Consumer medicine information

Cotellic

Cobimetinib

BRAND INFORMATION

Brand name

Cotellic

Active ingredient

Cobimetinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cotellic.

SUMMARY CMI

COTELLIC®

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 COTELLIC?

COTELLIC contains the active ingredient cobimetinib. COTELLIC is used to treat a type of skin cancer called melanoma that has spread to other parts of the body and cannot be removed by surgery. For more information, see Section 1. Why am I using COTELLIC? in the full CMI.

2. What should I know before I use COTELLIC?

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

3. What if I am taking other medicines?

Some medicines may interfere with COTELLIC 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 COTELLIC?

  • Take COTELLIC exactly as prescribed by your doctor. The recommended dose is three tablets (a total of 60mg) once a day.
    COTELLIC is taken once daily for 21 days followed by a 7 day treatment break (no medicine) in a 28 day cycle. Start your next COTELLIC treatment cycle after the 7 day treatment break.
    More instructions can be found in Section 4. How do I use COTELLIC? in the full CMI.

5. What should I know while using COTELLIC?

Things you should do
  • Remind any doctor (including a surgeon or anaesthetist), dentist or pharmacist you visit that you are using COTELLIC.
  • Tell your doctor straight away if you become pregnant or have changes to your vision while taking COTELLIC.
  • Check your skin and tell your doctor right away about any changes. Avoid going out in the sun.
  • Avoid drinking grapefruit juice.
  • Tell your doctor if you feel your medicine is not helping your condition.
Things you should not do
  • Do not stop taking COTELLIC 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 COTELLIC affects you. If COTELLIC affects your vision, consult your doctor before driving or operating machinery. COTELLIC 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 COTELLIC 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 COTELLIC? in the full CMI.

6. Are there any side effects?

This medicine helps most people who have 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, nausea, vomiting, fever, chills, dehydration, anaemia, sunburn or sun sensitivity, skin problems including rashes, spots, itching, thickened areas of the skin, painful red lumps or 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, muscle aches/spasms/weakness, dark/reddish urine, 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

COTELLIC® (Kho-teh-lick)

Active ingredient(s): cobimetinib (kho-bee-meh-tin'ib)

Consumer Medicine Information (CMI)

This leaflet provides important information about using COTELLIC. 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 COTELLIC.

Where to find information in this leaflet:

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

1. Why am I using COTELLIC?

COTELLIC contains the active ingredient cobimetinib.
COTELLIC is belongs to a group of medicines called anti-neoplastic (or anti-cancer) agents.

COTELLIC is used to treat a type of skin cancer called melanoma that has spread to other parts of the body and cannot be removed by surgery.

COTELLIC is used in combination with another medicine called ZELBORAF® (containing the active ingredient vemurafenib).

COTELLIC can only be used if your melanoma has a change (mutation) in the BRAF gene. Your doctor will have tested you for this gene mutation to make sure COTELLIC is suitable for you. The gene mutation has been shown to be involved in the development of melanoma.

COTELLIC targets the "MEK" protein and ZELBORAF targets the changed "BRAF" protein. Both proteins are important in controlling cancer cell growth.

When used together, these medicines slow down the growth of your cancer.

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

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

2. What should I know before I use COTELLIC?

Warnings

As COTELLIC is taken together with ZELBORAF, also read the Consumer Medicine Information for ZELBORAF before you take these medicines.

Do not use COTELLIC if:

  1. You are allergic to cobimetinib (the active ingredient), 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.
  1. The package is torn or shows signs of tampering
  2. 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.

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

Check with your doctor if you:

  1. You have any eye problems
  • It is important your doctor is aware of any eye problems. You should see your doctor immediately for an eye exam if you experience new or worsening loss in vision or other eye problems while you are taking COTELLIC.
  1. You have any heart problems
  • Your doctor should do tests before you start taking COTELLIC and during your treatment to check the ability of the heart to pump blood sufficiently.
  1. You have any liver problems
  • Your doctor will perform some blood tests before and during your treatment to monitor your liver function. If necessary, your doctor may decide to reduce your dose, interrupt your treatment temporarily or stop it altogether.
  1. You have any medical conditions that increase your risk of bleeding
  2. You have any muscle problems
  3. You have any problems with your kidneys
  4. You have allergies to any other medicines, foods, preservatives or dyes

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

Safety and effectiveness of COTELLIC 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.

  • It is not known whether COTELLIC is harmful to an unborn baby when taken by a pregnant woman. COTELLIC is not recommended during pregnancy.

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

  • It is not known whether COTELLIC passes into breast milk. Your doctor will discuss the risks and benefits of taking COTELLIC if you are breast feeding or plan to breast feed.

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 COTELLIC and affect how it works. These include:

  • itraconazole, voriconazole, posaconazole, fluconazole and miconazole, medicines used to treat fungal infections
  • clarithromycin, erythromycin and rifampicin, medicines used to treat bacterial infections
  • ritonavir, cobicistat, lopinavir, and fosamprenavir, medicines used to treat HIV infection
  • amiodarone, a medicine to treat a heart rhythm problems
  • diltiazem and verapamil, medicines used to treat high blood pressure
  • imatinib, a medicine used to treat cancer
  • carbamazepine and phenytoin, medicines used to treat seizures
  • St. John's Wort, a herbal medicine used to treat depression.

