient in Tafinlar, dabrafenib, is an ATP-competitive inhibitor of RAF kinases with IC50 values of 0.65, 0.5 and 1.84 nanoM for BRAF V600E, BRAF V600K and BRAF V600D enzymes, respectively. Tafinlar also inhibits a small number of other kinases, including wild type BRAF and CRAF with IC50 values of 3.2 and 5.0 nanoM, respectively. Mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumour cell growth. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50% of melanoma. The most commonly observed BRAF mutation, V600E, and the next most common, V600K, account for 95% of the BRAF mutations found in these cancers. A number of rare mutations also occur including V600D, V600G and V600R. Clinical inhibition of the MAPK pathway signalling depends on cellular and genotypic context (see Section 4.4 Special Warnings and Precautions for Use, Non-cutaneous malignancy).
Tafinlar inhibits BRAF V600 mutant melanoma, NSCLC and ATC cell growth in vitro and BRAF V600 mutant melanoma in vivo.

Tafinlar in combination with Mekinist.

The active ingredient in Mekinist, trametinib, is a reversible allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. Tafinlar and Mekinist inhibit two critical kinases in this pathway, BRAF and MEK, and the combination provides concomitant inhibition of the pathway. The combination of Tafinlar with Mekinist 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.

Tafinlar demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated ERK) in BRAF V600 mutant melanoma cell lines, in vitro and in animal models.
In patients with BRAF V600 mutant melanoma, administration of Tafinlar resulted in inhibition of tumour phosphorylated ERK relative to baseline.

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. Tafinlar monotherapy - open label studies. The efficacy of Tafinlar in the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma has been evaluated in 3 open label studies:
1. Phase III Study BRF113683 [BREAK-3];
2. Phase II Study BRF113929 [BREAK-MB]; and
3. Phase II Study BRF113710 [BREAK-2].
Included in these studies were 402 patients with BRAF V600E and 49 patients with BRAF V600K mutation.
Patients with evidence of active CNS disease (e.g. radiographically unstable or with symptomatic lesions) and those with disease progression in the brain in the last three months were excluded from the pivotal Phase III study.

Phase III study BREAK-3 in previously untreated melanoma patients.

The efficacy and safety of Tafinlar were evaluated in this Phase III randomised, open label study [BREAK-3] comparing Tafinlar 150 mg twice daily to IV dacarbazine (DTIC) 1000 mg/m2 every 3 weeks in previously untreated patients with BRAF V600E mutation positive unresectable or advanced (unresectable Stage III) or metastatic (Stage IV) melanoma. Screening included central testing of BRAF mutation V600E using a BRAF mutation assay conducted on the most recent tumour sample available. Two hundred and fifty patients were randomised 3:1 to receive either Tafinlar or intravenous DTIC. The primary objective was to evaluate the efficacy of Tafinlar compared to DTIC with respect to progression-free survival (PFS) per investigator assessment for patients with BRAF V600E mutation positive metastatic melanoma. Patients on the DTIC arm were allowed to cross over and receive Tafinlar after independent radiographic confirmation of initial progression. Baseline characteristics were balanced between treatment groups. Sixty percent of patients were male and 99.6% were Caucasian; the median age was 52 years with 21% of patients being ≥ 65 years, 98.4% had an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1, and 97% of patients had metastatic disease.
At the pre-specified analysis with a 19 December 2011 data cut, a significant improvement in the primary endpoint of PFS (HR = 0.30; 95% CI 0.18, 0.51; p < 0.0001) was achieved. PFS from the primary analysis is shown in Figure 1. Efficacy results from a post-hoc analysis with 6-months additional follow-up are summarised in Table 19. Overall survival data from a further post-hoc analysis based on an 18 December 2012 data cut is provided in Table 20 and shown in Figure 2. As of 25 June 2012, thirty-five patients (55.6%) of the 63 randomised to DTIC crossed over to Tafinlar. Median PFS after cross-over was 4.4 months. See Tables 19 and 20 and Figures 1 and 2.

