Cotellic

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Cobimetinib hemifumarate 22.2 mg equivalent to cobimetinib 20 mg
Available from:
Roche Products (NZ) Ltd
INN (International Name):
Cobimetinib hemifumarate 22.2 mg (equivalent to cobimetinib 20 mg)
Dosage:
20 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Cobimetinib hemifumarate 22.2 mg equivalent to cobimetinib 20 mg Excipient: Croscarmellose sodium Lactose monohydrate Macrogol 3350 Magnesium stearate Microcrystalline cellulose Polyvinyl alcohol Purified talc Purified water Titanium dioxide
Prescription type:
Prescription
Manufactured by:
F Hoffmann-La Roche Ltd
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.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVDC/Al - 63 dose units - 60 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-9966
Authorization date:
2016-04-21

Read the complete document

COTELLIC 200625

COTELLIC

®

Cobimetinib

New Zealand Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about COTELLIC. It does

not contain all the available

information. It does not take the

place of talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking COTELLIC

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What COTELLIC is

used for

COTELLIC contains the active

ingredient cobimetinib.

COTELLIC 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.

Safety and effectiveness of

COTELLIC in children younger than

18 years have not been established.

Before you take

COTELLIC

As COTELLIC is taken together

with ZELBORAF, also read the

Consumer Medicine Information

for ZELBORAF before you take

these medicines.

When you must not take it

1.

Do not take COTELLIC if you

have an allergy to:

cobimetinib (active ingredient) or

any of the ingredients listed at the

end of this leaflet.

Some of the symptoms of an allergic

reaction may include:

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue

or other parts of the body

rash, itching or hives on the skin.

2.

The package is torn or shows

signs of tampering

3.

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.

Before you start to take it

Tell your doctor if:

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.

2. 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.

3. 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.

4.

You have any medical

conditions that increase your

risk of bleeding

COTELLIC 200625

5.

You have any muscle problems

6.

You have any problems with

your kidneys

7.

You are pregnant or plan 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.

8.

You are breast feeding or plan

to breast feed

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.

9.

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.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

bought without a prescription from

your pharmacy, supermarket or

health food shop.

Some medicines and COTELLIC

may interfere with each other. These

include:

itraconazole, voriconazole,

posaconazole, fluconazole and

miconazole, medicines used to

treat fungal infections

clarithromycin, erythromycin and

rifampicin, medicines used to

treat fungal 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.

How to take

COTELLIC

Follow all directions given to you

by your doctor or pharmacist

carefully.

They may differ from the

information contained in this leaflet.

How much to take

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.

How to take it

Swallow the tablets whole with a

glass of water.

You can take COTELLIC with or

without food.

When to take it

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 it

If you vomit after taking

COTELLIC, do not take the same

dose again. Continue to take

COTELLIC as normal, the next

day.

How long to take it

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.

If you forget to take it

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 take too much

(overdose)

Immediately telephone your doctor

or the Poisons Information Centre

(telephone 13 11 26 in Australia,

telephone 0800 764 766) for advice,

or go to Accident and Emergency

COTELLIC 200625

at the nearest hospital, if you think

that you or anyone else may have

taken too much COTELLIC. Do

this even if there are no signs of

discomfort or poisoning.

You may need urgent medical

attention.

Keep telephone numbers for these

places handy.

While you are using

COTELLIC

Things you must 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.

Tell your doctor straight away if

you become pregnant while taking

COTELLIC.

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.

Tell your doctor immediately if

you get 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.

Check your skin and tell your

doctor right away about any

changes.

Tell your doctor if you 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.

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.

Things you must not do

Do not stop taking COTELLIC or

change the dose 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.

Things to be careful of

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.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking

COTELLIC.

This medicine helps most people

who have melanoma, but it may have

unwanted side effects in some

people.

All medicines can have side effects.

Sometimes they are serious, most of

the time they are not. You may need

medical attention if you get some of

the side effects.

Do not be alarmed by the following

list of side effects. You may not

experience any of them.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor or pharmacist if

you notice any of the following and

they worry you:

diarrhoea

nausea

vomiting

fever

chills

COTELLIC 200625

symptoms of dehydration, such as

dry or sticky mouth, low or no

urine output, urine looks dark

yellow, no tears or sunken eyes

symptoms of anaemia, such as

tiredness, headaches, being short

of breath when exercising,

dizziness and looking pale

sunburn or sun sensitivity

coughing, difficulty breathing,

wheezing

skin problems including rashes,

spots, itching, dry or scaly skin,

hardened or thickened areas of

the skin, painful red lumps or

warts.