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

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine. Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect COTELLIC.

4. How do I use COTELLIC?

How to use COTELLIC

  • Take COTELLIC exactly as your doctor has prescribed.
  • The recommended dose is three tablets (a total of 60 mg) once a day.
  • COTELLIC is taken once daily for 21 days followed by a 7 day treatment break (no drug) in a 28 day cycle. Start your next COTELLIC treatment cycle after the 7 day treatment break.
  • It is recommended you take ZELBORAF, as prescribed, during both the COTELLIC treatment phase AND the 7 day COTELLIC treatment break.
  • 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.
  • You can take COTELLIC with or without food
  • If you vomit after taking COTELLIC, do not take the same dose again. Continue to take COTELLIC as normal, the next day.
  • How long you will be treated with COTELLIC depends on how you are responding to treatment. Your doctor will discuss this with you.
  • Continue taking COTELLIC until your doctor tells you to stop.

When to use COTELLIC

  • 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 COTELLIC

  • Do not take the same dose again. Continue to take COTELLIC as normal, the next day.

If you forget to use COTELLIC

  • If it is more than 12 hours before your next dose, take the missed dose as soon as you remember.
  • If it is less than 12 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 the dose that you missed.
  • 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 COTELLIC

If you think that you or anyone else has taken too much COTELLIC, 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 COTELLIC?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking COTELLIC.
  • Tell any other doctors, dentists, and pharmacists who treat you that you are taking COTELLIC.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • Women who can get pregnant should use two effective forms of contraception to prevent pregnancy during treatment and for at least 3 months following the final dose.
  • Check your skin and tell your doctor right away about any changes.
  • Avoid going out in the sun.
  • If you are taking COTELLIC 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).
  • Avoid taking COTELLIC with grapefruit juice. Grapefruit juice can increase the amount of COTELLIC in your blood.
  • 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.

Call your doctor straight away if you:

  • Become pregnant while taking COTELLIC.
  • You have eye pain, swelling, redness, blurred vision, loss of vision, changes in colour, seeing a blurred outline around objects or other vision changes during your treatment. You should have your eyes immediately examined by your doctor if you experience eye problems while you are taking COTELLIC.
  • Notice changes in your skin, such as any crusty, non-healing sores; small lumps that are red, pale or pearly in colour; or new spots, freckles or any moles changing in colour. You may develop new skin cancers or skin lesions which are different from melanoma while taking COTELLIC. These cancers are usually removed by surgery and you can continue your treatment.

Things you should not do

  • Do not stop using this medicine suddenly without first checking with your doctor.
  • Do not use COTELLIC to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • 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 with a pharmacist.

Driving or using machines

  • Be careful before you drive or use any machines or tools until you know how COTELLIC affects you.
  • Be careful driving or operating machinery until you know how COTELLIC affects you. If COTELLIC affects your vision, consult your doctor before driving or operating machinery.
  • COTELLIC may affect your vision.

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 COTELLIC 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 one-and-a-half metres 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 effectsWhat to do
  • fever
  • chills
Signs and symptoms of low iron in your blood (anaemia):
  • tiredness
  • headaches
  • being short of breath when exercising
  • dizziness
  • looking pale
Signs and symptoms of dehydration:
  • dry or sticky mouth
  • low or no urine output
  • urine looks dark yellow
  • no tears
  • sunken eyes
Signs and symptoms of skin problems:
  • sunburn or sun sensitivity
  • rashes
  • spots
  • itching
  • dry or scaly skin
  • hardened or thickened areas of the skin
  • painful red lumps or warts
Signs and symptoms of respiratory problems:
  • coughing
Signs and symptoms of gastro-intestinal problems:
  • diarrhoea
  • nausea
  • vomiting
Some side effects can only be found when your doctor performs tests from time to time to check your progress, for example:
  • increased levels of liver enzymes or sugars in the blood
  • decreased levels of sodium or phosphate in the blood
  • increased levels of blood creatine phosphokinase, a marker of tissue damage
  • increased blood pressure (hypertension)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs and symptoms of severe skin problems:
  • a rash that covers a large area of your body
  • blisters
  • peeling skin
Signs and symptoms of muscle damage:
  • muscle aches
  • muscle spasms and weakness
  • dark, reddish urine
Signs and symptoms of a serious bleeding problem:
  • red or black stools that look like tar
  • blood in your urine or stools
  • unusual vaginal bleeding
  • headaches, dizziness, or feeling weak
Signs and symptoms of an allergic reaction:
  • 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
Signs and symptoms of heart problems:
  • persistent coughing or wheezing
  • shortness of breath
  • difficulty breathing
  • tiredness
  • increased heart rate
  • swelling of your ankles and feet
Signs and symptoms of severe eye or vision problems:
  • blurred vision, loss of vision or other vision changes
  • changes in colour
  • seeing a blurred outline around objects
  • eye pain, swelling or redness
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 COTELLIC contains

Active ingredient
(main ingredient)		cobimetinib (as a hemifumarate salt)
Other ingredients
(inactive ingredients)		microcrystalline cellulose (460)
croscarmellose sodium
magnesium stearate
polyvinyl alcohol
titanium dioxide (171)
macrogol 3350
purified talc
Potential allergenslactose monohydrate

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

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

What COTELLIC looks like

COTELLIC tablets are round and white with "COB" debossed on one side. (AUST R 237017).