Phase II study BREAK-MB in patients with stage IV BRAF mutation positive (V600E or V600K) brain metastases.

This multi-centre, open-label, two-cohort, Phase II study was designed to evaluate the intracranial response of Tafinlar in 172 patients with histologically confirmed (Stage IV) BRAF-mutation positive (V600E or V600K) melanoma metastatic to the brain. Patients were enrolled into Cohort A (patients with no prior local therapy for brain metastasis; n=89) or Cohort B (patients who received prior local therapy for brain metastasis; n=83).
The major efficacy outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort. The intracranial response rate as determined by an independent radiology review committee for the BRAF V600E group, masked to investigator response assessments, was 18% (95% CI: 10%, 28%) in Cohort A (n=74) and 18% (95% CI: 10%, 30%) in Cohort B (n=65). The median duration of intracranial response was 4.6 months in both cohorts.
Of note, the benefit risk, in terms of intracranial response, relative to surgery or stereotactic radio-surgery has not been studied directly however evidence from cohort B suggests that prior local treatment does not preclude subsequent benefit from BRAF inhibition.

Phase II study BREAK-2 in stage IV metastatic patients who were previously untreated or failed at least one prior systemic therapy.

This was a multi-centre, global, open-label, single-arm, Phase II study that enrolled 92 patients with histologically confirmed metastatic melanoma (Stage IV) with confirmed BRAF V600E or V600K mutation-positive melanoma. Patients were treatment-naïve (n = 15) or received prior treatment (n = 77) in the metastatic setting (i.e. chemotherapy, immunotherapy, prior targeted therapy, etc.).
The investigator assessed confirmed response rate in the primary efficacy population of patients with BRAF V600E metastatic melanoma (n = 76) was 59% (95% CI: 48.2, 70.3) including 7% complete response. Median PFS was 6.3 months (95% CI: 4.6, 7.7) and the median duration of response was 5.2 months (95% CI: 3.9, not calculable). Prior systemic therapy did not appear to significantly impact response. The investigator assessed confirmed response rate in a secondary efficacy population of patients with BRAF V600K mutation positive metastatic melanoma (n = 16) was 13% (95% CI: 0.0, 28.7) with a median duration of response of 5.3 months (95% CI: 3.7, 6.8). There were no complete responses in the V600K patient population. Although the evidence for the efficacy of Tafinlar is limited by the low number of patients, median OS appeared consistent with data in patients with BRAF V600E positive tumours.
Tafinlar in combination with Mekinist. The efficacy and safety of the recommended dose of Tafinlar (150 mg twice daily) in combination with Mekinist (2 mg once 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 an open-label study, the safety, PK, PD, and clinical activity of Tafinlar and Mekinist combination therapy were evaluated in patients with BRAF V600E, V600K, or V600D mutation positive 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 Tafinlar 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 Tafinlar (n = 135);
Part C was an open label randomised three arm phase II study determine the efficacy, safety, and tolerability of Mekinist and Tafinlar in patients with BRAF mutant metastatic melanoma (n = 162) and is described below;
Part D was a PK and safety evaluation of Mekinist and Tafinlar capsules (n = 110).
The determination of BRAF mutation positive status was required and was established by institutional laboratory for all patients enrolled in Parts A-D.

Prior BRAF inhibitor (BRAFi) therapy.