The above list includes the more

common side effects of COTELLIC.

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).

Tell your doctor immediately or go

to Accident and Emergency at

your nearest hospital if you notice

any of the following:

A rash that covers a large area of

your body, blisters, or peeling

skin.

Symptoms of muscle damage

such as:

muscle aches

muscle spasms and weakness

dark, reddish urine.

Symptoms of a serious bleeding

problem such as:

red or black stools that look

like tar

blood in your urine or stools

unusual vaginal bleeding

headaches, dizziness, or

feeling weak.

Symptoms of an allergic reaction

which 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.

Heart problems, including

inadequate pumping of the blood

by the heart. Signs and symptoms

of a decrease in the amount of

blood pumped include:

persistent coughing or

wheezing

shortness of breath

tiredness

increased heart rate

swelling of your ankles and

feet.

Any new or worsening problems

with your eyes or vision possibly

related to a condition called

“serous retinopathy” (a build-up

of fluid in the eye). These

problems may be severe and

could lead to blindness.

blurred vision, loss of vision

or other vision changes

changes in colour

seeing a blurred outline

around objects

eye pain, swelling or redness.

The above list includes serious side

effects. You may need urgent

medical attention.

This is not a complete list of all

possible side effects. Other side

effects may occur in some people and

there may be some others that are not

yet known.

Tell your doctor or pharmacist if

you notice anything that is making

you feel unwell.

After using COTELLIC

Storage

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 or

near a sink. Do not leave it on a

window sill or in the car.

Heat and dampness can destroy some

medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a-half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking COTELLIC or the expiry

date has passed, ask your

pharmacist what to do with any

medicine that is left over.

Product description

Availability

COTELLIC 20 mg film-coated

tablets come in blister packs of 63

tablets.

What COTELLIC looks like

COTELLIC tablets are round and

white with “COB” debossed on one

side.

COTELLIC 200625

Ingredients

COTELLIC tablets contain 20 mg of

cobimetinib (as a hemifumarate salt)

as the active ingredient.

Inactive ingredients:

cellulose – microcrystalline (460)

lactose monohydrate

croscarmellose sodium

magnesium stearate

polyvinyl alcohol

titanium dioxide (171)

macrogol 3350

talc - purified.

This medicine does not contain

sucrose, gluten, tartrazine or any

other azo dyes.

Manufacturer

Distributed in New Zealand by:

Roche Products (New Zealand)

Limited

PO Box 109113, Newmarket,

Auckland 1149

NEW ZEALAND

Medical enquiries: 0800 276 243

Distributed in Australia by:

Roche Products Pty Limited

ABN 70 000 132 865

Level 8, 30 – 34 Hickson

RoadSydney NSW 2000

AUSTRALIA

Medical enquiries: 1800 233 950

Please check with your pharmacist

for the latest Consumer Medicine

Information.

Australian Registration Number

AUST R 237017

This leaflet was prepared 22 July

2020

Read the complete document

Cotellic 200625

NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

Cotellic 20 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg cobimetinib (22mg of cobimetinib as a hemifumarate

salt).

Excipient with known effect:

Each film-coated tablet contains 36 mg lactose monohydrate.

For the full list of excipients, see section

List of excipients.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

4.

CLINICAL PARTICULAR

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

General

Cotellic

therapy

should

only

initiated

supervised

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 refer to the full Product Information for Zelboraf, which is used in combination with

Cotellic.

Dose

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).

Cotellic 200625

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 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 Recommendations

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 dose reduce either or both drugs should be based on clinical assessment.

Table 1 below gives general Cotellic dose modification advice.

Table 1. Recommended Cotellic Dose Modifications

Grade (CTC-AE)*

Recommended Cotellic dosage

Grade 1 or Grade 2 (tolerable)

No dose reduction

Grade 2 (intolerable) or Grade 3/4

1st appearance

Interrupt treatment until Grade ≤1,

restart treatment at 40 mg once daily

2nd appearance

Interrupt treatment until Grade ≤1,

restart treatment at 20mg once daily

3rd appearance

Consider permanent discontinuation

*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0

(CTC-AE)

Cotellic 200625

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

events

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.