Who distributes COTELLIC

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 20 April 2023

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Cotellic

Active ingredient

Cobimetinib

Schedule

S4

 

1 Name of Medicine

Cobimetinib fumarate.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains cobimetinib hemifumarate equivalent to 20 mg cobimetinib.

Excipients with known effect.

Each film-coated tablet contains 36 mg lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.
White, round film-coated tablets of approximately 6.6 mm diameter, with "COB" debossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Cotellic is indicated for use in combination with Zelboraf (vemurafenib) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutation.

4.2 Dose and Method of Administration

Dosage.

General.

Cotellic therapy should only be initiated and supervised by a healthcare professional experienced in the treatment of patients with cancer.
Patients treated with Cotellic in combination with Zelboraf must have BRAF V600 mutation positive melanoma tumour status confirmed by a validated test.
Please also see full product information for Zelboraf, which is used in combination with Cotellic.

Standard dosage.

The recommended dose of Cotellic is 60 mg (three 20 mg tablets) once daily for 21 days in a 28 day cycle.
Each Cotellic dose consists of three 20 mg tablets (60 mg) and should be taken once daily for 21 consecutive days (days 1 to 21 treatment period); followed by a 7 day break in Cotellic treatment (days 22 to 28 treatment break).
Each dose of three 20 mg tablets (60 mg) can be taken with or without food (see Section 5.2 Pharmacokinetic Properties). Cotellic tablets should be swallowed whole with water.

Duration of treatment.

Treatment with Cotellic should continue until the patient no longer derives benefit or until the development of unacceptable toxicity.

Delayed or missed doses.

If a dose of Cotellic is missed, it can be taken up to 12 hours prior to the next dose to maintain the once daily regimen.

Vomiting.

In case of vomiting after Cotellic administration, the patient should not take an additional dose of Cotellic on that day, and treatment should be continued as prescribed the following day.

Dose modification.

General. Cotellic dose modification should be based on the prescriber's assessment of individual patient safety or tolerability.
If doses are omitted for toxicity; missed doses should not be replaced.
Once the dose has been reduced, it should not be increased at a later time.
Dose modification of Cotellic is independent of Zelboraf dose modification. The decision on whether to reduce the dose of either or both drugs should be based on clinical assessment.
Table 1 gives general Cotellic dose modification advice.
Dose modification advice for specified adverse drug reactions.

Haemorrhage.

Grade 3 events: interrupt Cotellic treatment. There are no data on the effectiveness of Cotellic dose modification for haemorrhage events. Clinical judgment should be applied when considering restarting Cotellic treatment. Zelboraf dosing can be continued when Cotellic treatment is interrupted, if clinically indicated.
Grade 4 events or cerebral haemorrhage (all grades): interrupt Cotellic treatment. Permanently discontinue Cotellic for haemorrhage events attributed to Cotellic.

Left ventricular dysfunction.

Permanent discontinuation of Cotellic treatment should be considered if cardiac symptoms are attributed to Cotellic and do not improve after temporary interruption of Cotellic. See Table 2.
Zelboraf treatment can be continued when Cotellic treatment is modified (if clinically indicated).

Rhabdomyolysis and creatine phosphokinase (CPK) elevations.

Rhabdomyolysis or symptomatic CPK elevations: interrupt Cotellic treatment. If severity is improved by at least one grade within 4 weeks, restart Cotellic at a dose reduced by 20 mg, if clinically indicated. Zelboraf dosing can be continued when Cotellic treatment is modified, if clinically indicated.
If rhabdomyolysis or symptomatic CPK elevations do not improve within 4 weeks, permanently discontinue Cotellic treatment.
Asymptomatic CPK elevations: grade ≤ 3: Cotellic dosing does not need to be modified or interrupted to manage asymptomatic grade ≤ 3 creatine phosphokinase elevations (see Section 4.8 Adverse Effects (Undesirable Effects), Laboratory abnormalities).
Grade 4: interrupt Cotellic treatment. If improved to grade ≤ 3 within 4 weeks, restart Cotellic at a dose reduced by 20 mg, if clinically indicated. Zelboraf dosing can be continued when Cotellic treatment is modified, if clinically indicated. If CPK elevations do not improve to grade ≤ 3 within 4 weeks following dose interruption, permanently discontinue Cotellic treatment.
Dose modification advice for Cotellic when used with Zelboraf.

Liver laboratory abnormalities.

Grade ≤ 2: Cotellic and Zelboraf should be continued at the prescribed dose.
Grade 3: continue Cotellic at the prescribed dose. The dose of Zelboraf may be reduced as clinically appropriate. Please see full product information for Zelboraf.
Grade 4: interrupt Cotellic treatment and Zelboraf treatment. If liver laboratory abnormalities improve to grade ≤ 1 within 4 weeks, restart Cotellic at a dose reduced by 20 mg and Zelboraf at a clinically appropriate dose; please see full product information for Zelboraf. If liver laboratory abnormalities do not resolve to grade ≤ 1 within 4 weeks or if grade 4 liver laboratory abnormalities recur, discontinue Cotellic treatment and Zelboraf treatment.