There are limited data in patients taking the combination of Tafinlar with Mekinist 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 Mekinist 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 Mekinist 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 Tafinlar 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 Tafinlar alone (150 mg twice daily) in 162 patients. The primary efficacy endpoints were PFS, ORR, and DoR. Patients on the Tafinlar monotherapy arm were permitted to cross-over to the full-dose combination arm (150 mg Tafinlar plus 2 mg Mekinist) upon progression. A total of 43 patients (81%) in the Tafinlar monotherapy arm with disease progression crossed over to receive Tafinlar 150 mg and Mekinist 2 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 Tafinlar 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 Tafinlar 150 mg twice daily monotherapy. The hazard ratio was 0.39 (95% CI 0.25, 0.62, p < 0.0001). Overall response rate for Tafinlar 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 Tafinlar 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 150 mg Tafinlar plus 2 mg Mekinist combination.
A retrospective blinded independent committee review (BICR) was conducted and had the following results:
61% ORR (95 CI: 46.9%, 74.1%; P = 0.1486) for patients treated with 150 mg Tafinlar plus 2 mg Mekinist combination;
39% (95% CI: 25.9, 53.1; P = 0.5008) for patients treated with 150 mg Tafinlar plus 1 mg Mekinist combination; and
46% (95% CI: 32.6%, 60.4%) for patients treated with 150 mg Tafinlar monotherapy.
Median PFS was 9.2 months (95% CI: 7.6, NR; P = 0.0121) for patients treated with Tafinlar 150 mg plus 2 mg Mekinist combination.
Median PFS was 8.3 months (95% CI: 5.6, 11.3; P = 0.1721) for patients treated with 150 mg Tafinlar plus 1 mg Mekinist combination, and
Median PFS was 7.3 months (95% CI: 5.5, 9.4) for patients treated with 150 mg Tafinlar monotherapy.
Randomised open label study in BRAFi-treatment-naïve patients.

MEK116513 (COMBI-v, phase III study).

Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing Tafinlar and Mekinist combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of the study was OS (see Figure 3) 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 patients were randomised 1:1 to either the combination therapy arm (Tafinlar 150 mg twice daily and Mekinist 2 mg once daily) or the vemurafenib monotherapy arm (960 mg twice daily). Most patients were white (> 96%) and male (55%), with a median age of 55 years (24% were ≥ 65 years). The majority of patients had Stage IV M1c disease (61%). Most patients had LDH ≤ ULN (67%), ECOG performance status of 0 (70%), and visceral disease (78%) at baseline. Overall, 54% of patients had < 3 disease sites at baseline. The majority of patients had a BRAF V600E mutation (89%).
The final OS analysis demonstrated continued benefit for the combination of dabrafenib and trametinib compared with vemurafenib monotherapy; the median OS for the combination arm was approximately 8 months longer than the median OS for vemurafenib monotherapy (26.0 months versus 17.8 months) with 5 year survival rates of 36% (95% CI: 30.5, 40.9) for the combination versus 23% (95% CI: 18.1, 27.4) for vemurafenib monotherapy (Table 21, Figure 3). The Kaplan-Meier OS curve appears to stabilise from 3 years to 5 years (see Figure 3).
Clinically meaningful improvements for the secondary endpoint of PFS were sustained over a 5 year timeframe in the combination arm compared to vemurafenib monotherapy. Clinically meaningful improvements were also observed for overall response rate (ORR) and a longer duration of response (DoR) was observed in the combination arm compared to vemurafenib monotherapy (see Table 21).
Randomised double-blind study in BRAFi-treatment-naïve patients.

MEK115306 (COMBI-d, phase III study).