Table 2. Recommended Dose Modifications for Cotellic

in patients with left ventricular ejection fraction (LVEF) decrease from baseline

Patient

LVEF value

Recommended

Cotellic

Dose

Modification

LVEF value

following treatment

break

Recommended

Cotellic

daily dose

Asymptomatic

≥ 50%

(or 40 – 49% and < 10%

absolute decrease from

baseline)

Continue at

current dose

Not applicable

Not applicable

< 40%

(or 40 – 49% and ≥ 10%

absolute decrease from

baseline)

Interrupt

treatment for 2

weeks

< 10% absolute

decrease from baseline

1st occurrence: 40mg

2nd occurrence: 20mg

3rd occurrence:

permanent

discontinuation

< 40%

(or ≥ 10% absolute

decrease from

baseline)

Permanent

discontinuation

Symptomatic

Not applicable

Interrupt

treatment for 4

weeks

Asymptomatic and

< 10% absolute

decrease from baseline

1st occurrence: 40mg

2nd occurrence: 20mg

3rd occurrence:

permanent

discontinuation

Asymptomatic and

< 40%

(or ≥ 10% absolute

decrease from

baseline)

Permanent

discontinuation

Symptomatic

regardless of LVEF

Permanent

discontinuation

Zelboraf treatment can be continued when Cotellic treatment is modified (if clinically

indicated).

Cotellic 200625

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

Cotellic dosing

does

need

modified

interrupted

manage

asymptomatic

creatine

phosphokinase

elevations

(see

section

4.8,

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

improve

Grade

≤3

within

weeks

following

dose

interruption,

permanently

discontinue Cotellic treatment.

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 refer to the full Product Information for Zelboraf.

Grade

Interrupt

Cotellic

treatment

Zelboraf

treatment.

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 refer to the 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 refer to the 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 rash:

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).

Non-acneiform or maculopapular rash: Cotellic dosing can be continued without

modification (if clinically indicated). Zelboraf

dosing may be either

temporarily

interrupted and/or reduced, please refer to the full Product Information for Zelboraf.

Cotellic 200625

Special populations

Elderly

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

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 Renal impairment).

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

Hepatic Impairment).

Liver laboratory

abnormalities can occur when Cotellic is used in

combination with Zelboraf (see section 4.4, Liver Laboratory Abnormalities).

Paediatric Populations

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

established.

Method of Administration

Cotellic is for oral use. The tablets should be swallowed whole with water. Cotellic can be taken

with or without food (see section 5.2).

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

Please also refer to the 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).

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 Modification Recommendations).

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). 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.

Cotellic 200625

patients

reporting

symptoms

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 Modification Recommendations).

Left Ventricular Dysfunction

Decrease in left ventricular ejection fraction (LVEF) from baseline has been reported in patients

receiving Cotellic (see section 4.8). 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

with

treatment

discontinuation

(see

section

4.2,

Dose

Modification

Recommendations).

patients

restarting

treatment

with

dose

reduction

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 refer to the full Data Sheet for Zelboraf).

Liver

laboratory

abnormalities,

specifically

increases

alanine

aminotransferase

(ALT),

aspartate aminotransferase (AST), and alkaline phosphatase (ALP), have been observed in

patients treated with Cotellic plus Zelboraf (see section 4.8, Laboratory Abnormalities).

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 Modification

Recommendations).

Rhabdomyolysis and CPK elevations

Rhabdomyolysis has been reported in patients receiving Cotellic (see section 4.8,

Adverse

reactions from spontaneous reporting).

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

treatment

discontinuation

required

(see

Section

4.2,

Dose

Modification

Recommendations).

Grade 3 or

4 CPK elevations, including asymptomatic elevations over baseline, have been

reported

patients

receiving

Cotellic

with

Zelboraf

clinical

trials

(see

section

4.8,

Laboratory Abnormalities). The median time to first occurrence of Grade 3 or 4 CPK elevations

Cotellic 200625

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

severity

symptoms

elevation,

treatment

interruption,

dose

reduction or treatment discontinuation may be required (see Section 4.2, Dose Modification

Recommendations).

Dermatological reactions

Severe rash and other skin reactions can occur with Cotellic (see section 4.8). Prescribers should

follow the dosage modification recommendations for rash if events occur (see section 4.2, Dose

Modification Recommendations).

Photosensitivity

Photosensitivity, including severe cases, can occur with Cotellic, when used with Zelboraf (see

section 4.8).

Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum

UVA/UVB sun screen and lip balm (SPF ≥ 30+) when outdoors. Manage photosensitivity with

dose modification (see section 4.2, Dose Modification Recommendations).

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, Study NO25395 (BRIM7)]. Use of Cotellic in this

population should be guided by careful benefit-risk assessment of the treatment and disease.

Paediatric Use

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

established.

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, Special Populations).

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, Special Populations).

Cotellic should be used with caution in patients with severe renal impairment.

Use in Hepatic Impairment

No dose adjustment is recommended in patients with hepatic impairment

(see Section 5.2,

Special

Populations).

Liver

laboratory

abnormalities

occur

when

Cotellic is

used

combination with Zelboraf (see section 4.4, Liver laboratory abnormalities).

Effect of Gender

Gender does not have an effect on Cotellic exposure (see section 5.2, Special Populations).

Cotellic 200625

4.5

Interaction with other medicines and other forms of interaction

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 co-administered with moderate CYP3A inducers and

inhibitors (see section 4.2, Dose Modification Recommendations)

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 co-administered with

medications that are substrates of CYP3A and CYP2D6.

Other Anti-Cancer 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 of P-glycoprotein (P-gp). In vitro studies

also show that cobimetinib is not a substrate of breast cancer resistance protein (BCRP).

In vitro studies show that cobimetinib is not a substrate of the liver uptake transporters

OATP1B1, OATP1B3, or OCT1,

In vitro data suggest that cobimetinib is a weak to moderate inhibitor of BCRP, and a weak

inhibitor of OATP1B1, OATP1B3 and OCT1. The clinical relevance of these findings has not

been investigated.

Cobimetinib is not an inhibitor of P-gp, 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.

Paediatric population

Interaction studies have only been performed in adults.

Cotellic 200625

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use two effective contraceptive methods

during

treatment with Cotellic and for at least three months following treatment discontinuation.

Pregnancy

Cotellic is not recommended during pregnancy.

There are no data regarding the use of Cotellic in pregnant women.

When

administered

pregnant

rats,

cobimetinib

caused

embryolethality

foetal

malformations of the great vessels and skull,

and decreased ossification sites at clinically

relevant exposures (see section 5.3).

The safe use of Cotellic during labour and delivery has not been established.

Breast-feeding

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 breast-feeding or to

administer Cotellic, taking into account the importance of the medicine to the mother.

Fertility

No dedicated fertility studies in animals have been performed with Cotellic but adverse effects

were seen on reproductive organs (see section 5.3).

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and to use machines have been performed.

Visual disturbances have been reported in some patients treated with Cotellic during clinical

trials (see section 4.4,

Serous retinopathy and section 4.8). Patients should be advised not to

drive or use machines without first consulting with their prescriber if their vision is impaired.

4.8

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.

Cotellic 200625

Tabulated summary of adverse reactions

The table below summarises the ADRs occurring at a ≥ 5% higher incidence (all grades) or at a

≥ 2% higher incidence (grades 3 -

4) of patients treated with Cotellic in combination with

Zelboraf

in the GO28141 study. The following categories of frequency have been used:

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).

Table 3. Adverse Reactions of All Grades (Incidence ≥ 5% over the control arm)

or Grade 3 - 4 (Incidence ≥ 2% over the control arm)

ADRs

Phase III study: GO28141

Frequency

a

(All Grades)

Cotellic + Zelboraf

(n = 247)

Placebo +

Zelboraf

(n = 246)

All grades

(%)

Grade 3 - 4

(%)

All grades

(%)

Grade 3 -4

(%)

Blood and Lymphatic

System Disorders

Anaemia

very common

Eye Disorders

Chorioretinopathy

< 1

< 1

very common

Vision Blurred

very common

Retinal Detachment

< 1

common

Gastrointestinal

disorders

Diarrhoea

very common

Nausea

very common

Vomiting

very common

General disorders and

administration site

conditions

Pyrexia

very common

Chills

very common

Investigations

Decreased Ejection

Fraction

common

Metabolism and nutrition

disorders

Dehydration

common

Hyponatremia

< 1

common

Neoplasms benign,

malignant and unspecified

Basal cell carcinoma

common

Skin and subcutaneous

tissue disorders

Photosensitivity

very common

Maculo−papular rash

very common

Acneiform rash

very common

Vascular Disorders

Hypertension

very common

Based on the Phase III study GO28141 adverse events of all grades

Combined figure includes reports of photosensitivity reaction, sunburn, solar dermatitis, actinic elastosis

Cotellic 200625

ADRs (all grades) Reported with < 5% Greater Incidence in the Cotellic-Plus- Zelboraf

Arm than the Placebo-Plus-Zelboraf Control Arm in Study GO28141

Eye disorders: visual impairment (3% in the Cotellic arm vs. 0% in the control arm) (see section

4.4).

Metabolism and nutrition disorders: hyperglycemia (3% in the Cotellic arm vs. 1% in the

control arm), hypophosphatemia (4% in the Cotellic arm vs 1% in the control arm).

Respiratory, thoracic and mediastinal disorders: pneumonitis (1% in the Cotellic arm vs. < 1%

in the control arm).

Skin and subcutaneous tissue disorders: rash (40% in the Cotellic arm vs. 38% in the control

arm).

Adverse reactions from spontaneous reporting

Table 4. Post-Marketing Experience

System Organ Class (SOC)

Adverse Drug Reaction (ADR)

Musculoskeletal and

connective tissue disorders

Rhabdomyolysis

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 were observed for

cerebral haemorrhage (1% vs. 0%), gastrointestinal (GI)

tract haemorrhage (4% vs. 1%),

reproductive system haemorrhage (2% vs. <1%), and haematuria (3% vs. 1%).

The majority of events were Grade 1 or 2 and non-serious (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.

Photosensitivity

Photosensitivity has been observed with a higher frequency in the Cotellic arm vs. the control

arm (47% vs. 35%). 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

apparent

trends

time

onset

Grade

events.

Grade

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

Modification Recommendations).

No evidence of phototoxicity was observed with Cotellic as a single agent.

Cutaneous Squamous Cell Carcinoma, Keratoacanthoma and Hyperkeratosis

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%).

Cotellic 200625

Laboratory Abnormalities

Table 5. Liver function and other laboratory tests observed in the phase III study

GO28141

Test*

Cotellic + Zelboraf

(n = 247)

(%)

Placebo + Zelboraf

(n = 246)

(%)

All Grades

Grades 3-4

All Grades

Grades 3-4

Liver Function Test

Increased ALP

Increased ALT

Increased AST

Increased GGT

Increased blood bilirubin

Haematology

Anaemia

Lymphopenia

Thrombocytopenia

Other Laboratory Abnormalities

Increased blood CPK

<1

*based on reported laboratory data

ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-

glutamyltransferase, , CPK = creatine phosphokinase

Special populations

Elderly patients

Phase

study

with

Cotellic

combination

with

vemurafenib

patients

with

unresectable or metastatic melanoma (n = 247), 183 patients (74%) were <65 years of age, and

44 patients (18%) were 65-74 years of age, 16 (6%) were 75-84 years of age, and 4 patients

(2%) were aged

85 years. The proportion of patients experiencing adverse events (AE) was

similar in the patients aged

65 years and those aged

65 years. Patients ≥ 65 years were more

likely

experience

serious

adverse

events

(SAEs)

experience

leading

discontinuation of cobimetinib than those

65 years.

Renal impairment

pharmacokinetic

trial

subjects

with

renal

impairment

been

conducted.

Dose

adjustment is not recommended for mild to moderate renal impairment based on the results of

the population pharmacokinetic analysis. There are minimal data for Cotellic in patients with

severe renal impairment. 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

Cotellic 200625

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 advice on the management of overdose please contact the National Poisons Centre on

0800 764 766.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XE38

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 anti-tumour

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

less

susceptible

dynamic

conformational

changes

seen

with

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.

pre-clinical

studies,

treatment

MAPK-dysregulated

cancer

cells

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 pro-mitogenic 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 pre-clinical models

than vemurafenib alone.

Cotellic 200625

Pharmacodynamic effect, Clinical efficacy and safety

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 (ORR),

duration of response and PFS as assessed by an independent review facility (IRF).

Efficacy results are summarised in Table 6.

Cotellic 200625

Table 6. Efficacy results from Study GO28141

Cotellic + Zelboraf

n = 247

Placebo + Zelboraf

n = 248

PRIMARY ENDPOINT

Progression-free survival (Inv)

a, g

Median by Kaplan Meier (KM) estimate

(months)

(95% CI)

(9.0, NE)

(5.6, 7.4)

Hazard ratio (95% CI)

0.51 (0.39, 0.68)

(p-value < 0.0001)

KEY SECONDARY ENDPOINTS

Progression-free survival (IRF)

b,c

Median by KM-estimate (months)

(95% CI)

11.3

(8.5, NE)

(5.6, 7.5)

Hazard ratio (95% CI)

0.60 (0.45; 0.79)

(p-value 0.0003)

Overall survival

Median KM estimate (months)

(95% CI)

22.3

(20.3, NE)

17.4

(15.0, 19.8)

Hazard ratio (95% CI)

0.70 (95% CI: 0.55, 0.90)

(p-value = 0.0050

Objective response

a

Objective response rate (ORR), n (%)

(95% CI

167 (67.6%)

(61.4%, 73.4%)

111 (44.8%)

(38.5%, 51.2%)

Difference in ORR %

(95% CI

22.85 (14.13, 31.58)

(p-value < 0.0001)

Best Overall Response

Complete Response, n (%)

25 (10.1%)

11 (4.4%)

Partial Response, n (%)

142 (57.5%)

100 (40.3%)

Stable disease, n (%)

49 (19.8%)

105 (42.3%)

Duration of response

Median duration of response (months)

95% CI for median

9.3, NE

5.8, NE

Assessed and confirmed by the investigator (Inv) using RECIST v1.1

Assessed and confirmed by an independent review facility (IRF) assessment using RECIST v1.1

Stratified analysis by geographic region and metastasis classification (disease stage)

Using Clopper-Pearson method

The OS p-value (0.0050) crossed the pre-specified boundary (p-value <0.0499)

Using Hauck-Anderson method

See text for discussion of post-hoc analysis of PFS

NE = not evaluable

Note: The table represents results from the primary analysis (cut-off date 9 May 2014). The exception is the pre-

planned final analysis of overall survival (cut-off date 28 August 2015)

Cotellic 200625

Figure 1. Kaplan-Meier Curves of Progression-free Survival (Inv):

Intent-to-Treat Population

Figure 2. Kaplan-Meier Curves of Final Overall Survival:

Intent-to-Treat Population

Cotellic 200625

Figure 3. Forest Plots for Hazard Ratios of Progression-Free Survival Subgroup Analyses:

Intent-to-Treat Population

Cotellic 200625

Figure 4. Forest Plot for Hazard Ratios of Final Overall Survival Subgroup Analyses:

Intent-to-Treat Population

Additionally, in a post hoc analysis with a cut-off 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.

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, dyspnea, 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.

Cotellic 200625

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 T

of 2.4 hours. The mean steady-state C

and AUC

0-24

were 273

ng/mL and 4340 ng.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.

Biotransformation

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.

Elimination

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.

Cotellic 200625

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).

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

body weight were identified as statistically significant co-variates on cobimetinib clearance and

volume of distribution respectively. However, sensitivity analysis suggests neither of these co-

variates 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

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

pre-clinical

data

human

mass

balance

study,

cobimetinib

mainly

metabolised, with minimal renal elimination. No formal PK study has been conducted in

patients with renal impairment.

population

analysis

using

data

from

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 (AUC

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, Special Populations and section 4.4 Liver Laboratory

Abnormalities).

Cotellic 200625

Paediatric population

No studies have been conducted to investigate the pharmacokinetics of cobimetinib in paediatric

patients.

QT Prolongation

No additive clinical effect on QT interval prolongation is observed when patients are treated

with Cotellic in combination with Zelboraf (see section 5.3).

5.3

Preclinical safety data

No carcinogenicity studies have been conducted with Cotellic.

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.

No dedicated fertility studies in animals have been performed with Cotellic.

In toxicology

studies,

degenerative

changes

were

observed

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.

When

administered

pregnant

rats,

cobimetinib

caused

embryolethality

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).

In vitro, cobimetinib produced moderate hERG ion channel inhibition (IC

= 0.5 μM [266

ng/mL]), which is approximately 18-fold higher than peak plasma concentrations (C

) at the

60 mg dose (unbound C

= 14 ng/mL [0.03 μM]).

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.

Non-clinical studies revealed no other special hazard for humans based on conventional studies

of safety pharmacology and genotoxicity.

Cotellic 200625

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose (E460)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Film coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Purified talc (E553b)

6.2

Incompatibilities

Not applicable

6.3

Shelf life

60 months

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

PVC/PVDC duplex blisters with an aluminium foil lidding. Each pack contains 63 tablets.

6.6

Special precautions for disposal

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

New Zealand: Prescription

8.

SPONSOR

Distributed in New Zealand by:

Roche Products (New Zealand) Limited

PO Box 109113 Newmarket

Auckland 1149

NEW ZEALAND

Medical enquiries: 0800 276 243

Cotellic 200625

9.

DATE OF FIRST APPROVAL

13 April 2017

10. DATE OF REVISION OF THE TEXT

22 July 2020

Summary of Changes Table

Section Changed

Summary of new information

Minor formatting updates

Revision to shelf life information

Update to Medical Enquiries Contact Number

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