Photosensitivity.

Grade ≤ 2 (tolerable): manage with supportive care.
Grade 2 (intolerable) or grade ≥ 3: Cotellic and Zelboraf should be interrupted until resolution to grade ≤ 1. Treatment can be restarted with no change in Cotellic dose. Zelboraf dosing should be reduced, please see full product information for Zelboraf.

Rash.

Rash events may occur with either Cotellic or Zelboraf treatment. The dose of Cotellic and/or Zelboraf may be either interrupted and/or reduced as clinically indicated.
Grade ≤ 2 (tolerable): manage with supportive care.
Grade 2 (intolerable) or grade ≥ 3: Acneiform rash. Follow general dose modification recommendations in Table 4 for Cotellic. Zelboraf dosing can be continued when Cotellic treatment is modified (if clinically indicated).
Nonacneiform or maculopapular rash. Cotellic dosing can be continued without modification (if clinically indicated). Zelboraf dosing may be either temporarily interrupted and/or reduced, please see full product information for Zelboraf.

Special dosage instructions.

Elderly patients.

No dose adjustment of Cotellic is required in patients ≥ 65 years of age.

Children.

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

Renal impairment.

No dose adjustment is recommended in patients with mild or moderate renal impairment, based on population pharmacokinetic analysis. The safety and efficacy of Cotellic have not been established in patients with severe renal impairment (see Section 5.2 Pharmacokinetic Properties). Cotellic should be used with caution in patients with severe renal impairment.

Hepatic impairment.

No dose adjustment is recommended in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties). Liver laboratory abnormalities can occur when Cotellic is used in combination with Zelboraf (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Cotellic is contraindicated in patients with known hypersensitivity to cobimetinib or any of the excipients.

4.4 Special Warnings and Precautions for Use

Please also see full product information for Zelboraf, which is used in combination with Cotellic.

Haemorrhage.

Haemorrhage, including major haemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with Cotellic (see Section 4.8 Adverse Effects (Undesirable Effects)).
Caution should be used in patients with additional risk factors for bleeding, such as brain metastases, and/or in patients that use concomitant medications that increase the risk of bleeding (including antiplatelet or anticoagulant therapy).
Prescribers should follow the dose modification guidance for haemorrhage management (see Section 4.2 Dose and Method of Administration).

Serous retinopathy.

Serous retinopathy (fluid accumulation within the layers of the retina) has been observed in patients treated with MEK inhibitors, including Cotellic (see Section 4.8 Adverse Effects (Undesirable Effects)). The majority of events were reported as chorioretinopathy or retinal detachment.
Median time to initial onset of serous retinopathy events was 1 month (range 0-9 months). Most events observed in clinical trials were resolved, or improved to asymptomatic grade 1, following dose interruption or reduction.
For patients reporting any symptoms of new or worsening visual disturbances, prompt ophthalmologic examination is recommended. If serous retinopathy is diagnosed, Cotellic treatment should be withheld until visual symptoms improve to grade ≤ 1. Serous retinopathy can be managed with treatment interruption, dose reduction or with treatment discontinuation (see Section 4.2 Dose and Method of Administration).

Left ventricular dysfunction.

Decrease in left ventricular ejection fraction (LVEF) from baseline has been reported in patients receiving Cotellic (see Section 4.8 Adverse Effects (Undesirable Effects)). Median time to initial onset of events was 4 months (1-13 months).
LVEF should be evaluated before initiation of treatment to establish baseline values, then after the first month of treatment and at least every 3 months or as clinically indicated until treatment discontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see Section 4.2 Dose and Method of Administration).
All patients restarting treatment with a dose reduction of Cotellic should have LVEF measurements taken after approximately 2 weeks, 4 weeks, 10 weeks and 16 weeks, and then as clinically indicated.
Patients with a baseline LVEF either below institutional lower limit of normal (LLN) or below 50% have not been studied.

Liver laboratory abnormalities.

Liver laboratory abnormalities can occur when Cotellic is used in combination with Zelboraf, and when Zelboraf is used as a single agent (please see full product information for Zelboraf).
Liver laboratory abnormalities, specifically increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), have been observed in patients treated with Cotellic plus Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitor for liver value abnormalities by liver laboratory tests before initiation of combination treatment and monthly during treatment, or more frequently as clinically indicated.
Manage grade 3 liver laboratory abnormalities with treatment interruption or dose reduction of Zelboraf. Manage grade 4 liver laboratory abnormalities with dose interruption, reduction or discontinuation of treatment of both Cotellic and Zelboraf (see Section 4.2 Dose and Method of Administration).

Rhabdomyolysis and CPK elevations.

Rhabdomyolysis has been reported in patients receiving Cotellic (see Section 4.8 Adverse Effects (Undesirable Effects)).
Interrupt treatment with Cotellic if rhabdomyolysis is diagnosed, and monitor CPK levels and other symptoms until resolution. Depending on the severity of rhabdomyolysis, dose reduction or treatment discontinuation may be required (see Section 4.2 Dose and Method of Administration).
Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, have been reported in patients receiving Cotellic with Zelboraf in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). The median time to first occurrence of grade 3 or 4 CPK elevations was 16 days (range: 11 days to 10 months); the median time to complete resolution was 16 days (range: 2 days to 15 months).
Serum CPK and creatinine levels should be measured before initiation of treatment to establish baseline values and then monitored monthly during treatment, or as clinically indicated. If serum CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, treatment interruption, dose reduction or treatment discontinuation may be required (see Section 4.2 Dose and Method of Administration).

Dermatological reactions.

Severe rash and other skin reactions can occur with Cotellic (see Section 4.8 Adverse Effects (Undesirable Effects)). Prescribers should follow the dosage modification recommendations for rash if events occur (see Section 4.2 Dose and Method of Administration).

Photosensitivity.

Photosensitivity, including severe cases, can occur with Cotellic, when used with Zelboraf (see Section 4.8 Adverse Effects (Undesirable Effects)).
Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30+) when outdoors. Manage photosensitivity with dose modification (see Section 4.2 Dose and Method of Administration).

Use in patients who have progressed on a BRAF inhibitor.

There are limited data in patients taking the combination of Cotellic with Zelboraf who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Use of Cotellic in this population should be guided by careful benefit/ risk assessment of the treatment and disease.

Use in the elderly.

Age does not have a clinically significant effect on the exposure of cobimetinib, based on a population pharmacokinetic analysis (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

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

Use in renal impairment.

No dose adjustment is recommended in patients with mild or moderate renal impairment, based on population pharmacokinetic analysis. The safety and efficacy of Cotellic have not been established in patients with severe renal impairment (see Section 5.2 Pharmacokinetic Properties).

Use in hepatic impairment.

No dose adjustment is recommended in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties). Liver laboratory abnormalities can occur when Cotellic is used in combination with Zelboraf (see Section 4.4 Special Warnings and Precautions for Use).

Effect of gender.

Gender does not have an effect on Cotellic exposure (see Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of concomitant medications on cobimetinib.

CYP3A inhibitors/ inducers.

Cobimetinib is metabolised by CYP3A. Cobimetinib AUC increased approximately 7-fold in the presence of a potent CYP3A inhibitor (itraconazole) in healthy subjects. Since cobimetinib is a sensitive substrate of CYP3A, it is likely that cobimetinib exposures will be significantly lower in the presence of CYP3A inducers. Therefore concomitant administration of potent CYP3A inducers and inhibitors is not recommended. Use of cobimetinib in the presence of moderate CYP3A inhibitors or inducers should be avoided where possible. Caution should be exercised when cobimetinib must be coadministered with moderate CYP3A inducers and inhibitors (see Section 4.2 Dose and Method of Administration for advice about reducing dose on the basis of adverse events).

Acid reducing agents.

Cobimetinib was administered in the presence of rabeprazole (a proton pump inhibitor) in healthy subjects to determine the effect of increased gastric pH. Cobimetinib pharmacokinetics were not altered and thus, gastric pH elevations do not affect cobimetinib absorption.

Effects of cobimetinib on concomitant medications.

CYP substrates.

In vitro data indicate that cobimetinib is an inhibitor of CYP3A and CYP2D6. A clinical drug-drug interaction study in cancer patients showed that plasma concentrations of midazolam (a sensitive CYP3A substrate) and dextromethorphan (a sensitive CYP2D6 substrate) were not altered in the presence of cobimetinib. Therefore cobimetinib can be coadministered with medications that are substrates of CYP3A and CYP2D6.

Other anticancer agents.

Zelboraf.

There is no evidence of any clinically significant drug-drug interaction between Cotellic and Zelboraf in unresectable or metastatic melanoma patients.

Interactions mediated by drug transport systems.

In vitro studies show that cobimetinib is a substrate but not an inhibitor of P-glycoprotein (P-gp). In vitro studies also show that cobimetinib is not a substrate of breast cancer resistance protein (BCRP) but is a weak to moderate inhibitor of BCRP.
In vitro studies show that cobimetinib is not a substrate of the liver uptake transporters OATP1B1, OATP1B3, or OCT1, however, it weakly inhibits these transporters. The clinical relevance of these findings has not been investigated.
Cobimetinib is not an inhibitor of OAT1, OAT3 or OCT2. It is unlikely that cobimetinib would alter the renal uptake or renal excretion of drugs that are substrates of these transporters.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No dedicated fertility studies in animals have been performed with Cotellic.
In toxicology studies, degenerative changes were observed in reproductive tissues including increased apoptosis/ necrosis of corpora lutea and seminal vesicle, epididymal and vaginal epithelial cells and follicular cysts of ovaries in rats, and apoptosis/ necrosis of epididymal epithelial cells in dogs at exposure ≥ 3 times the expected clinical exposure based on AUC. The effect of cobimetinib on human fertility is unknown.
(Category D)
Cotellic is not recommended during pregnancy.
There are no data regarding the use of Cotellic in pregnant women.
Use two effective forms of contraception during treatment with Cotellic and for at least three months following treatment discontinuation.
When administered to pregnant rats, cobimetinib caused embryolethality and foetal malformations of the great vessels and skull, and decreased ossification sites at clinically relevant exposures (systemic exposures approximately 0.9 to 1.4 times the human clinical plasma AUC exposure).
The safe use of Cotellic during labour and delivery has not been established.
 It is not known whether Cotellic is excreted in human breast milk. A risk to newborns/ infants cannot be excluded. A decision should be made whether to recommend breastfeeding or to administer Cotellic, taking into account the importance of the medicine to the mother.

4.7 Effects on Ability to Drive and Use Machines

Cotellic has influence on the ability to drive and use machines. Chorioretinopathy, blurred vision, or retinal detachment may occur during treatment with Cotellic (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be advised not to drive or use machines if they experience visual disturbances or any other adverse effects that may affect their ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety of Cotellic in combination with Zelboraf has been evaluated in 247 patients with advanced BRAF V600 mutated melanoma in the phase III study GO28141. The median time to onset of first grade ≥ 3 adverse events was 0.6 months in the Cotellic plus Zelboraf arm vs. 0.8 months in the placebo plus Zelboraf control arm.
The safety of Cotellic in combination with Zelboraf has also been evaluated in 129 patients with advanced BRAF V600 mutated melanoma in the phase Ib study NO25395. The safety profile of Cotellic in NO25395 was consistent with that observed in study GO28141.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions (ADRs) from clinical trials are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction 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 < 1/1000), very rare (< 1/10,000). See Table 3.

Description of selected adverse reactions.

Haemorrhage.

Bleeding events have been reported more frequently in the Cotellic arm than in the control arm (all types and grades: 13% vs. 7%). Higher frequencies in the Cotellic arm are given in Table 4.
The majority of events were grade 1 or 2 and nonserious (12% of patients in the Cotellic arm vs. 7% patients in the control arm). Most events resolved or were resolving with no change in Cotellic dose.
Grade 3 to 4 events were experienced by 1% of patients in each arm (see Section 4.4 Special Warnings and Precautions for Use).

Photosensitivity.

The majority of events were grades 1 or 2, with grade ≥ 3 events occurring in 4% of patients in the Cotellic arm vs. 0% in the control arm.
There were no apparent trends in the time of onset of grade ≥ 3 events. Grade ≥ 3 photosensitivity events in the Cotellic arm were treated with primary topical medication in conjunction with dose interruptions of both Cotellic and Zelboraf (see Section 4.2 Dose and Method of Administration).
No evidence of phototoxicity was observed with Cotellic as a single agent.

Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis.

In patients with unresectable or metastatic melanoma, cutaneous squamous cell carcinoma has been reported with a lower frequency in the Cotellic arm vs. the control arm (all grade: 3% vs. 13%). Keratoacanthoma has been reported with a lower frequency in the Cotellic arm vs. control arm (all grade: 2% vs. 9%). Hyperkeratosis has been reported with a lower frequency in the Cotellic arm vs. control arm (all grades: 11% vs. 30%).

Laboratory abnormalities.

See Table 5.

Post-marketing experience.

The following adverse drug reactions have been identified from postmarketing experience with Cotellic (Table 6). Adverse drug reactions are listed according to system organ classes in MedDRA and any corresponding frequency category estimation for each adverse drug reaction 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), not known (cannot be estimated from the available data).

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 experience with overdosage in human clinical trials. In case of suspected overdose, Cotellic should be withheld and supportive care instituted. There is no specific antidote for overdosage with Cotellic.
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/ Other antineoplastic agents/ Mitogen-activated protein kinase inhibitors, ATC code: L01EE02.

Mechanism of action.

The mitogen activated protein kinase (MAPK)/ extracellular signal regulated kinase (MEK) pathway is a key signaling pathway that regulates cell proliferation, cell cycle regulation, cell survival, angiogenesis, and cell migration.
Cobimetinib is an orally available inhibitor of MEK1 and MEK2 tyrosine threonine kinases. It has shown high inhibitory potency in biochemical and cell based assays, as well as antitumour activity in vivo in xenograft tumour models mutated for BRAF. Cobimetinib also showed efficacy in some KRAS mutant models.
In biochemical and structural studies, cobimetinib has been shown to interact with MEK in a manner that is less susceptible to the dynamic conformational changes seen with the phosphorylation state of MEK. As a result cobimetinib maintains binding affinity and inhibitory activity when MEK becomes phosphorylated. Due to this distinct allosteric mechanism of inhibition, cobimetinib has shown strong activity in cancer cell lines and tumours with high phosphorylated MEK levels, as is frequently observed in BRAF mutant tumours.
In preclinical studies, treatment of MAPK dysregulated cancer cells and tumours with cobimetinib results in inhibition of phosphorylation of ERK1/2, the only known substrates of MEK1/2. Functional mediation of the MAPK pathway is dependent upon ERK1/2 activity that phosphorylates protein targets in the cytoplasm and nucleus that induce cell cycle progression, cell proliferation, survival and migration. Cobimetinib therefore opposes the promitogenic and oncogenic activity induced by the MAPK pathway through inhibition of the MEK1/2 signaling node.
By simultaneously targeting BRAF and MEK the combination of vemurafenib and cobimetinib inhibits MAPK pathway reactivation through MEK1/2 resulting in stronger inhibition of signaling, greater tumour cell apoptosis and enhanced tumour responses in preclinical models than vemurafenib alone.

Clinical trials.

Study GO28141 (coBRIM).

Study GO28141 is a multicentre, randomised, double blind, placebo controlled, phase III study to evaluate the safety and efficacy of Cotellic in combination with Zelboraf compared to Zelboraf plus placebo, in patients with previously untreated BRAF V600 mutation positive unresectable locally advanced (stage IIIC) or metastatic melanoma (stage IV). Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from the study.
Key baseline characteristics included: 58% of patients were male, median age was 55 years (range 23 to 88 years), 60% had metastatic melanoma stage M1c and the proportion of patients with elevated lactate dehydrogenase (LDH) was 46.3% in the Cotellic plus Zelboraf arm and 43.0% in the placebo plus Zelboraf arm.
Following confirmation of a BRAF V600 mutation using the cobas 4800 BRAF V600 mutation test, 495 patients with unresectable locally advanced or metastatic melanoma were randomised to receive either:
Cotellic 60 mg once daily on days 1-21 of each 28 day treatment cycle and 960 mg Zelboraf twice daily on days 1-28.
Placebo once daily on days 1-21 of each 28 day treatment cycle and 960 mg Zelboraf twice daily on days 1-28.
Progression free survival (PFS) as assessed by the investigator (Inv) was the primary endpoint. Secondary efficacy endpoints included overall survival (OS), objective response rate, duration of response and PFS as assessed by an independent review facility (IRF).
Efficacy results are summarised in Table 7.
Additionally, in a post hoc analysis with a cutoff date of 16 January 2015, a median PFS benefit of 12.3 months (95% CI: 9.5, 13.4) was seen in the Cotellic plus Zelboraf arm compared to 7.2 months (95% CI: 5.6, 7.5) in the placebo plus Zelboraf arm [HR 0.58 (0.46, 0.72)]. The median follow-up of patients was 14.2 months. See Figures 1, 2, 3, and 4.
Global health status/ health related quality of life, symptom severity, and functional interference of symptoms by patient report were measured for each treatment arm using the EORTC QLQ-C30 questionnaire. Scores for all functioning domains (cognitive, emotional, social, role, and physical), and most symptoms (appetite loss, constipation, nausea and vomiting, dyspnoea, pain, fatigue) did not demonstrate a clinically meaningful change (< 10 point change from baseline) and were similar between the two treatment arms. Patients in the Cotellic plus Zelboraf arm reported significant worsening of diarrhoea from baseline at only cycle 1 day 15 and cycle 2 day 15 as measured by the EORTC QLQ-C30; but not at subsequent timepoints.

Study NO25395 (BRIM7).

The efficacy of Cotellic was evaluated in a phase Ib study, NO25395, which was designed to assess the safety, tolerability, pharmacokinetics and efficacy of Cotellic when added to Zelboraf for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (as detected by the cobas 4800 BRAF V600 mutation test).
This study treated 129 patients with Cotellic and Zelboraf: 63 were naïve to BRAF inhibitor (BRAFi) therapy and 66 patients had previously progressed on prior Zelboraf therapy. Within the BRAFi naïve patient population (n = 63), there were 20 patients (32%) who had received prior systemic therapy.
Results of the BRAFi naïve population from study NO25395 were generally consistent with those from study GO28141. The BRAFi naïve patients (n = 63) attained an 87% objective response rate, including a complete response in 10% of patients. The median duration of response was 12.5 months. The median PFS for BRAFi naïve patients was 13.7 months, with median follow-up time of 12.7 months.
Among patients who had progressed on Zelboraf (n = 66), the objective response rate was 15%, the median duration of response was 6.7 months and the median PFS was 2.8 months.

5.2 Pharmacokinetic Properties

Absorption.

Following oral dosing of 60 mg in cancer patients, cobimetinib showed a moderate rate of absorption with a median Tmax of 2.4 hours. The mean steady-state Cmax and AUC0-24 were 273 nanogram/mL and 4340 nanogram.h/mL respectively. The mean accumulation ratio at steady-state was approximately 2.4-fold.
Cobimetinib has linear pharmacokinetics in the dose range of ~3.5 mg to 100 mg.
The absolute bioavailability of cobimetinib was 45.9% (90% CI: 39.7%, 53.1%) in healthy subjects. A human mass balance study was conducted in healthy subjects, and showed that cobimetinib was extensively metabolised and eliminated in faeces. The fraction absorbed was ~88% indicating high absorption and first pass metabolism.
The pharmacokinetics of cobimetinib are not altered when administered in the fed state (high fat meal) compared with the fasted state in healthy subjects. Since food does not alter the pharmacokinetics of cobimetinib, it can be administered with or without food.

Distribution.

Cobimetinib is 94.8% bound to human plasma proteins in vitro. No preferential binding to human red blood cells was observed (blood to plasma ratio 0.93).
The volume of distribution (Vss) was 1050 L in healthy subjects given an intravenous (IV) dose of 2 mg. The apparent volume of distribution (Vss) was 806 L in cancer patients based on population PK analysis.

Metabolism.

Oxidation by CYP3A and glucuronidation by UGT2B7 appear to be the major pathways of cobimetinib metabolism. Cobimetinib is the predominant moiety in plasma. No oxidative metabolites greater than 10% of total circulating radioactivity or human specific metabolites were observed in plasma. Unchanged drug in faeces and urine accounted for 6.6% and 1.6% of the administered dose, respectively, indicating that cobimetinib is primarily metabolised with very little renal elimination.

Excretion.

Cobimetinib and its metabolites were characterised in a mass balance study in healthy subjects. On average, 94% of the dose was recovered within 17 days. Cobimetinib was extensively metabolised and eliminated in faeces; no single metabolite was predominant.
Following IV administration of a 2 mg dose of cobimetinib, the mean plasma clearance (CL) was 10.7 L/hr. The mean CL/F following oral dosing of 60 mg in cancer patients based on a population pharmacokinetic analysis was 13.4 L/hr.
The mean elimination half-life following oral dosing of cobimetinib was 43.6 hours (range: 23.1 to 69.6 hours).

Pharmacokinetics in special populations.

Based on a population pharmacokinetic analysis, gender, race, ethnicity, baseline ECOG, mild and moderate renal impairment did not affect the PK of cobimetinib. Baseline age and baseline bodyweight were identified as statistically significant covariates on cobimetinib clearance and volume of distribution respectively. However, sensitivity analysis suggests neither of these covariates had a clinically significant impact on steady-state exposure.

Gender.

Gender does not have an effect on the exposure of cobimetinib, based on a population pharmacokinetic analysis including 210 women and 277 men.

Elderly population.

Age does not have a clinically significant effect on the exposure of cobimetinib, based on a population pharmacokinetic analysis which included 133 patients ≥ 65 years of age.

Renal impairment.

Based on preclinical data and the human mass balance study, cobimetinib is mainly metabolised, with minimal renal elimination. No formal PK study has been conducted in patients with renal impairment.
A population PK analysis using data from 151 patients with mild renal impairment (creatinine clearance (CrCl) 60 to less than 90 mL/min), 48 patients with moderate renal impairment (CrCl 30 to less than 60 mL/min), and 286 patients with normal renal function (CrCl greater than or equal to 90 mL/min), showed that CrCl had no meaningful influence on exposure of cobimetinib.
Mild to moderate renal impairment does not influence cobimetinib exposure based on the population PK analysis. The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to limited data.

Hepatic impairment.

The pharmacokinetics of cobimetinib were evaluated in 6 subjects with mild hepatic impairment (Child-Pugh A), 6 subjects with moderate hepatic impairment (Child-Pugh B), 6 subjects with severe hepatic impairment (Child-Pugh C) and 10 healthy subjects. Exposures of total cobimetinib after a single dose were similar in subjects with mild or moderate hepatic impairment compared to healthy subjects; while subjects with severe hepatic impairment had lower exposures (AUC0-∞ geometric mean ratio of 0.69 compared to healthy subjects) which is not considered to be clinically significant. Exploratory analysis of unbound cobimetinib concentrations show that exposure of unbound cobimetinib in subjects with mild and moderate hepatic impairment were similar to subjects with normal hepatic function while subjects with severe hepatic impairment had 2-fold higher exposures.
Therefore, no dose adjustment is recommended when administering Cotellic to patients with hepatic impairment (see Section 4.2 Dose and Method of Administration).

QT prolongation.

No additive clinical effect on QT interval prolongation is observed when patients are treated with Cotellic in combination with Zelboraf. In vitro, cobimetinib produced moderate hERG ion channel inhibition (IC50 = 0.5 micromolar [266 nanogram/mL]), which is approximately 18-fold higher than peak plasma concentrations (Cmax) at the 60 mg dose (unbound Cmax = 14 nanogram/mL [0.03 micromolar]).

5.3 Preclinical Safety Data

Genotoxicity.

Standard genotoxicity studies with cobimetinib were all negative. Cobimetinib was assessed for genotoxicity in S. typhimurium and E. coli, in vitro in primary human lymphocytes, and in vivo in a rat bone marrow micronucleus assay.

Carcinogenicity.

No carcinogenicity studies have been performed to establish the carcinogenic potential of Cotellic.

Other toxicological information.

Toxicity studies in rats and dogs identified generally reversible degenerative changes in the bone marrow, gastrointestinal tract, skin, thymus, adrenal gland, liver, spleen, lymph node, kidney, heart, ovary, and vagina at plasma exposures below clinical efficacious levels.
Nonclinical studies revealed no other special hazard for humans based on conventional studies of safety pharmacology and genotoxicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate.
Tablet coating: Polyvinyl alcohol, titanium dioxide, macrogol 3350, purified talc.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Polyvinyl chloride/polyvinylidene chloride duplex blisters with an aluminium foil lidding containing 21 tablets.
Each pack contains 63 tablets.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Cobimetinib fumarate is described chemically as (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl] methanone hemifumarate. It has a molecular formula of 2(C21H21F3IN3O2).C4H4O4 and a molecular weight of 1178.7 g/mol.
Cobimetinib is a white to off-white solid. The solubility of cobimetinib is high in low pH media (> 10 mg/mL at pH 1.0). The dissociation constant for cobimetinib is 8.86 (corresponding to the piperidine cation), with a distribution coefficient of 2.42 at pH 7.4.

Chemical structure.


CAS number.

1369665-02-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes