Consumer medicine information

Zelboraf

Vemurafenib

BRAND INFORMATION

Brand name

Zelboraf

Active ingredient

Vemurafenib

Schedule

SUMMARY CMI

Zelboraf^®

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.

1. Why am I using Zelboraf?

Zelboraf contains the active ingredient vemurafenib. Zelboraf is used to treat a type of skin cancer called melanoma that has spread to other parts of the body. For more information, see Section 1. Why am I using Zelboraf? in the full CMI.

2. What should I know before I use Zelboraf?

Do not use if you have ever had an allergic reaction to Zelboraf 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 Zelboraf? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Zelboraf 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 Zelboraf?

Take Zelboraf exactly as prescribed by your doctor. The recommended dose is 4 tablets twice a day. Take 4 tablets in the morning, then 4 tablets in the evening, about 12 hours later.

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

5. What should I know while using Zelboraf?

Things you should do	Remind any doctor (including a surgeon or anaesthetist), dentist or pharmacist you visit that you are using Zelboraf. Tell your doctor straight away if you become pregnant or have changes to your vision while taking Zelboraf. Check your skin and tell your doctor right away about any changes. Avoid going out in the sun. Tell your doctor if you feel your medicine is not helping your condition.
Things you should not do	Do not stop taking Zelboraf or change the dose without first checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays.
Driving or using machines	Be careful driving or operating machinery until you know how Zelboraf affects you. If Zelboraf affects your vision, consult your doctor before driving or operating machinery. Zelboraf may affect your vision.
Looking after your medicine	Keep your tablets in the blister pack until it is time to take them. Keep the tablets in a cool dry place where the temperature stays below 30°C. Do not store Zelboraf in the bathroom or near a sink. Do not leave it on a window sill or in the car.

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

6. Are there any side effects?

This medicine helps most people who have metastatic melanoma, but it may have unwanted side effects in some people (see the full CMI for more details). Tell your doctor or pharmacist if you notice any of the following and they worry you. Common side effect may include diarrhoea, constipation, nausea, vomiting, fever, chills, cough, fatigue, sunburn or sun sensitivity, skin problems including rashes, itching, dry or scaly skin, and skin problems including warts. Tell your doctor or nurse immediately or go to the nearest hospital Emergency Department if you experience signs or symptoms of a serious allergic reaction such as swelling of the face, lips, tongue or other parts of the body, shortness of breath or difficulty breathing, rash, itching or hives on the skin. Some other serious side effects may include blisters or peeling skin, bleeding, dizziness, heart problems and/or vision problems. 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.

FULL CMI

Zelboraf^® (ZEL-bor-af)

Active ingredient(s): vemurafenib

Consumer Medicine Information (CMI)

This leaflet provides important information about using Zelboraf. 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 Zelboraf.

Where to find information in this leaflet:

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

1. Why am I using Zelboraf?

Zelboraf contains the active ingredient vemurafenib.

Zelboraf belongs to a group of medicines called anti-neoplastic (or anti-cancer) agents.

Zelboraf is used to treat metastatic melanoma (a type of skin cancer that has spread to other parts of the body). It can only be used if your melanoma has a change (mutation) in the BRAF gene. Your doctor will have tested you for this gene. This change has been shown to be involved in the development of melanoma.

Zelboraf works by targeting proteins made from the BRAF gene to slow down the development of your cancer.

Ask your doctor if you have any questions about why Zelboraf has been prescribed for you. Your doctor may have prescribed it for another reason.

Zelboraf is not addictive. This medicine is available only with a doctor's prescription.

2. What should I know before I use Zelboraf?

Warnings

Do not use Zelboraf if:

You are allergic to vemurafenib, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

The package is torn or shows signs of tampering. If the package is damaged, return it to your pharmacist for disposal.
The expiry date (EXP) printed on the pack has passed.

If you take this medicine after the expiry date has passed it may not work as well.

Check with your doctor if you:

1. You have a heart disorder

Your doctor will test to check that your heart is working properly before and during your treatment with Zelboraf. If necessary, your doctor may decide to interrupt your treatment temporarily or stop it altogether.

2. You have liver problems

Before and regularly during your treatment, your doctor will do some blood tests to monitor your liver function. If necessary, your doctor may decide to reduce your dose, interrupt your treatment temporarily or stop it altogether.

3. You have any problem with your kidneys.

Kidney problems may affect the activity of Zelboraf. Your doctor will do some blood tests to monitor your kidney function.

4. You have been told that you have low blood levels of potassium, calcium, or magnesium in your blood.

These levels may need to be corrected before treatment with Zelboraf begins.

5. You have been previously diagnosed with other types of cancer

6. You have previously received radiation treatment

7. You are allergic to any other medicines, foods, dyes or preservatives

If you have not told your doctor about any of the above, tell him or her before you start taking Zelboraf.

Zelboraf is not recommended for use in children and adolescents. The safety and effectiveness of Zelboraf in children younger than 18 years have not been established.

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?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Zelboraf is not recommended for use during pregnancy. There is no information about the safety of Zelboraf in pregnant women. However if there is a need to take Zelboraf when you are pregnant your doctor will discuss the risks and benefits to you and the unborn baby.

Women of childbearing potential and men should use adequate contraception during treatment and for 6 months after the end of treatment with Zelboraf.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether Zelboraf passes into breast milk. Breast-feeding is not recommended during treatment with Zelboraf.

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 Zelboraf and affect how it works. These include:

Ipilimumab, a medicine used to treat metastatic melanoma
warfarin, a medicine used to prevent blood clots
medicines that are mainly eliminated by or affect a metabolising protein called CYP3A4 such as;
- ketoconazole, itraconazole or voriconazole, medicines used to treat fungal infections
- atazanavir, saquinavir, ritonavir, nelfinavir or indinavir, medicines used to treat HIV infection
- phenytoin, carbamazepine or phenobarbital, medicines used to treat convulsions
- rifampicin, rifabutin, rifapentine, clarithromycin or telithromycin, medicines used to treat bacterial infections
- nefazodone or herbal medicines derived from St. John's Wort, used to treat depression
- some oral, injectable, or implantable contraceptives, for example "the Pill", used for birth control
medicines that are mainly eliminated by a metabolizing protein called CYP1A2 such as;
- caffeine, a stimulant
- olanzapine, clozapine, medicines used in treat schizophrenia and depression
- theophylline, a medicine used to treat asthma
- tizanidine, a medicine used as muscle relaxant
medicines that influence, or are affected by, a protein called P-glycoprotein such as;
- verapamil, a medicine used to treat high blood pressure and angina (chest pain)
- cyclosporin, a medicine used to suppress the immune system
- dronedarone or digoxin, medicines used treat heart problems
medicines that may affect your heartbeat such as:
- those used to treat heart rhythm problems, such as amiodarone
- those used to treat depression, such as amitriptyline or imipramine
- those used to treat bacterial infections, such as azithromycin and clarithromycin
- ondansetron or domperidone, medicines used to treat nausea and vomiting.
medicines that influence, or are affected by, a protein called BCRP such as:
- methotrexate, medicine used to treat arthritis and some types of cancer
- mitoxantrone, a medicine used to treat some types of cancer
- rosuvastatin, a medicine used to lower high cholesterol

These medicines may be affected by Zelboraf or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

4. How do I use Zelboraf?

How to use Zelboraf

Take Zelboraf exactly as your doctor has prescribed.
The recommended dose is 4 tablets twice a day. Take 4 tablets in the morning, then 4 tablets in the evening, about 12 hours later.
If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.
If you experience any side effects, your doctor may need to lower the dose to carry on your treatment.
Swallow the tablets whole with a glass of water.
Do not chew or crush the tablets.
Take Zelboraf on an empty stomach either at least 1 hour before or at least 2 hours after a meal in the morning and evening.
Food may interfere with the absorption of Zelboraf.
How long you will be treated with Zelboraf depends on how you are responding to treatment. Your doctor will discuss this with you.
Continue taking Zelboraf until your doctor tells you to stop.

When to take Zelboraf

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

If you vomit after taking Zelboraf

If you vomit after taking Zelboraf, do not take the same dose again. Then take the next dose at the usual time.

If you forget to use Zelboraf

Zelboraf should be used regularly at the same time each day. If you miss your dose at the usual time, take your dose as soon as you remember it.
If it is less than 4 hours before your next dose, skip the missed dose. Then take the next dose at the usual time.
Do not take a double dose to make up for a forgotten dose. This may increase the chance of getting an unwanted side effect.
If you are not sure what to do, ask your doctor or pharmacist.
If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much Zelboraf

If you think that you or anyone else has taken too much Zelboraf, you may need urgent medical attention. Keep the following telephone numbers handy.

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 Zelboraf?

Things you should do

If you are about to be started on any new medicine or start radiation treatment, remind your doctor and pharmacist that you are taking Zelboraf.
Tell any other doctors, dentists, and pharmacists who treat you that you are taking Zelboraf.
If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
Check your skin and tell your doctor right away about any changes such as a new wart, a skin sore or reddish bump, sore that bleeds or does not heal.
Regularly during treatment and for up to 6 months after your treatment, your doctor needs to check your skin for a type of cancer called cutaneous squamous cell carcinoma. There is a high risk of developing these skin cancers while taking Zelboraf.
In clinical trials, one in four patients developed these skin cancers. These skin cancers may develop as early as the first month of Zelboraf treatment. Factors that increase your risk of developing these cancers are being 65 years old or older, prior skin cancer and long-term sun exposure.
Usually, this change appears on sun damaged skin, remains local and can be cured by surgical removal. If your doctor finds this type of skin cancer, they may treat it or may send you to another doctor for treatment.
In addition, check your skin and tell your doctor right away about any changes.
You may develop new melanomas while taking Zelboraf. These lesions are usually removed by surgery and you can continue your treatment.
Avoid going out in the sun.
If you are taking Zelboraf you may become more sensitive to sunlight and get symptoms of sunburn (such as redness, itching, swelling and blistering) more easily or get sunburns that can be severe.
To help protect against sunburn, if you do plan to go into the sun wear clothing which protects your skin, including head, face, arms and legs. Use a broad spectrum (UVA/UVB) sunscreen and lip balm (minimum of SPF 30+, re-applied every 2 - 3 hours).
Women of childbearing potential and men should use adequate contraception during treatment and for 6 months after the end of treatment with Zelboraf.
Tell your doctor if you are breast-feeding while being treated with Zelboraf.
Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.
Tell your doctor if you feel your medicine is not helping your condition.
Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Things you should not do

Do not stop talking Zelboraf or change the dose without first checking with your doctor.
Do not let yourself run out of medicine over the weekend or on holidays.
Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.
Do not give Zelboraf to anyone else even if they have the same condition as you.
You should not breast-feed your infant during treatment with Zelboraf. It is not known whether Zelboraf crosses into human breast milk.

Driving or using machines

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

Zelboraf may affect the ability to drive or operate machinery due to side effects, which may be experienced while taking Zelboraf, as such

feeling tired
dizziness
eye problems.

Looking after your medicine

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.
Keep the tablets in a cool dry place where the temperature stays below 30°C.
Do not store Zelboraf or any other medicine in the bathroom, near a sink, on a window sill or in the car. Heat and dampness can destroy some medicines.
Follow the instructions in the carton on how to take care of your medicine properly.
Keep it where young children cannot reach it. A locked cupboard at least 1.5 m above the ground is a good place to store medicines.

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 effects

What to do

General signs and symptoms

fever
feeling tired (fatigue), unusual weakness or lacking energy
frequent infections such as fever, severe chills, sore throat or mouth ulcers
joint, muscle, or back pain
excess fluid (swelling), usually in the legs

Signs and symptoms of nervous system problems:

headache
tingling, burning feelings, or pain in your hands or feet
drooping eyelid and sagging muscles on one side of the face caused by a paralysed nerve in the face (often reversible)
thickening or appearance of visible cords, bands or lumps in the palm of one or both hands or feet

Signs and symptoms of skin problems:

sunburn or sun sensitivity
increased sensitivity to light
red skin rashes
itching
dry or scaly skin
hardened or thickened areas of the skin
painful red lumps or warts
hair loss

Signs and symptoms of respiratory problems:

coughing

Signs and symptoms of gastro-intestinal problems:

diarrhoea
nausea
vomiting
constipation
changes in the way things taste
loss of appetite and weight loss
sore mouth or mouth ulcers, inflammation of mucus membranes (stomatitis)

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Signs and symptoms of severe skin problems:

severe skin rash, itching, hives
severe blisters or bleeding of your lips, mouth, nose, or eyes
a severe skin reaction starting with painful red areas, then large blisters and ends with peeling of layers of skin. This is accompanied by fever and chills, aching muscles and generally feeling unwell.
fever associated with a mild to severe skin rash

Signs and symptoms of muscle damage:

muscle aches
dark coloured urine

Signs and symptoms of eye or vision problem:

blurred vision, loss of vision or other vision changes
irritated eyes
eye pain or redness
yellowing of the skin and eyes

Signs and symptoms of heart problems:

severe light headedness or dizziness or feel your heart is beating irregularly or fast
difficulty breathing, chest tightness or wheezing.
shortness of breath

Signs and symptoms of gastro-intestinal problems:

severe upper stomach pain, often with nausea and vomiting (signs of inflammation of the pancreas)
light coloured bowel motion

Signs and symptoms of systemic inflammatory disorder (sarcoidosis):

shortness of breath
cough
chest discomfort and/or pain
tender, painful, reddish bumps or patches on the skin
swollen and painful joints
swollen lymph nodes
eye pain
blurry vision and/or light sensitivity

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 Zelboraf contains

Active ingredient (main ingredient)	vemurafenib
Other ingredients (inactive ingredients)	croscarmellose sodium colloidal anhydrous silica magnesium stearate hydroxypropylcellulose hypromellose acetate succinate The film-coating contains: polyvinyl alcohol titanium dioxide CI77891 macrogol 3350 talc, purified iron oxide red CI77491
Potential allergen	None

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

What Zelboraf looks like

Zelboraf tablets are oval, biconvex, pinkish white to orange white tablets with "VEM" engraved on one side. (AUST R 183674)

Who distributes Zelboraf

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Medical enquiries: 1800 233 950

This leaflet was prepared in May 2025

Published by MIMS August 2025

BRAND INFORMATION

Brand name

Zelboraf

Active ingredient

Vemurafenib

Schedule

1 Name of Medicine

Vemurafenib.

2 Qualitative and Quantitative Composition

Each tablet contains 240 mg vemurafenib (as a coprecipitate of vemurafenib and hypromellose acetate succinate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablets.
Oval, biconvex, pinkish white to orange white tablets with "VEM" engraved on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Zelboraf is indicated for the treatment of unresectable stage IIIC or stage IV metastatic melanoma positive for a BRAF V600 mutation.

4.2 Dose and Method of Administration

Dose.

Before taking Zelboraf, patients must have BRAF V600 mutation positive tumour status confirmed by a TGA approved assay performed by a NATA accredited laboratory.
The recommended dose of Zelboraf is 960 mg (four 240 mg tablets) twice daily (equivalent to a total daily dose of 1920 mg). The first dose should be taken in the morning and the second dose should be taken in the evening approximately 12 hours later. Both doses of Zelboraf should be taken either at least 1 hour before or at least 2 hours after a meal.
Zelboraf tablets should be swallowed whole with a glass of water.
Zelboraf tablets should not be chewed or crushed.
It is recommended that treatment with Zelboraf continue until disease progression or the development of unacceptable toxicity (see Table 1 and Table 2).

Missed doses.

If a planned dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time.

Vomiting.

In case of vomiting after Zelboraf administration, the patient should not take an additional dose of the medicine but the treatment should be continued as usual.

Dose modifications.

Management of symptomatic adverse events or prolongation of QTc may require dose reduction, temporary interruption or treatment discontinuation of Zelboraf (see Section 4.4 Special Warnings and Precautions for Use). Dose modifications or interruptions are not recommended for cutaneous squamous cell carcinoma (cuSCC). Dose reductions resulting in a dose below 480 mg twice daily are not recommended.
Dose modifications should be made according to Table 1 and Table 2.

Special populations.

Paediatrics.

The safety and efficacy of Zelboraf in patients under the age of 18 years have not been established. Zelboraf is not approved for use in patients under the age of 18 years (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

Elderly.

In clinical trials, all patients received the same starting dose of Zelboraf independent of age. No dose adjustment is required in elderly patients aged 65 years and older (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). The potential need for dose adjustment in patients with severe hepatic impairment cannot be determined due to insufficient data. Cases of liver injury, including severe liver injury, have been reported with Zelboraf (see Section 4.4 Special Warnings and Precautions for Use, Liver injury for important information on monitoring and management).

Renal impairment.

No adjustment to the starting dose is required in patients with mild or moderate renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 5.2 Pharmacokinetic Properties). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data.

4.3 Contraindications

Zelboraf is contraindicated in patients with hypersensitivity to vemurafenib or to any of its excipients.

4.4 Special Warnings and Precautions for Use

General.

Before taking Zelboraf, patients must have BRAF V600 mutation positive tumour status confirmed by a TGA approved assay performed by a NATA accredited laboratory.
The efficacy and safety of Zelboraf in patients with tumours expressing BRAF V600 non-E mutations have not been convincingly established (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Malignancies.

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 Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects)). CuSCC usually occurred early in the course of treatment. Potential risk factors associated with cuSCC in Zelboraf clinical trials included age (≥ 65 years old), prior skin cancer, and chronic sun exposure. Cases of cuSCC were typically managed with simple excision, and patients were able to continue treatment without dose adjustment.
It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and be monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per local standard of care. Monitoring should continue for up to 6 months following discontinuation of Zelboraf or until initiation of another antineoplastic therapy.
Patients should be instructed to inform their physicians upon the occurrence of any skin changes, including rash and photosensitivity.

Noncutaneous squamous cell carcinoma (non-cuSCC).

In clinical studies rare cases of squamous cell carcinoma of the head and neck (tongue and tonsils) have been reported. Patients should undergo a head and neck examination, consisting of at least a visual inspection of oral mucosa and lymph node palpation prior to initiation of treatment and every 3 months during treatment. Pelvic (for women) and anal examinations are recommended before and at the end of treatment or when considered clinically indicated. As per routine disease management, chest CT scans performed prior to initiation of treatment and every 6 months during treatment should be reviewed for non-cuSCC. Following discontinuation of Zelboraf, monitoring for non-cuSCC should continue for up to 6 months or until initiation of another antineoplastic therapy. Abnormal findings should be evaluated as clinically indicated.

New primary malignant melanoma.

New primary malignant melanomas have been reported in clinical trials. Cases were managed with resection and patients continued on treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above for cutaneous squamous cell carcinoma.

Hypersensitivity reactions.

Serious hypersensitivity reactions, including anaphylaxis have been reported in association with Zelboraf and upon reinitiation of treatment (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). Severe hypersensitivity reactions included generalised rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, Zelboraf treatment should be permanently discontinued.

Dermatologic reactions.

Severe dermatologic reactions have been reported in patients receiving Zelboraf, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). In patients who experience a severe dermatologic reaction, Zelboraf treatment should be permanently discontinued.

Photosensitivity.

Mild to severe photosensitivity was reported in patients who were treated with Zelboraf in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). All patients should be advised to avoid sun exposure while taking Zelboraf. While taking Zelboraf, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sun screen and lip balm (SPF ≥ 30+) when outdoors to help protect against sunburn.
For photosensitivity, grade 2 (intolerable) or greater adverse events, dose modifications are recommended (see Section 4.2 Dose and Method of Administration).

Dupuytren's contracture and plantar fascial fibromatosis.

Dupuytren's contracture and plantar fascial fibromatosis have been reported with Zelboraf. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren's contracture have also been reported (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).
Events should be managed with dose reduction, treatment interruption, or with treatment discontinuation (see Section 4.2 Dose and Method of Administration, Dose modifications).

Ophthalmologic reactions.

Serious ophthalmologic reactions including uveitis have been reported in patients treated with Zelboraf. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Additionally, blurry vision, iritis, photophobia and retinal vein occlusion have been reported. Patients should be monitored routinely for ophthalmologic reactions, and be advised to urgently seek medical attention in the event of acute onset eye pain and/or change in visual acuity.

QT prolongation.

Exposure dependent QT prolongation was observed in an uncontrolled, open label phase II QT substudy in previously treated patients with metastatic melanoma (see Section 4.8 Adverse Effects (Undesirable Effects)). QT prolongation may lead to an increased risk of ventricular arrhythmias including torsade de pointes. Treatment with Zelboraf is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval.
ECG and electrolytes should be monitored before treatment with Zelboraf and after dose modification. Further monitoring should occur monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with Zelboraf is not recommended in patients with QTc > 500 ms. If, during treatment, the QTc exceeds 500 ms (CTCAE ≥ grade 3), Zelboraf treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Reinitiation of treatment should not occur until the QTc decreases below 500 ms and should be reinitiated at a lower dose, as described (see Section 4.2 Dose and Method of Administration, Dose modifications). Permanent discontinuation of Zelboraf treatment is recommended if, after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pretreatment values.

Pancreatitis.

Pancreatitis has been reported in Zelboraf treated subjects, generally occurring within two weeks after initiation of Zelboraf treatment. Unexplained abdominal pain should be promptly investigated, including appropriate diagnostic tests for pancreatitis. Patients should be closely monitored when restarting Zelboraf after an episode of pancreatitis.

Liver injury.

Liver injury, including cases of severe liver injury, has been reported with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).
Liver laboratory abnormalities may occur with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical trials). Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be measured before initiation of treatment and monitored monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or with treatment discontinuation (see Section 4.2 Dose and Method of Administration, Dose modifications).

Concurrent administration with ipilimumab.

In a phase I trial, asymptomatic grade 3 increases in transaminases and bilirubin were reported with concurrent administration of ipilimumab (3 mg/kg) and Zelboraf (960 mg twice daily or 720 mg twice daily). Based on these data, the concurrent administration of ipilimumab and Zelboraf is not recommended outside of a clinical trial.

Use in renal impairment.

Limited data are available in patients with renal impairment. A risk for increased exposure in patients with severe renal impairment cannot be excluded (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Other malignancies.

Based on its mechanism of action, Zelboraf may cause progression of cancers associated with RAS mutations (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). Zelboraf should be used with caution in patients with a prior or concurrent cancer associated with RAS mutation.

Use in hepatic impairment.

Limited data are available in patients with hepatic impairment. As vemurafenib is cleared by the liver, patients with severe hepatic impairment may have increased exposure (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). Cases of liver injury, including severe liver injury, have been reported with Zelboraf (see Section 4.4 Special Warnings and Precautions for Use, Liver injury for important information on monitoring and management).

Paediatric use.

The safety and efficacy of Zelboraf in paediatric patients below 18 years of age have not been established.

Use in the elderly.

Ninety-four (94) of 336 patients (28%) with unresectable or metastatic melanoma treated with Zelboraf in the phase III study were ≥ 65 years old. Elderly patients (≥ 65 years old) may be more likely to experience adverse events, including cuSCC, decreased appetite, and cardiac disorders. The effects of Zelboraf on overall survival, progression free survival and best overall response rate were similar in the elderly and younger patients (see Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

Creatinine.

Creatinine increases, mostly cases of mild (> 1-1.5 x ULN) to moderate (> 1.5 - 3 x ULN) and mostly reversible in nature, have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Serum creatinine should be measured before initiation of treatment and periodically monitored during treatment as clinically indicated. For recommended dose modifications, see Section 4.2 Dose and Method of Administration, Dose modifications.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of vemurafenib on other medicinal products.

CYP1A2 inhibition was observed when a single dose of caffeine (CYP1A2 substrate) was coadministered after repeat dosing with vemurafenib for 15 days. This resulted in a 2.6-fold increase (geometric mean ratio) (maximum 5-fold) in caffeine plasma exposure after vemurafenib treatment. In another clinical trial, vemurafenib increased AUC_last and AUC_inf of a single 2 mg dose of tizanidine (CYP1A2 substrate) approximately 4.2 and 4.7-fold, respectively. Vemurafenib may increase the plasma exposure of substances predominantly metabolised by CYP1A2 and dose adjustments should be considered for CYP1A2 substrates with narrow therapeutic indices (such as theophylline, tizanidine, neuroleptics, including clozapine, olanzapine, carbamazepine and phenytoin, tricycle antidepressants, methadone, cyclosporine and warfarin) if coadministration cannot be avoided.
When a single dose of dextromethorphan (CYP2D6 substrate) was coadministered after repeat dosing with vemurafenib for 15 days, the plasma AUC of dextromethorphan and its metabolite dextrorphan increased by 47% (geometric mean ratio). The reason for this is unknown but does not appear related to CYP2D6 inhibition.
CYP3A4 induction was observed when a single dose of midazolam (CYP3A4 substrate) was co-administered after repeat dosing with vemurafenib for 15 days. This resulted a 39% decrease (geometric mean ratio) (maximum 80%) in midazolam plasma exposure after vemurafenib treatment. Vemurafenib may decrease the plasma exposure of substances predominantly metabolised by CYP3A4 and dose adjustments should be considered for CYP3A4 substrates with narrow therapeutic indices. The efficacy of contraceptives metabolised by CYP3A4 may be decreased.
When a single dose of warfarin (CYP2C9 substrate) was coadministered after repeat dosing with vemurafenib for 15 days, some patients exhibited increased warfarin exposure (18% for S-warfarin by geometric mean ratio). Exercise caution and consider additional INR monitoring when vemurafenib is used concomitantly with warfarin.
Vemurafenib moderately inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown, but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot be excluded. Concomitant administration of CYP2C8 substrates with a narrow therapeutic window should be made with caution since vemurafenib may increase their concentrations.
Due to the long half-life of vemurafenib, the full modulatory effect of vemurafenib on a concomitant medicine might not be seen for 8 days. After ceasing vemurafenib, a washout of 8 days may be needed to avoid an interaction with a subsequent treatment.

Effects of other medicinal products on vemurafenib.

Vemurafenib is a substrate of CYP3A4 and, therefore, concomitant administration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Coadministration of rifampin, a strong CYP3A4 inducer, significantly decreased the plasma exposure of vemurafenib (AUC) by approximately 40% following a single 960 mg dose of vemurafenib (see Section 5.2 Pharmacokinetic Properties, Metabolism). Coadministration of itraconazole, a strong CYP3A4 inhibitor, increased steady state vemurafenib AUC by approximately 40%. Caution should be used when vemurafenib is co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inducers (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, phenobarbital, rifapentine, St John's wort [hypericin]). Dose reduction of vemurafenib may be considered during co-administration with a strong CYP3A4 inhibitor, if clinically indicated (see Section 4.2 Dose and Method of Administration, Dose modifications).

Interaction of vemurafenib with drug transport systems.

In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporter P-glycoprotein (P-gp). Clinical drug interaction study GO28394 using a P-gp substrate drug (digoxin) demonstrated that multiple oral doses of vemurafenib (960 mg twice daily) increased the exposure of a single oral dose of digoxin, with an approximately 1.8 and 1.5-fold increase in digoxin AUC_last and C_max, respectively. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates. Dose reduction of the concomitant P-gp substrate drug may be considered, if clinically indicated.
Vemurafenib is a weak P-gp substrate in vitro and its pharmacokinetics may be affected by medicines that inhibit or influence P-gp (e.g. verapamil, clarithromycin, ciclosporin, ritonavir, dronedarone, amiodarone, itraconazole, ranolazine). Concomitant administration of potent inducers of P-gp and vemurafenib should be avoided since the efficacy of vemurafenib may be reduced.
In vitro studies have demonstrated that vemurafenib is both a substrate and an inhibitor of breast cancer resistance protein (BCRP). The effects of vemurafenib on drugs that are substrates of BCRP, and the effects of P-gp or BCRP inducers and inhibitors on vemurafenib exposure are unknown but vemurafenib may increase the exposure of coadministered drugs that are substrates for BCRP.
In vitro, at clinically-relevant concentrations, vemurafenib was an inhibitor of the bile salt export pump (BSEP).
In vitro, vemurafenib was not a substrate for OATP1B1 or OATP1B3. It is unknown if vemurafenib is a substrate to other transport proteins.

Potentiation of radiation toxicity.

Cases of radiation recall and radiation sensitisation have been reported in patients treated with radiation either prior, during or subsequent to Zelboraf treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). In the majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day (hypofractionated regimens).
Zelboraf should be used with caution when given concomitantly or sequentially with radiation treatment. Most cases were cutaneous in nature but some cases involving visceral organs had fatal outcomes.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies have been conducted with Zelboraf. No histopathological findings were noted in male and female reproductive organs at subclinical systemic exposures in repeat-dose toxicology studies.
(Category D)
Women of childbearing potential and men should use effective contraception while receiving Zelboraf and for at least 6 months after discontinuation of Zelboraf.
Zelboraf is not recommended during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.
No clinical studies of Zelboraf in pregnant women have been performed, however placental transfer of vemurafenib to a fetus has been reported. Based on its mechanism of action, vemurafenib could cause fetal harm when administered to a pregnant woman. The teratogenic potential of vemurafenib has not been adequately evaluated in animal studies, although no unequivocal treatment related increases in the incidences of malformations were observed in the fetuses of rats at doses up to 250 mg/kg/day (approximately 1.4 times the human clinical exposure based on AUC) and rabbits at doses up to 450 mg/kg/day (approximately 0.5 times the human clinical exposure based on AUC).
It is not known whether Zelboraf is excreted in human breast milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or discontinue Zelboraf therapy after considering the benefits of breastfeeding for the child and the benefits of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Zelboraf on the ability to drive and use machines have been performed.
However, on the basis of reported adverse effects, Zelboraf may have a minor influence on the ability to drive and use machines. Fatigue, dizziness and eye problems may occur during treatment with Zelboraf (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Summary of the safety profile.

An estimated total of 6,300 patients have received Zelboraf in the clinical development program.
Adverse drug reactions (ADRs) were identified from two clinical trials, a phase III randomised, active controlled study in treatment naïve patients (n = 336) with BRAF V600 mutation positive unresectable or metastatic melanoma (NO25026) and a phase II study (NP22657) in patients with BRAF V600 mutation positive metastatic melanoma whom had failed at least one prior systemic therapy (n = 132).
In the phase III open label study (NO25026), patients randomised to the Zelboraf arm received a twice daily oral starting dose of 960 mg, and patients randomised to the active control arm received dacarbazine 1000 mg/m² administered intravenously every 3 weeks. At the time of analysis, the median duration of Zelboraf treatment was 6.6 months compared to 0.8 months for dacarbazine. The phase II study (NP22657) was an open label, uncontrolled, single arm study in which patients received Zelboraf 960 mg twice daily. The median treatment duration in this study was 5.7 months.
The most common ADRs of any grade (≥ 30% in either study) were arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea, diarrhoea, headache, pruritus, vomiting, skin papilloma and hyperkeratosis. The most common (≥ 5%) grade 3 ADRs were cuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. The incidence of grade 4 adverse reactions was ≤ 4% in both studies.
The incidence of adverse events resulting in permanent discontinuation of study medication in NO25026 was 7%. In NP22657, the incidence of adverse events resulting in permanent discontinuation of study medication was 3%.
Table 3 summarises the ADRs occurring in patients with melanoma and the frequency categories given are the highest incidence seen in any of the major clinical trials. ADRs are listed by MedDRA system organ class. The corresponding frequency category for each ADR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Gender.

The grade 3 adverse events reported more frequently in females than males were rash, arthralgia and photosensitivity (see Section 5.2 Pharmacokinetic Properties, Gender).
Description of selected ADRs from clinical trials.

Cutaneous squamous cell carcinoma (cuSCC) (see Section 4.4 Special Warnings and Precautions for Use).

In patients with unresectable or metastatic melanoma the incidence of cuSCC in Zelboraf treated patients across studies was approximately 20%. The majority of excised lesions reviewed by an independent central dermatopathology laboratory were classified as SCC-keratoacanthoma subtype or with mixed keratoacanthoma features (52%), both of which are a more benign, less invasive type of cuSCC. Most lesions classified as other (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis, cyst/benign cyst). CuSCC usually occurred early in the course of treatment. Among patients who developed cuSCC, the median time to onset ranged from 7.1 to 8.1 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Cases of cuSCC were typically managed with simple excision, and patients generally continued on treatment without dose modification.

Hypersensitivity reactions (see Section 4.4 Special Warnings and Precautions for Use).

A case of hypersensitivity reaction with rash, fever, rigors and hypotension 8 days after starting Zelboraf 960 mg twice daily was reported in a clinical trial. Similar symptoms were observed upon reinitiation of treatment with a single dose of 240 mg Zelboraf. The patient discontinued Zelboraf permanently and recovered without sequelae.

QT prolongation (see Section 4.4 Special Warnings and Precautions for Use).

Analysis of centralised ECG data from an open label uncontrolled phase II QT substudy in 132 patients treated with Zelboraf 960 mg twice daily showed a mean increase from baseline in QTc from day 1 (3.3 ms; upper 95% CI: 5 ms) to day 15 (12.8 ms; upper 95% CI: 14.9 ms). An exposure dependent QTc prolongation was observed in this study and the mean QTc effect remained stable between 12 and 15 ms beyond the first month of treatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed within the first 6 months of treatment (n = 90 patients). Two patients (1.5%) developed treatment emergent absolute QTc values > 500 ms (CTCAE grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of > 60 ms.
Modeling and simulation of QT prolongation resulted in the following estimates: for the 960 mg twice daily dose, the percentage of patients with QTcP (population correction formula) prolongation exceeding 60 ms was predicted to be 0.05%. This percentage was predicted to increase to 0.2%, for obese patients with BMI of 45 kg/m². The percentage of patients with a change from baseline in QTcP greater than 60 ms was predicted to be 0.043% for males and 0.046% for females. The percentage of patients with QTcP values above 500 ms was predicted to be 0.05% for males and 1.1% for females.

Laboratory abnormalities.

Liver laboratory abnormalities in the phase III clinical study are summarised in Table 4 as the proportion of patients who experienced a shift from baseline to grade 3 or 4.

Creatinine changes from baseline in the Phase III clinical study are summarised in Table 5.

Postmarketing experience.

The following ADRs have been identified from post-marketing experience with Zelboraf (Table 6) based on spontaneous case reports and literature cases. ADRs are listed according to system organ classes in MedDRA and any corresponding frequency category estimation for each ADR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Description of selected ADRs from postmarketing experience.

Acute kidney injury.

A broad spectrum of renal ADR cases has been reported with Zelboraf ranging from mild/moderate creatinine elevations to acute interstitial nephritis and acute tubular necrosis, some observed in the setting of dehydration events. In most cases, creatinine elevations appear to be reversible in nature (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration, Table 1).

Laboratory abnormalities.

Liver laboratory abnormalities including ≥ 5 times the upper limit of normal (ULN) for ALT, ≥ 2 times the ULN for ALP, and ≥ 3 times the ULN for ALT and simultaneous elevation of bilirubin concentration (> 2 times the ULN) have been reported in the post-marketing setting (see Section 4.4 Special Warnings and Precautions for Use).
Creatinine lab abnormalities were reported in the post marketing setting (see Section 4.4 Special Warnings and Precautions for Use).

Reporting of suspected adverse reactions.

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

There is no specific treatment for Zelboraf overdose.
Patients who develop adverse reactions should receive appropriate symptomatic treatment. Dose limiting toxicities for Zelboraf include rash with pruritus and fatigue.
In the event of suspected overdose, Zelboraf should be withheld and treatment should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE15.

Mechanism of action.

Zelboraf is a protein kinase inhibitor, selective for the activating mutation of the oncogenic BRAF serine-threonine kinase enzyme.
Vemurafenib is an inhibitor of BRAF serine-threonine kinase, and other kinases, such as CRAF, ARAF, SRMS, ACK1, MAP4K5 and FGR. Mutations in the BRAF gene result in constitutive activation of BRAF proteins, which can cause cell proliferation without associated growth factors.
Preclinical data generated in biochemical assays demonstrated that vemurafenib can inhibit BRAF kinases with activating codon 600 mutations (see Table 7).

This inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assays in available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assays the inhibitory concentration 50 (IC50) against V600 mutated cell lines (V600E, V600R, V600D and V600K mutated cell lines) ranged from approximately 0.015 to 1 microM whereas the IC50 against BRAF wild type cell lines were > 10 microM.

Clinical trials.

The efficacy of Zelboraf has been evaluated in 337 patients from a phase III randomised, active controlled clinical trial and 132 patients from a phase II single arm clinical trial. Prior to study enrolment, tumour specimens from all patients were tested for the presence of a BRAF V600 mutation using a real time polymerase chain reaction assay. During clinical trials the cobas 4800 BRAF V600 Mutation Test was used to assess the BRAF mutation status of DNA isolated from formalin fixed, paraffin embedded tumour tissue. Please refer to the package insert of the cobas 4800 BRAF V600 mutation test, or other approved test kits for detailed information.
Among the tumour specimens sequenced retrospectively from enrolled patients, the majority (92%) were BRAF V600E mutation-positive and 8% carried non-E mutations (primarily V600K). The efficacy and safety of Zelboraf in patients with tumours expressing BRAF V600 non-E mutations have not been convincingly established.

Treatment naïve patients (study NO25026, BRIM3).

An open label, multicenter, multinational, randomised phase III study supports the use of Zelboraf in previously untreated patients with BRAF V600 mutation positive unresectable stage IIIC or stage IV melanoma. In this study, patients were randomised to treatment with Zelboraf (960 mg, orally, twice daily) or dacarbazine (1000 mg/m² every 3 weeks, intravenously).
A total of 675 patients were randomised to Zelboraf (n = 337) or dacarbazine (n = 338). Randomisation was stratified according to disease stage, lactate dehydrogenase (LDH), ECOG performance status and geographic region. Baseline characteristics were well balanced between treatment groups. For patients randomised to Zelboraf, most patients were male (59%) and Caucasian (99%), the median age was 56 years (28% were ≥ 65 years old), all patients had ECOG performance status of 0 or 1, and the majority of patients had stage M1c disease (66%). The coprimary efficacy endpoints of the study were overall survival (OS) and progression free survival (PFS). Key secondary endpoints included confirmed best overall response rate (BORR) and response duration.
Statistically significant and clinically meaningful improvements were observed in the coprimary endpoints of OS (p < 0.0001) and PFS (p < 0.0001) (unstratified log-rank test) based on the prespecified interim analysis at the data cut off of 30 December 2010. The median follow-up time for OS in the Zelboraf group at the 30 December 2010 data cut off was 3.75 months (range 0.3 - 10.8 months) and in the dacarbazine group was 2.33 months (range < 0.1 - 10.3 months). At the time of analysis, Kaplan-Meier estimates of median OS for both treatment arms were considered unreliable due to the small number of patients in follow-up (< 10%) beyond month 7. The secondary endpoint of confirmed BORR [complete response (CR) + partial response (PR)], as assessed by the investigator, was significantly improved (p < 0.0001) in the Zelboraf arm (48.4%) (95% CI: 41.6%, 55.2%) compared to the dacarbazine arm (5.5%) (95% CI: 2.8%, 9.3%). There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the Zelboraf arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm. Stable disease assessed according to RECIST 1.1 was observed in 37% of Zelboraf treated patients and 24% of dacarbazine treated patients.
Improvement in OS, PFS and confirmed BORR in favour of Zelboraf treatment were generally observed across subgroups (age, sex, baseline LDH, ECOG performance status, metastatic disease stage) and geographic regions.
The proportion of patients with improvement in the physician's assessment of performance status was higher in the Zelboraf group (63.4%) (95% CI: 57%, 69%) than in the dacarbazine group (20.2%) (95% CI: 15%, 26%).
After the prespecified interim analysis with a December 30, 2010 data cut-off the study was modified to permit dacarbazine patients to cross over to receive Zelboraf. Post hoc survival analyses were undertaken thereafter as described in Table 8. At the time of the December 20, 2012 data cut-off analysis the median follow-up time in the Zelboraf arm was 13.4 months (range 0.4 to 33.3 months). The Kaplan-Meier estimate of median OS for Zelboraf was 13.6 months (95% CI: 12.0, 15.3). (See Figure 1.)

Table 9 and Figure 2 show the progression-free survival in treatment-naïve patients with BRAF V600 mutation positive melanoma.

Patients who failed at least one prior systemic therapy (study NP22657, BRIM2).

A phase II single arm, multicenter, multinational study was conducted in 132 metastatic melanoma patients with BRAF V600 mutation positive tumours who had received at least one prior therapy. Patients received 960 mg Zelboraf twice daily. The median age was 52 years old with 19% of patients being older than 65 years old. The majority of patients were male (61%), Caucasian (99%), and had stage M1c disease (61%). Forty-nine percent of patients had failed ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 - 11.3 months).
The primary endpoint of confirmed BORR (CR + PR) as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). The median time to response was 1.4 months, with 75% of responses occurring by 1.6 months of treatment.
Efficacy results are summarised in Table 10.

Patients with brain metastases.

An open-label, single-arm, multicenter, phase II study (n = 146) of Zelboraf was conducted in adult patients with histologically confirmed metastatic melanoma harbouring the BRAF V600 mutation and with brain metastases. Patients could be either symptomatic or asymptomatic for their brain metastases. The study included two simultaneously enrolling cohorts:
Previously untreated patients (cohort 1: n = 90): Patients who had not received previous treatment for brain metastases; prior systemic therapy for metastatic melanoma was allowed.
Previously treated patients (cohort 2: n = 56): Patients who had been previously treated for their brain metastases and had progressed following this treatment. For patients treated with stereotactic radiotherapy (SRT) or surgery, a new RECIST-assessable brain lesion must have developed following this prior therapy.
The median age of the patients was 54 years (range 26 to 83 years), and was similar in the two cohorts. The majority of patients were men (61.6%) and similarly distributed between the two cohorts. A total of 135 patients (92.5%) were reported as white, with the race of 11 patients (7.5%) not reported due to local regulations. The median number of brain target lesions at baseline was 2 (range 1 to 5), in both cohorts.
The primary objective of the study was to evaluate the efficacy of Zelboraf using best overall response rate (BORR) in the brain of metastatic melanoma patients with previously untreated brain metastases, as assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
Secondary objectives included an evaluation of the efficacy of Zelboraf using BORR in the brain of previously treated patients, duration of response (DOR), progression-free survival (PFS) and overall survival (OS) in patients with melanoma metastatic to the brain. (See Table 11.)

5.2 Pharmacokinetic Properties

The pharmacokinetic (PK) parameters for vemurafenib were determined using non compartmental analysis in a phase I and a phase III study. Mean C_max, C_min and AUC_0-12hr were approximately 62 microgram/mL, 53 microgram/mL and 600 microgram.h/mL, respectively. Population PK analysis using pooled data from 458 patients estimated the median of the steady-state C_max, C_min and AUC to be 62 microgram/mL, 59 microgram/mL and 734 microgram.h/mL, respectively. The median accumulation ratio estimate for a twice daily regimen is 7.36. The PK of vemurafenib is shown to be dose proportional between 240 and 960 mg twice daily dosing, and population PK analysis also confirmed that the PK of vemurafenib is linear.

Absorption.

Vemurafenib is absorbed with a median T_max of approximately 4 hours following a single 960 mg dose (four 240 mg tablets). Vemurafenib exhibits marked accumulation after repeat dosing at 960 mg twice daily with high interpatient variability. In the phase II study mean vemurafenib plasma concentration at 4 hours post dose increased from 3.6 microgram/mL on day 1 to 49.0 microgram/mL on day 15 (range 5.4 - 118 microgram/mL).
The bioavailability of vemurafenib at steady state was 57.8% (geometric mean).
At steady state (reached by day 15 in 80% of patients), the mean vemurafenib exposure in plasma is stable (concentrations before and 2 - 4 hours after the morning dose) as indicated by the mean ratio of 1.13. Similar marked interpatient variability in plasma exposure was observed at steady-state independent of dose reduction.
Following oral dosing, the absorption rate constant for the population of metastatic melanoma patients is estimated to be 0.19 hr^-1 (with 101% inter-patient variability).
Food (high fat meal) increases the relative bioavailability of a single 960 mg dose of vemurafenib. The geometric mean ratios between the fed and fasted states for C_max and AUC were 2.5 and 4.6 to 5.1-fold, respectively. The median T_max was increased from 4 to 7.5 hours when a single vemurafenib dose was taken with food. Safety and efficacy data from pivotal studies were collected from patients taking vemurafenib with or without food.
The effect of food on steady-state vemurafenib exposure is currently unknown.

Distribution.

The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is estimated to be 91 L (with 64.8% interpatient variability). It is highly bound to human plasma proteins in vitro (> 99%).

Metabolism.

The relative proportions of vemurafenib and its metabolites were characterised in a human mass balance study with a single dose of ¹⁴C-labeled vemurafenib administered orally at steady state.
On average, 95% of the dose was recovered within 18 days. The majority (94%) in faeces, with < 1% recovered in urine. While CYP3A4 is the primary enzyme responsible for the metabolism of vemurafenib in vitro, conjugation metabolites (glucuronidation and glycosylation) were also identified in humans. However, the parent compound was the predominant component (95%) in plasma. Although metabolism does not appear to result in a relevant amount of metabolites in plasma, the importance of metabolism for excretion cannot be excluded. Coadministration of rifampin, a strong CYP3A4 inducer, significantly decreased the plasma exposure of vemurafenib (AUC) by approximately 40% following a single 960 mg dose of vemurafenib, suggesting CYP3A4 pathway could be important elimination pathway for vemurafenib. Coadministration of itraconazole, a strong CYP3A4 inhibitor, increased steady state vemurafenib AUC by approximately 40%.

Excretion.

The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated to be 29.3 L/day (with 31.9% interpatient variability). The median of the individual elimination half-life estimates for vemurafenib is 56.9 hours (the 5^th and 95^th percentile range).