MEK115306 (COMBI-d) was a Phase III, randomised, double-blind study comparing the combination of Tafinlar and Mekinist to Tafinlar 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 progression-free survival (PFS) with a key secondary endpoint of Overall Survival (OS). Patients were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ ULN) and BRAF mutation (V600E versus V600K).
Four hundred and twenty three patients were randomised 1:1 to either the combination therapy arm (Tafinlar 150 mg twice daily and Mekinist 2 mg once daily) (N = 211) or Tafinlar 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 (28% were ≥ 65 years). The majority of patients had an ECOG performance score of 0 (72%) and had Stage IVM1c disease (66%). Most patients had the BRAF V600E mutation (85%); the remaining 15% of patients had the BRAF V600K mutation. Patients with brain metastases were not included in the trial.
The final OS analysis demonstrated continued benefit for the combination of dabrafenib and trametinib compared with dabrafenib monotherapy; the median OS for the combination arm was approximately 7 months longer than for dabrafenib monotherapy (25.8 months versus 18.7 months) with 5 year survival rates of 32% (95% CI: 25.1, 38.3) for the combination versus 27% (95% CI: 20.7, 33.0) for dabrafenib monotherapy (Table 22, Figure 4). The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 4).
Clinically meaningful improvements for the primary endpoint of PFS were sustained over a 5-year timeframe in the combination arm compared to dabrafenib monotherapy. Clinically meaningful improvements were also observed for overall response rate (ORR) and a longer duration of response (DoR) was observed in the combination arm compared to dabrafenib monotherapy (Table 22).
BRF117277/ DRB436B2204 (COMBI-MB) Metastatic melanoma patients with brain metastases. The efficacy and safety of Tafinlar in combination with Mekinist in patients with BRAF mutant-positive melanoma that has metastasised to the brain was studied in a non-randomised, open label, multi-centre, Phase II study (COMBI-MB study).
A total of 125 patients were enrolled into four cohorts:
Cohort A: patients with BRAFV600E mutant melanoma with asymptomatic brain metastases without prior local brain-directed therapy and ECOG performance status of 0 or 1.
Cohort B: patients with BRAFV600E mutant melanoma with asymptomatic brain metastases with prior local brain-directed therapy and ECOG performance status of 0 or 1.
Cohort C: patients with BRAFV600D/K/R mutant melanoma with asymptomatic brain metastases, with or without prior local brain-directed therapy and ECOG performance status of 0 or 1.
Cohort D: patients with BRAFV600D/E/K/R mutant melanoma with symptomatic brain metastases, with or without prior local brain-directed therapy and ECOG performance status of 0 or 1 or 2.
The primary endpoint of the study was intracranial response in Cohort A, defined as the percentage of patients with a confirmed intracranial response assessed by the investigator using modified Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Efficacy results are summarised in Table 23. Secondary endpoints were duration of intracranial response, ORR, PFS and OS. Efficacy results are summarised in Table 23.

Study BRF115532/ DRB436F2301 (COMBI-AD).

The efficacy and safety of Tafinlar in combination with Mekinist was studied in a Phase III, multicentre, randomised, double-blind, placebo-controlled study in patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
Patients were randomised 1:1 to receive either dabrafenib and trametinib combination therapy (Tafinlar 150 mg twice daily and Mekinist 2 mg once daily) or two placebos for a period of 12 months. Enrolment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomisation. Any prior systemic anticancer treatment, including radiotherapy, was not allowed. Patients with a history of prior malignancy, if disease free for at least 5 years, were eligible. Patients presenting with malignancies with confirmed activating RAS mutations were not eligible. Patients were stratified by BRAF mutation status (V600E or V600K) and stage of disease prior to surgery (by Stage III sub-stage, indicating different levels of lymph node involvement and primary tumour size and ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), defined as the time from randomisation to disease recurrence or death from any cause. Radiological tumour assessment was conducted every 3 months for the first two years and every 6 months thereafter, until first relapse was observed. Secondary endpoints include overall survival (OS; key secondary endpoint) and distant metastasis-free survival (DMFS).
A total of 870 patients were randomised to the combination therapy (n=438) and placebo (n=432) arms. Most patients were Caucasian (99%) and male (55%), with a median age of 51 years (18% were ≥ 65 years). The study included patients with all sub-stages of Stage III disease prior to resection; 18% of these patients had lymph node involvement only identifiable by microscope and no primary tumour ulceration. The majority of patients had a BRAF V600E mutation (91%). At the time of the primary analysis, the median duration of follow-up (time from randomisation to last contact or death) was 2.83 years in the dabrafenib and trametinib combination arm and 2.75 years in the placebo arm.
Results for the primary analysis of RFS are presented in Table 24. The study showed a statistically significant difference for the primary outcome of RFS between treatment arms, with an estimated 53% risk reduction in the dabrafenib and trametinib combination arm as compared to the placebo arm (HR=0.47; 95% CI: 0.39, 0.58; p=1.53 x 10-14). Results were consistent across subgroups, including stratification factors for disease stage and BRAF V600 mutation type. Median RFS was 16.6 months for the placebo arm and was not reached for the combination arm at the time of the primary analysis.
Based on updated data with an additional 29 months of follow-up compared to the primary analysis (minimum follow-up of 59 months), the RFS benefit was maintained with an estimated HR of 0.51 ([95% CI: (0.42, 0.61)] (Figure 5). The 5-year RFS rate was 52% (95% CI: 48, 58) in the combination arm compared to 36% (95% CI: 32, 41) in the placebo arm.
Based on 153 events (60 (14%) in the combination arm and 93 (22%) in the placebo arm) corresponding to a 26% information fraction of the total target of 597 OS events, the estimated hazard ratio for OS was 0.57 (95% CI: 0.42, 0.79; p=0.0006). These results did not meet the pre-specified boundary to claim statistical significance at this first OS interim analysis (HR=0.50; p=0.000019). Survival estimates at 1 and 2 years from randomisation were 97% and 91% in the combination arm and 94% and 83% in the placebo arm, respectively. The Kaplan-Meier curve for this OS interim analysis is shown in Figure 6.
Locally advanced or metastatic anaplastic thyroid cancer (ATC).

Study BRF117019/ CDRB436X2201.

The efficacy and safety of Tafinlar in combination with Mekinist was studied in a Phase II, nine-cohort, multicentre, non-randomised, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic anaplastic thyroid cancer (ATC).
The study had pre-specified interim analyses that were performed approximately every 12 weeks. Patients received Tafinlar 150 mg twice daily and Mekinist 2 mg once daily. The primary endpoint was the investigator-assessed overall response rate (ORR) using the 'Response Evaluation Criteria In Solid Tumors' (RECIST 1.1 assessed by the investigator). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. ORR, DoR, and PFS were also assessed by an Independent Review Committee (IRC).
Thirty-six patients were enrolled and were evaluable for response in the ATC cohort. The median age was 71 years (range: 47 to 85); 44% were male, 50% white, 44% Asian; and 94% had ECOG performance status of 0 or 1. Prior anti-cancer treatments included surgery (n=30, 83%), external beam radiotherapy (n=30, 83%), and systemic therapy (n=24, 67%) for ATC. Central laboratory testing confirmed the BRAF V600E mutation in 33 patients (92%).
For the primary endpoint, the investigator-assessed ORR was 56% (95% CI: 38.1, 72.1) in the ATC cohort. The ORR results assessed by IRC and investigator-assessment were consistent (Table 25).
Responses were durable with a median DoR in the ATC cohort of 14.4 months (95% CI: 7.4, 43.6) by investigator assessment, and a median PFS of 6.7 months (95% CI: 4.7, 13.8). For ATC patients, the median OS was 14.5 months (95% CI: 6.8, 23.2). Kaplan-Meier estimate of overall survival at 12 months for ATC patients was 51.7% (95% CI: 33.6, 67.1).
Advanced NSCLC.

Study E2201 (BRF113928).

The efficacy and safety of Tafinlar in combination with Mekinist was studied in a Phase II, three-cohort, multicentre, non-randomised, open-label study enrolling patients with Stage IV BRAF V600E mutant NSCLC.
The primary endpoint was the investigator-assessed overall response rate (ORR) using the 'Response Evaluation Criteria In Solid Tumors' (RECIST 1.1 assessed by the investigator). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety 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 (Tafinlar 150 mg twice daily): 84 patients enrolled. 78 patients had previous systemic treatment for their metastatic disease.
Cohort B (n=57): Combination therapy (Tafinlar 150 mg twice daily and Mekinist 2 mg once 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 (Tafinlar 150 mg twice daily and Mekinist 2 mg once daily): 34 patients enrolled (note: the two patients from Cohort B that did not have any previous systemic treatment were included in the analysis for patients enrolled in Cohort C for a total of 36 patients). All patients received study medication as first-line treatment for metastatic disease.
Among the total of 93 patients who were enrolled in the combination therapy in Cohorts B and C most patients were Caucasians (n = 79, 85%). There was a similar female to male ratio (54% vs 46%). The median age was 64 years in patients who had at least one prior therapy and 68 years in patients who were treatment naïve for their advanced disease. Most patients (n=87, 94%) enrolled in the combination therapy treated Cohorts had an ECOG performance status of 0 or 1. Twenty-six (26) patients (28%) had never smoked. Ninety-one (91) patients (97.8%) had a non-squamous histology. In the pre-treated population, 38 patients (67%) had one line of systemic anti-cancer therapy for metastatic disease.
At the time of the primary analysis, 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 Tafinlar for both NSCLC populations was less than or equal to 30%.
The efficacy of the combination with Mekinist was superior when indirectly compared to Tafinlar monotherapy in Cohort A. The final analysis of efficacy performed 5 years after last subject first dose is presented in Table 26.
Pyrexia management analysis.

Other studies study CPDR001F2301 (COMBI-i) and study CDRB436F2410 (COMBI-Aplus).

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

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

Study DRB436G2201.

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

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

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

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

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

5.2 Pharmacokinetic Properties

The pharmacokinetics of Tafinlar were determined in patients with BRAF mutation positive metastatic melanoma after single dose and after repeat dosing at 150 mg twice daily with dosing approximately 12 hours apart.

Absorption.

Tafinlar is absorbed orally with median time to achieve peak plasma concentration of 2 hours post-dose. Mean absolute bioavailability of oral Tafinlar is 95% (90% CI: 81, 110%). Tafinlar exposure (Cmax and AUC) increased in a dose proportional manner between 75 and 150 mg following single dose administration, but the increase was slightly less than dose-proportional after repeat twice daily dosing. There was a decrease in exposure observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios averaged 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0-τ) and predose concentration (Cτ) at steady state were 1,478 nanogram/mL, 4,341 nanogram*hr/mL and 26 nanogram/mL, respectively.

Effect of food on Tafinlar.

Administration of Tafinlar capsule with food reduced the bioavailability (Cmax and AUC decreased by 51% and 31%, respectively) and delayed absorption of Tafinlar capsules when compared to the fasted state. Patients should take Tafinlar as monotherapy or in combination with Mekinist at least one hour prior to or two hours after a meal due to the effect of food on Tafinlar absorption (see Section 4.2 Dose and Method of Administration).

Distribution.

The active in Tafinlar binds to human plasma protein and is 99.7% bound. The steady-state volume of distribution following intravenous microdose administration is 46 L.
Tafinlar is a substrate of human P-glycoprotein (Pgp) and murine BCRP in vitro. However, these transporters have minimal impact on Tafinlar oral bioavailability and elimination and the risk for clinically relevant drug-drug interactions with inhibitors of Pgp or BCRP is low.
Tafinlar is not an in vitro substrate of OATP1B1, OATP1B3, OATP2B1, OATP1A2 or OCT1 transporters.
Neither Tafinlar nor its 3 main metabolites were demonstrated to be inhibitors of Pgp in vitro.

Metabolism.

The metabolism of Tafinlar is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hours while the carboxy- and desmethyl-metabolites exhibited longer half-lives (21 to 22 hours). Mean metabolite to parent AUC ratios following repeat dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of Tafinlar; while the activity of carboxy-dabrafenib is not likely to be significant.

Excretion.

Terminal half-life following IV microdose is 2.6 hours. Tafinlar terminal half-life is 8 hours due to a prolonged terminal phase after oral administration. IV plasma clearance after single dose is 12 L/hour. Following repeat oral dose administration, the oral clearance (CL/F) is 35 L/hour.
Faecal excretion mediated via CYP3A4 and CYP2C8 metabolism is the major route of elimination after oral dose, accounting for 71% of a radioactive dose while urinary excretion accounted for 23% of radioactivity as metabolites.

Special patient populations.

Hepatic impairment.

A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels (based on National Cancer Institute [NCI] classification) do not significantly affect Tafinlar oral clearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have a significant effect on Tafinlar metabolite plasma concentrations. No data are available in patients with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of Tafinlar and its metabolites, administration of Tafinlar should be undertaken with caution in patients with moderate to severe hepatic impairment (see Section 4.2 Dose and Method of Administration).

Renal impairment.

A population pharmacokinetic analysis suggests that mild renal impairment does not affect oral clearance of Tafinlar. Although data in moderate renal impairment are limited these data may indicate no clinically relevant effect. No data are available in patients with severe renal impairment (see Section 4.2 Dose and Method of Administration).

Paediatric use.

The pharmacokinetics of dabrafenib in glioma and other solid tumours were evaluated in 243 paediatric patients (1 to < 18 years old) following single or repeat weight-adjusted dosing. Pharmacokinetic characteristics (drug absorption rate, metabolite ratios, drug clearance) of dabrafenib in paediatric patients are comparable to those of adults. Weight was found to influence dabrafenib oral clearance. The pharmacokinetic exposures of dabrafenib at the recommended weight-adjusted dosage in paediatric patients were within range of those observed in adults.

Use in the elderly.

Based on the population pharmacokinetic analysis, age had no significant effect on Tafinlar pharmacokinetics. Age greater than 75 years was a significant predictor of carboxy- and desmethyl-dabrafenib plasma concentrations with a 40% greater exposure in patients ≥ 75 years of age, relative to patients < 75 years old.

Body weight and gender.

Based on the population pharmacokinetic analysis, gender and weight were found to influence Tafinlar oral clearance; weight also impacted oral volume of distribution and distributional clearance. These pharmacokinetic differences were not considered clinically relevant for adult patients.

Race/ ethnicity.

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

5.3 Preclinical Safety Data

Genotoxicity.

Tafinlar was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.

Carcinogenicity.

Carcinogenicity studies with Tafinlar have not been conducted. An increase in cutaneous malignancies has been observed with BRAF inhibitors with preliminary evidence suggesting this occurs in patients harbouring other MAPK pathway mutations, including RAS, in skin (see Section 4.4 Special Warnings and Precautions for Use, Cutaneous squamous cell carcinoma (cuSCC), New primary melanoma, Non-cutaneous malignancy).

6 Pharmaceutical Particulars

6.1 List of Excipients

Hard capsule.

Tafinlar capsules contain the following inactive ingredients: microcrystalline cellulose, magnesium stearate (vegetable source), colloidal anhydrous silica, iron oxide red, titanium dioxide, hypromellose, iron oxide black, shellac, butan-1-ol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.

Dispersible tablet.

Tafinlar dispersible tablets contain the following ingredients: mannitol, microcrystalline cellulose, crospovidone, hypromellose, acesulfame potassium, magnesium stearate, artificial berry flavour 59454 AP0551 (Proprietary Ingredient No. 4614), colloidal anhydrous silica.

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

Hard capsule.

Store Tafinlar capsules below 30°C. Store in the original container in order to protect from light and moisture.

Dispersible tablet.

Store Tafinlar dispersible tablets below 25°C. Store in original container in order to protect from moisture. Do not remove desiccant.

6.5 Nature and Contents of Container

Hard capsule.

Tafinlar capsules are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures. The packs contain either 28* or 120 capsules and a dessicant.

Dispersible tablet.

Tafinlar dispersible tablets are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures. The bottles contain 210 dispersible tablets and a desiccant. There are either 1 or 2 bottles in a carton. Two dosing cups are provided in the carton.
* Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


CAS number.

Chemical Abstracts Service (CAS) number: 1195768-06-9.
Chemical name: N-{3-[5-(2-amino-4-pyrimidinyl)-2- (1,1-dimethylethyl)-1,3- thiazol-4-yl]-2- fluorophenyl}-2,6- difluorobenzenesulfonamide, methane sulfonate salt.
Molecular formula: C23H20F3N5O2S2.CH4O3S.
Molecular weight: 615.68.
Dabrafenib mesilate is a nitrogen- and sulphur-containing heterocycle possessing an aromatic sulphonamide. It is a white to slightly coloured solid. In aqueous media, dabrafenib mesilate is very slightly soluble at pH 1, and practically insoluble above pH 4. The pKa of the sulphonamide moiety is 6.6, the pKa of the pyrimidine moiety is 2.2 and the pKa of the thiazole moiety is -1.5. The partition coefficient (log P) is 2.9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes