Uptravi

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Selexipag 400 µg
Available from:
Janssen-Cilag (New Zealand) Ltd
INN (International Name):
Selexipag 400 µg
Dosage:
400 mcg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Selexipag 400 µg Excipient: Carnauba wax Hyprolose Hypromellose Disintergrant/Low substituted hydroxypropyl cellulose Iron oxide red Magnesium stearate Maize starch Mannitol Propylene glycol Titanium dioxide
Prescription type:
Prescription
Manufactured by:
Almac Sciences Limited
Therapeutic indications:
UPTRAVI, is indicated for the treatment of: · idiopathic pulmonary arterial hypertension · heritable pulmonary arterial hypertension · pulmonary arterial hypertension associated with connective tissue disease · pulmonary arterial hypertension associated with congenital heart disease with repaired shunts · pulmonary arterial hypertension associated with drugs and toxins in patients with WHO functional class II, III or IV symptoms. UPTRAVI is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.
Product summary:
Package - Contents - Shelf Life: Blister pack, Polyamide/al/HDPE/PE with desiccant agent/HDPE with Al foil (Alu/Alu blister with desiccant) - 60 dose units - 3 years from date of manufacture stored at or below 30°C protect from moisture
Authorization number:
TT50-9698a
Authorization date:
2015-01-05

Read the complete document

UPTRAVI (190826) ACMI

Page 1 of 5

UPTRAVI

®

(UP-tra-vee)

selexipag (se-le-xi-pag) 200, 400, 600, 800, 1000, 1200, 1400, 1600 microgram film coated tablets

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about UPTRAVI.

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 using this medicine against the

benefits they expect it will have for

you.

If you have any concerns about

using this medicine, speak to your

doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What UPTRAVI is used

for

UPTRAVI contains the active

substance selexipag. It is a medicine

that acts on a receptor that is the target

of a natural substance called

"prostacyclin".

UPTRAVI is used for the long-term

treatment of pulmonary arterial

hypertension (PAH) in adults.

It can be used on its own or with other

medicines for PAH. PAH is high

blood pressure in the blood vessels

that carry blood from the heart to the

lungs (the pulmonary arteries). In

people with PAH, these arteries

narrow, so the heart has to work

harder to pump blood through them.

This may cause people to feel tired,

dizzy, short of breath, or experience

other symptoms.

UPTRAVI widens the pulmonary

arteries and reduces their hardening.

This makes it easier for the heart to

pump blood through the pulmonary

arteries. It relieves the symptoms

PAH and improves the course of the

disease.

Your doctor however, may prescribe

UPTRAVI for another purpose.

Ask your doctor if you have any

questions about why it has been

prescribed for you.

Before you take

UPTRAVI

When you must not take

UPTRAVI

Do not take UPTRAVI if

1. You have ever had an allergic

reaction to selexipag or any of the

ingredients listed at the end of this

leaflet.

Please consult your doctor

immediately if you experience any

signs or symptoms of a serious

allergic reaction:

Wheezing

Swelling of the

lips/mouth/throat/face

Difficulty in breathing

or tightness in the

throat

Hives or rash

fainting

2. You have severe liver problems

(Child-Pugh Class C)

3. You have had a stroke within the

last 3 months

4. You have severe coronary heart

disease or unstable angina

5. You have had a myocardial

infarction (heart attack) within the

last 6 months

6. You have a weak heart

(decompensated cardiac failure)

that is not under close medical

observation

7. You have severe arrhythmias

(irregular heartbeat problem)

8. You have defect of your heart

valves (inborn or acquired) that

causes the heart to work poorly (not

related to pulmonary hypertension)

9. Contraindicated with strong

inhibitors of CYP2C8 (e.g.

gemfibrozil).

UPTRAVI is not recommended during

pregnancy and breastfeeding. There is

no experience with the use of this

medicine during human pregnancy.

Women with PAH should avoid

becoming pregnant as your condition

may worsen. If you are a woman who

can have children, you should use an

effective contraceptive method while

taking UPTRAVI.

If you are pregnant or breast-feeding,

think you may be pregnant, or are

planning to have a baby, ask your

doctor for advice before taking this

medicine

Male fertility - the potential risk for

humans is unlikely. Talk to your

doctor if you have any questions or

concerns about this.

Do not use UPTRAVI after the

expiry date [EXP.] printed on the

pack.

If you use it after the expiry

date has passed, it may not work as

well.

Do not use UPTRAVI if the

packaging is torn or shows signs of

tampering.

If you're not sure whether you should

be using UPTRAVI, talk to your

doctor.

Do not use UPTRAVI in children

under 18 years of age. There is no

experience with the use of this

medicine in children or adolescents

under 18 years old.

UPTRAVI (190826) ACMI

Page 2 of 5

Before you start to take

UPTRAVI

You must tell your doctor if:

You are allergic to foods,

dyes, preservatives or any

other medicines

You are pregnant, trying or

become pregnant

You are breastfeeding or

planning to breastfeed

You experience dizziness or

fainting

You have problems with

your liver

You are undergoing dialysis

Taking Other medicines

Tell your doctor or pharmacist if you

are taking any other medicines,

including any that you buy without a

prescription from your pharmacy,

supermarket or health food shop.

Some medicines may affect the way

other medicines work.

Your doctor or pharmacist will be able

to tell you what to do when using

UPTRAVI with other medicines.

UPTRAVI may interact with other

medicines such as:

Rifampicin (antibiotic used

to treat infections)

Sodium Valproate (used to

treat epilepsy)

Gemfibrozil (medicine used

to lower the levels of fat in

the blood)

Lopinavir and ritonavir

(antivirals used to treat

HIV)

How to take UPTRAVI

Always take this medicine exactly as

your doctor has told you. Check with

your doctor if you are not sure.

How much to take

Your doctor will decide what dose of

UPTRAVI is suitable for you.

Take UPTRAVI in the monring and in

the evening, consistently either with or

without meals. You might tolerate the

medicine better when you take it with

meals. Swollow the tablets whole, do

not split, crush or chew the UPTRAVI

tablets.

Finding the right dose for you

At the start of treatment, you will take

the lowest dose. This is one 200

microgram tablet in the morning and

another 200 microgram tablet in the

evening. As instructed by your doctor,

you will gradually increase your dose.

This is called titration. It lets your

body adjust to the new medicine. The

goal of titration is to reach the highest

dose you can tolerate. This can be up

to a maximum dose of (1600

microgram twice a day).

During titration, you will receive a

titration pack containing light yellow

UPTRAVI 200 microgram tablets.

These tablets have a “2” stamped on

one side. Your doctor will tell you to

increase your dose in steps, usually

every week. With each step, you will

add one 200 microgram tablet to your

morning and evening doses. Below is

a diagram to show the dose and the

number of tablets at each step for the

first 4 steps.

If you reach a dose of 800 micrograms

in the morning and 800 micrograms in

the evening, your doctor may instruct

you to increase your dose to 1000

micrograms in the morning and 1000

micrograms in the evening. This will

be done by taking one green 800

microgram tablet and adding one

light-yellow 200 microgram tablet.

For this, you will receive a pack

containing green UPTRAVI 800

microgram tablets (with an “8”

stamped on one side) and a titration

pack containing light yellow

UPTRAVI 200 microgram tablets

(with a “2” stamped on one side).

Your doctor will tell you to increase

your dose in steps, usually every

week. As before, with each step, you

will add a 200 microgram tablet to

your morning and evening doses. The

maximum dose of UPTRAVI is 1600

micrograms in the morning and in the

evening. However, not every patient

will reach this dose.

Below is a diagram to show the dose

and the number of tablets at each step

starting with step 5.

You will receive a titration guide

providing information on how to

increase your dose and allowing you

to record the number of tablets you

take every day. Remember to record

the number of tablets you take every

day. Remember to talk to your PAH

doctor or nurse regularly during

titration.

Stepping down to a lower dose due to

side effects

During titration, you may experience

side effects such as headache, jaw

pain, aching joints, muscle pain or a

general feeling of being in pain,

diarrhoea, feeling sick, being sick,

stomach ache or reddening of the face.

If these side effects are difficult for

you to tolerate, talk to your doctor

about how to manage or treat them.

There are treatments available that can

help relieve the side effects. Do not

stop taking UPTRAVI unless your

doctor tells you to.

If the side effects cannot be treated or

do not gradually get better on the dose

you are taking, your doctor may adjust

your dose by reducing by one the

number of 200 microgram yellow

tablets you take in the morning and in

the evening. The diagram below

shows stepping down to a lower dose.

Do this only if instructed to do so by

your doctor.

Do not stop taking

UPTRAVI unless your doctor tells

you to.

UPTRAVI (190826) ACMI

Page 3 of 5

If your side effects are manageable

after stepping down your dose, your

doctor may decide that you should

continue to stay at that level. Please

see section "

Maintenance dose

" below

for more information.

Maintenance dose

The highest dose that you can tolerate

during titration will become your

maintenance dose. Your maintenance

dose is the dose you should continue

to take on a regular basis, in the

morning and in the evening with the

minimum side effects.

Every patient with PAH is different.

Not everyone will end up on the same

maintenance dose. Your maintenance

dose will be between 200 micrograms

and 1600 micrograms in the morning

and in the evening. What is important

is that you reach the dose that is most

appropriate to treat you.

Your doctor can prescribe an

equivalent single-tablet strength for

your maintenance dose.

This allows

you to take one tablet in the

morning and one in the evening,

instead of multiple tablets for each.

The single tablet will be of a different

color depending on the dose. Each

tablet will have a number on its

surface showing the dose (in hundreds

of micrograms). For a full description

including colours and marking, please

see Product Description section of this

leaflet.

Over time, your doctor may adjust

your maintenance dose as needed.

If, at any time, after taking the same

dose for a long time, you experience

side effects that you cannot tolerate or

side effects that have an impact on

your normal daily activities, contact

your doctor.

Do not stop taking

UPTRAVI unless your doctor tells

you to.

How long to take it

Use UPTRAVI for as long as your

doctor advises you to. UPTRAVI is

generally used over a prolonged

period of time, possibly years. It

should not be stopped suddenly.

If you forget to take it

If you forget to take UPTRAVI, take a

dose as soon as you remember, then

continue to take your tablets at the

usual times. If it is nearly time for

your next dose (within six hours

before you would normally take it)

you should skip the missed dose and

continue to take your medicine at the

usual time. Do not take a double dose

to make up for a forgotten tablet.

If you stop taking UPTRAVI

Do not stop taking UPTRAVI unless

your doctor tells you to. If, for any

reason, you stop taking UPTRAVI for

more than 3 consecutive days (if you

missed 3 morning and 3 evening doses

or 6 doses in a row or more),

contact

your doctor immediately as your

dose may need to be adjusted to

avoid side effects

. Your doctor may

decide to restart your treatment on a

lower dose, gradually increasing to

your previous maintenance dose.

If you have any further questions on

the use of this medicine, ask your PAH

doctor or nurse.

If you use too much

(overdose)

Immediately telephone your doctor or

the Poisons Information Centre or go

to Accident and Emergency at your

nearest hospital, if you think that you

or anyone else may have used too

much UPTRAVI. Do this even if

there are no signs of discomfort or

poisoning. Always take the labelled

medicine carton with you, even if it is

empty.

You may need urgent medical

attention. Ask your doctor if you have

any concerns.

Poison Information Centre telephone

numbers:

Australia: 13 11 26

New Zealand: 0800 POISON or

0800 764 766

While you are using

UPTRAVI

Things you must do

Tell your doctor or pharmacist that

you are taking UPTRAVI if you are

about to start on any new medicines.

Tell your doctor if you become

pregnant or are trying to become

pregnant.

Tell your doctor if you are

breastfeeding or plan to breastfeed.

Tell your doctor if, for any reason,

you have not used your medicine

exactly as prescribed.

Keep all of your doctor or clinic

appointments.

Your doctor may do certain tests,

including blood tests, from time to

time to make sure the medicine is

working and to prevent unwanted side

effects.

Things you must not do

UPTRAVI is a treatment that you will

need to keep on taking to control your

PAH. Do not stop taking UPTRAVI

unless you have agreed this with your

doctor.

If you have any further questions on

the use of UPTRAVI, ask your doctor

or pharmacist.

Do not give this medicine to anyone

else, even if their symptoms seem

similar to yours.

UPTRAVI (190826) ACMI

Page 4 of 5

Do not use UPTRAVI to treat any

other complaints unless your doctor

says to.

Things to be careful of

UPTRAVI can cause side effects such

as headaches and low blood pressure

and the symptoms of your condition

can also make you less fit to drive

Be careful driving or operating

machinery until you know how

UPTRAVI affects you. If you are

affected, do not drive or operate

machinery.

Side Effects

Check with your doctor as soon as

possible if you have any problems

while taking UPTRAVI, even if you

do not think the problems are

connected with the medicine or are

not listed in this leaflet.

Like all medicines, UPTRAVI can

cause side effects in some people.

You may experience side effects not

only during the titration period when

your dose is being increased, but also

later after taking the same dose for a

long time.

If you experience any of these side

effects:

headache

jaw pain

aching joints

muscle pain or a general

feeling of being in pain

diarrhoea

feeling sick /being sick

stomach ache

reddening of the face

that you cannot tolerate or cannot

be treated, you should contact your

doctor as the dose you are taking

may be too high for you and may

need to be reduced

Very common side effects

(may

affect more than 1 in 10 people)

Headache

Flushing (reddening of the

face)

Nausea and vomiting (feeling

sick and being sick)

Diarrhoea

Jaw pain, muscle pain, joint

pain

Rash

Stuffy nose

Common side effects

(may affect up

to 1 in 10 people)

Anaemia (low red blood cell

levels)

Hyperthyroidism (overactive

thyroid gland)

Decreased appetite

Weight loss

Hypotension (low blood

pressure)

Stomach pain

Pain

Changes in some blood test

results including those

measuring blood cell counts

or your thyroid function

Increased heart rate

Eye pain

If you get any side effects, talk to your

doctor or pharmacist. This includes

any possible side effects not listed in

this leaflet

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

This is not a complete list of all

possible side-effects. Others may

occur in some people and there may

be some side-effects not yet known.

Tell your doctor if you notice

anything else that is making you feel

unwell, even if it is not on this list.

Storing UPTRAVI

Storage

Keep this medicine 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.

Do not leave them in the car or on

window sills.

Do not use this medicine after the

expiry date which is stated on the

carton after EXP.The expiry date

refers to the last day of that month.

Store below 30 C. Protect from

moisture.

Medicines should not be disposed of

in wastewater or household waste.

Ask your pharmacist how to dispose

of medicines you no longer require.

These measures will help to protect

the environment.

Product description

What it looks like

UPTRAVI 200 microgram

film-

coated tablets are: Round, light

yellow, film-coated tablets with “2”

marked on one side.

UPTRAVI 400 microgram

film-

coated tablets are: Round, red, film-

coated tablets with “4” marked on one

side.

UPTRAVI 600 microgram

film-

coated tablets are: Round, light violet,

film-coated tablets with “6” marked

on one side.

UPTRAVI 800 microgram

film-

coated tablets are: Round, green, film-

coated tablets with “8” marked on one

side.

UPTRAVI 1000 microgram

film-

coated tablets are: Round, orange,

film-coated tablets with “10” marked

on one side.

UPTRAVI 1200 microgram

film-

coated tablets are: Round, dark violet,

film-coated tablets with “12” marked

on one side.

UPTRAVI 1400 microgram

film-

coated tablets are: Round, dark

yellow, film-coated tablets with “14”

marked on one side.

UPTRAVI 1600 microgram

film-

coated tablets are: Round, brown,

film-coated tablets with “16” marked

on one side.

Pack size

UPTRAVI 200 microgram film-coated

tablets are supplied in blister packs of

10, 60 or 140 tablets.

UPTRAVI 400, 600, 800, 1000, 1200,

1400, and 1600 microgram film-

coated tablets are supplied in blister

packs of 60 tablets.

UPTRAVI (190826) ACMI

Page 5 of 5

Ingredients

Active ingredient:

Selexipag

Each tablet contains 200, 400, 600,

800, 1000, 1200, 1400, or 1600

micrograms of selexipag.

Inactive ingredients:

The other ingredients are:

tablet core:

Mannitol, maize starch,

hydroxypropylcellulose, magnesium

stearate

film coat:

200 microgram:

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide yellow (E172),

carnauba wax

400 microgram

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide red (E172),

carnauba wax

600 microgram:

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide red (E172), iron

oxide black (E172), carnauba wax

800 microgram:

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide yellow (E172), iron

oxide black (E172), carnauba wax

1000 microgram:

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide red (E172), iron

oxide yellow (E172), carnauba wax

1200 microgram:

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide black (E172), iron

oxide red (E172), carnauba wax

1400 microgram:

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide yellow (E172),

carnauba wax

1600 microgram

:

hypromellose,

propylene glycol, titanium dioxide

(E171), iron oxide black (E172), iron

oxide red (E172), iron oxide yellow

(E172), carnauba wax

Sponsor

JANSSEN-CILAG Pty Ltd

1-5 Khartoum Road

Macquarie Park NSW 2113 Australia

Telephone: 1800 226 334

NZ Office: Auckland New Zealand

Telephone: 0800 800 806

This leaflet was prepared in August

2019.

UPTRAVI tablets packs:

200 microgram blister packs of

60 tablets AUST R 234161

200 microgram blister packs of

140 tablets AUST R 234161

400 microgram blister packs of

60 tablets AUST R 234160

600 microgram blister packs of

60 tablets AUST R 234159

800 microgram blister packs of

60 tablets AUST R 234166

1000 microgram blister packs of

60 tablets AUST R 234162

1200 microgram blister packs of

60 tablets AUST R 234163

1400 microgram blister packs of

60 tablets AUST R 234165

1600 microgram blister packs of

60 tablets AUST R 234164

Read the complete document

UPTRAVI NEW ZEALAND DATA SHEET

CCDS210413 Page 1 of 28

UPTRAVI (210531) ADS

1 PRODUCT NAME

UPTRAVI® selexipag 200 microgram film coated tablets

UPTRAVI® selexipag 400 microgram film coated tablets

UPTRAVI® selexipag 600 microgram film coated tablets

UPTRAVI® selexipag 800 microgram film coated tablets

UPTRAVI® selexipag 1000 microgram film coated tablets

UPTRAVI® selexipag 1200 microgram film coated tablets

UPTRAVI® selexipag 1400 microgram film coated tablets

UPTRAVI® selexipag 1600 microgram film coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

UPTRAVI 200 microgram film coated tablets

Each film coated tablet contains 200 micrograms of selexipag

UPTRAVI 400 microgram film coated tablets

Each film coated tablet contains 400 micrograms of selexipag

UPTRAVI 600 microgram film coated tablets

Each film coated tablet contains 600 micrograms of selexipag

UPTRAVI 800 microgram film coated tablets

Each film coated tablet contains 800 micrograms of selexipag

UPTRAVI 1000 microgram film coated tablets

Each film coated tablet contains 1000 micrograms of selexipag

UPTRAVI 1200 microgram film coated tablets

Each film coated tablet contains 1200 micrograms of selexipag

UPTRAVI 1400 microgram film coated tablets

Each film coated tablet contains 1400 micrograms of selexipag

UPTRAVI 1600 microgram film coated tablets

Each film coated tablet contains 1600 micrograms of selexipag

3 PHARMACEUTICAL FORM

UPTRAVI 200 microgram film coated tablets

Round light yellow, film-coated tablet with '2' debossed on one side

UPTRAVI 400 microgram film coated tablets

Round red yellow, film-coated tablet with '4' debossed on one side

UPTRAVI 600 microgram film coated tablets

Round light violet, film-coated tablet with '6' debossed on one side

UPTRAVI 800 microgram film coated tablets

Round green, film-coated tablet with '8' debossed on one side

UPTRAVI NEW ZEALAND DATA SHEET

CCDS210413 Page 2 of 28

UPTRAVI (210531) ADS

UPTRAVI 1000 microgram film coated tablets

Round orange, film-coated tablet with '10' debossed on one side

UPTRAVI 1200 microgram film coated tablets

Round dark violet, film-coated tablet with '12' debossed on one side

UPTRAVI 1400 microgram film coated tablets

Round dark yellow, film-coated tablet with '14' debossed on one side

UPTRAVI 1600 microgram film coated tablets

Round brown, film-coated tablet with '16' debossed on one side

4 CLINICAL PARTICULARS

Therapeutic indications

UPTRAVI is indicated for the treatment of:

idiopathic pulmonary arterial hypertension

heritable pulmonary arterial hypertension

pulmonary arterial hypertension associated with connective tissue disease

pulmonary arterial hypertension associated with congenital heart disease with repaired shunts

pulmonary arterial hypertension associated with drugs and toxins

in patients with WHO functional class II, III or IV symptoms.

UPTRAVI is effective in combination with an endothelin receptor antagonist (ERA) or a

phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or

as monotherapy.

Dose and method of administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of

PAH.

Selexipag can be used in combination with an ERA or a PDE-5 inhibitor, or in triple combination with

an ERA and a PDE-5 inhibitor, or as monotherapy.

Dosage

Individualised dose titration

The goal is to reach the individually appropriate dose for each patient (the individualised

maintenance dose).

The recommended starting dose of UPTRAVI is 200 micrograms given twice daily, approximately 12

hours apart. The dose is increased in increments of 200 micrograms given twice daily, usually at

weekly intervals, until adverse pharmacological effects that cannot be tolerated or medically

managed are experienced, or until a maximum dose of 1600 micrograms twice daily is reached.

During dose titration, it is recommended not to discontinue treatment in the event of expected

pharmacological side effects since they are usually transient or manageable with symptomatic

UPTRAVI NEW ZEALAND DATA SHEET

CCDS210413 Page 3 of 28

UPTRAVI (210531) ADS

treatment (see Section 4.8 UNDESIRABLE EFFETCS). If a patient reaches a dose that cannot be

tolerated the dose should be reduced to the previous dose level.

Individualised maintenance dose

The highest tolerated dose reached during dose titration should be maintained. If the therapy is less

tolerated at a given dose over time, symptomatic treatment or a dose reduction to the next lower

dose should be considered. PAH patients have variable degrees of IP receptor expression.

Differences in maintenance dose of selexipag between individuals may be related to differences in IP

receptor expression levels.

Interruptions and discontinuations

If a dose of medication is missed, it should be taken as soon as possible. The missed dose should not

be taken if it is almost time for the next scheduled dose (within approximately 6 hours).

If treatment is missed for 3 days or more, UPTRAVI should be re-started at a lower dose and then

titrated.

Dosage Adjustment with Co-administration of Moderate CYP2C8 Inhibitors

When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and

teriflunomide), reduce the dosing of UPTRAVI to once daily

Revert back to twice daily dosing

frequency of UPTRAVI when co-administration of moderate CYP2C8 inhibitor is stopped. (see Section

4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS)

Dosage adjustment in elderly patients (≥ 65 years)

No adjustment to the dosing regimen is needed in elderly patients.

Dosage adjustment in patients with hepatic impairment

No adjustment to the dosing regimen is needed in patients with mild hepatic impairment (i.e., Child-

Pugh class A). A once-daily regimen is recommended in patients with moderate hepatic impairment

(Child- Pugh class B) due to the increased exposure to selexipag and its active metabolite.

Dosage adjustment in patients with renal impairment

No adjustment to the dosing regimen is needed in patients with mild or moderate renal impairment.

No change in starting dose is required in patients with severe renal impairment. Dose titration in

these patients should be done with caution.

Method of administration

Oral use.

The film-coated tablets are to be taken orally in the morning and in the evening. UPTRAVI should be

taken consistently with or without food. Tolerability may be improved when taken with food.

The tablets should not be split, crushed or chewed, and are to be swallowed with some water.

Contraindications

UPTRAVI is contraindicated in patients with known hypersensitivity to the active substance or to any

of the excipients listed in section 6.1 LIST OF EXCIPIENTS.

Severe hepatic impairment (Child-Pugh class C).

Severe coronary heart disease or unstable angina.

UPTRAVI NEW ZEALAND DATA SHEET

CCDS210413 Page 4 of 28

UPTRAVI (210531) ADS

Myocardial infarction within the last 6 months.

Decompensated cardiac failure if not under close medical supervision.

Severe arrhythmias.

Cerebrovascular events (e.g., transient ischaemic attack, stroke) within the last 3 months.

Congenital or acquired valvular defects with clinically relevant myocardial function disorders not

related to pulmonary hypertension.

Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Special warnings and precautions for use

Additional Information on Special Populations

Studies with selexipag have been mainly performed in PAH patients classified as WHO functional

Class II and III. Selexipag has only been studied in a limited number of patients with WHO functional

Class IV. Selexipag has only been studied in a limited number of patients with PAH due to drugs or

toxins.

Hypotension

UPTRAVI has vasodilatory properties that may result in lowering of blood pressure. Before

prescribing UPTRAVI, physicians should carefully consider whether patients with certain underlying

conditions could be adversely affected by vasodilatory effects (e.g., patients on antihypertensive

therapy or with resting hypotension, hypovolaemia, severe left ventricular outflow obstruction or

autonomic dysfunction).

Increase in heart rate

UPTRAVI may cause a moderate increase in heart rate after each dose.

Hyperthyroidism

Hyperthyroidism has been observed with UPTRAVI (2% patients on selexipag and 0% of placebo-

treated patients) and other prostacyclin receptor agonists. Thyroid function tests are recommended

as clinically indicated.

Pulmonary veno-occlusive disease

Should signs of pulmonary oedema occur, consider the possibility of associated pulmonary veno-

occlusive disease. If confirmed, discontinue UPTRAVI.

Elderly

There is limited clinical experience with selexipag in patients over the age of 75 years, therefore

UPTRAVI should be used with caution in this population.

Paediatric

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

Genotoxicity

Selexipag and its active metabolite are not genotoxic under in vivo conditions. The weight of

evidence from a battery of genotoxicity studies indicates no cause for clinical concern.

Patients with hepatic impairment

No adjustment to the dosing regimen is needed in patients with mild hepatic impairment (Child-

Pugh class A). A once-daily regimen is recommended in patients with moderate hepatic impairment

(Child-Pugh class B) due to the increased exposure to selexipag and its active metabolite in this

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UPTRAVI (210531) ADS

population. There is no experience with UPTRAVI in patients with severe hepatic impairment (Child-

Pugh class C).

Patients with renal impairment

In patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2)

caution should be exercised during dose titration. There is no experience with UPTRAVI in patients

undergoing dialysis.

Interaction with other medicines and other forms of interaction

U

In vitro studies

Selexipag is hydrolysed to its active metabolite by carboxylesterases) [see Section 5.2

PHARMACOKINETICS]. Selexipag and its active metabolite both undergo oxidative metabolism

mainly by CYP2C8 and to a smaller extent by CYP3A4. The glucuronidation of the active metabolite is

catalysed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1

and OATP1B3. Selexipag is a substrate of P-gp, and the active metabolite is a substrate of the

transporter breast cancer resistance protein (BCRP).

Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes or transport

proteins at clinically relevant concentrations.

U

In vivo studies

PAH-specific therapies: In the Phase 3 placebo-controlled study in patients with PAH, no relevant

changes in the exposure (area under the plasma concentration-time curve during a dose interval) to

selexipag and its active metabolite were observed when administered in combination with an ERA

and/or PDE-5 inhibitor.

Anticoagulants or inhibitors of platelet aggregation

: Selexipag is an inhibitor of platelet aggregation

in vitro. In the Phase 3 placebo-controlled study in patients with PAH, no increased risk of bleeding

was detected with selexipag compared to placebo, including when selexipag was administered with

anticoagulants (such as heparin, coumarin-type anticoagulants) or inhibitors of platelet aggregation.

In a study in healthy subjects, selexipag (400 micrograms twice a day) did not alter the exposure to

S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 20 mg

warfarin. Selexipag did not influence the pharmacodynamic effect of warfarin on the international

normalised ratio. The pharmacokinetics of selexipag and its active metabolite were not affected by

warfarin.

Lopinavir/ritonavir:

In the presence of 400/100 mg lopinavir/ritonavir, twice a day, a strong CYP3A4,

OATP (OATP1B1 and OATP1B3), and P-gp inhibitor, exposure to selexipag increased approximately 2-

fold, whereas the exposure to the active metabolite of selexipag did not change.

U

Rifampicin:

In the presence of 600 mg rifampicin, once a day, an inducer of CYP2C8 and UGT

enzymes, the exposure to selexipag did not change whereas exposure to the active metabolite was

reduced by half. Dose adjustment of

UPTRAVI may be required.

Midazolam: At steady state after up-titration to 1600 μg selexipag twice a day, no change in

exposure to midazolam, a sensitive intestinal and hepatic CYP3A4 substrate, or its metabolite, 1-

hydroxymidazolam, was observed. Concomitant administration of selexipag with CYP3A4 substrates

does not require dose adjustment.

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UPTRAVI (210531) ADS

Inhibitors of UGT1A3 and UG2B7: The effect of strong inhibitors of UGT1A3 and UGT2B7 on the

exposure to selexipag or its active metabolite has not been studied. Concomitant administration

may result in a significant increase in exposure or its active metabolite.

Inhibitors of CYP2C8: In the presence of 600 mg gemfibrozil, twice a day, a strong inhibitor of

CYP2C8, exposure to selexipag increased approximately 2-fold whereas exposure to the active

metabolite increased approximately 11-fold. Concomitant administration of UPTRAVI with strong

inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated (see Section 4.3 CONTRAINDICATIONS).

Concomitant administration of selexipag with clopidogrel (loading dose 300 mg or maintenance dose

of 75 mg once a day), a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to

selexipag and increased the exposure to the active metabolite by approximately 2.2-fold and 2.7-fold

following loading dose and maintenance dose, respectively. Dosing frequency of UPTRAVI should be

reduced to once daily when co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel,

deferasirox, teriflunomide). Dosing frequency of UPTRAVI should be reverted back to twice daily

when co-administration of moderate CYP2C8 inhibitor is stopped (see Section 4.2 DOSE AND

METHOD OF ADMINISTRATION - Dosage adjustment with co-administration of moderate CYP2C8

inhibitors).

Hormonal contraceptives: Specific drug-drug interaction studies with hormonal contraceptives have

not been conducted. Since selexipag did not affect the exposure to the CYP3A4 substrates

midazolam and R-warfarin or the CYP2C9 substrate S-warfarin, reduced efficacy of hormonal

contraceptives is not expected.

U

Pharmacodynamic interactions

Reductions in blood pressure may occur when UPTRAVI is administered with diuretics,

antihypertensive agents, or other vasodilators.

Fertility, pregnancy and lactation

Effects on Fertility

Selexipag had no effect on fertility of male and female rats. In the rat pre- and post-natal

development study, selexipag induced no effects on maternal and pup reproductive function.

Use in pregnancy (Category B)

There are limited data on the use of selexipag in pregnant women. Selexipag was not teratogenic in

rats and rabbits. As a precautionary measure, it is preferable - unless clearly needed - to avoid the

use of UPTRAVI during pregnancy.

Use in Lactation

It is unknown whether selexipag or its metabolites are excreted in human milk.

In rats, selexipag and/or its metabolites are excreted in the milk. Breastfeeding is not recommended

during treatment with UPTRAVI.

Effects on ability to drive and use machines

No studies on the effect of UPTRAVI on the ability to drive and use machines have been performed.

UPTRAVI has a minor influence on the ability to drive and use machines. The clinical status of the

patient and the adverse reaction profile of selexipag (such as headache or hypotension) should be

kept in mind when considering the patient’s ability to drive and use machines.

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UPTRAVI (210531) ADS

Undesirable effects

The most commonly reported adverse drug reactions related to the pharmacological effects of

UPTRAVI are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in the extremity,

flushing, and arthralgia. These reactions are more frequent during the dose titration phase. The

majority of these reactions are of mild to moderate intensity.

The safety of selexipag has been evaluated in a long-term, Phase 3 placebo-controlled study

enrolling 1156 patients with symptomatic PAH. The mean treatment duration was 76.4 weeks

(median 70.7 weeks) for patients receiving selexipag versus 71.2 weeks (median 63.7 weeks) for

patients on placebo. The exposure to selexipag was up to 4.2 years.

Table 1 presents adverse events over the entire treatment period in the Phase 3 study.

Table 1

Adverse events occurring in ≥ 5 % of selexipag or placebo treated subjects (during

treatment and up to 7 days after treatment discontinuation)

Double blind PAH

GRIPHON

System organ class

Selexipag

N = 575

Placebo

N = 577

Blood and lymphatic system

disorders

Anaemia

8% (48)

5% (31)

Cardiac disorders

Right ventricular failure

8% (46)

10% (58)

Palpitations

6% (34)

6% (32)

Gastrointestinal disorders

Diarrhoea

42% (244)

18% (106)

Nausea

33% (192)

18% (105)

Vomiting

18% (104)

9% (49)

Abdominal pain

8% (48)

6% (33)

General disorders and

administration site conditions

Oedema peripheral

14% (79)

18% (103)

Fatigue

8% (46)

10% (59)

Chest pain

7% (39)

7% (42)

Asthenia

5% (31)

4% (24)

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UPTRAVI (210531) ADS

Double blind PAH

GRIPHON

System organ class

Selexipag

N = 575

Placebo

N = 577

Infections and Infestations

Upper respiratory tract infection

13% (75)

14% (79)

Nasopharyngitis

13% (75)

11% (63)

Bronchitis

8% (47)

8% (43)

Pneumonia

5% (30)

6% (33)

Urinary tract infection

5% (26)

5% (30)

Respiratory tract infection

4% (21)

5% (28)

Metabolism and nutrition disorders

Decreased appetite

6% (34)

3% (19)

Hypokalaemia

4% (25)

5% (28)

Musculoskeletal and connective

tissue disorders

Jaw pain

26% (148)

6% (33)

Pain in extremity

17% (97)

8% (44)

Myalgia

16% (92)

6% (34)

Arthralgia

11% (62)

8% (44)

Back pain

6% (35)

6% (35)

Nervous system disorders

Headache

65% (375)

32% (182)

Dizziness

15% (86)

15% (85)

Syncope

6% (37)

9% (51)

Psychiatric disorders

Insomnia

4% (23)

5% (28)

Respiratory, thoracic and

mediastinal disorders

Pulmonary arterial hypertension

22% (125)

36% (206)

Dyspnoea

16% (91)

21% (121)

Cough

10% (56)

12% (67)

Epistaxis

5% (30)

5% (29)

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UPTRAVI (210531) ADS

Double blind PAH

GRIPHON

System organ class

Selexipag

N = 575

Placebo

N = 577

Skin and subcutaneous tissue

disorders

Rash

11% (64)

8% (48)

Vascular disorders

Flushing

12% (70)

5% (28)

Hypotension

5% (29)

3% (18)

Table 2 presents adverse drug reactions reported in selexipag-treated subjects at an incidence ≥ 3 %

and with a placebo-corrected difference ≥ 1 % (during treatment and up to 7 days after treatment

discontinuation).

Table 2

Adverse drug reactions reported by ≥ 3% of selexipag treated patients with a

placebo-corrected difference ≥ 1% (during treatment and up to 7 days after

treatment discontinuation

)

§

Double blind PAH

GRIPHON

System organ class

Selexipag

N = 575

Placebo

N = 577

Infections and Infestations

Nasopharyngitis

13% (75)

11% (63)

Influenza

4% (20)

2% (14)

Blood and lymphatic system

disorders

Anaemia

8% (48)

5% (31)

Hemoglobin decreased

10 % (55)

7% (42)

Nervous system disorders

Headache*

65% (375)

32% (182)

Respiratory, thoracic and

mediastinal disorders

Nasal congestion

3% (17)

2% (11)

Gastrointestinal disorders

Diarrhoea*

42% (244)

18% (106)

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Double blind PAH

GRIPHON

System organ class

Selexipag

N = 575

Placebo

N = 577

Nausea*

33% (192)

18% (105)

Vomiting*

18% (104)

9% (49)

Abdominal pain*

8% (48)

6% (33)

Dyspepsia

4% (25)

2% (14)

Abdominal discomfort

4% (21)

2% (14)

Metabolism and nutrition disorders

Decreased appetite

6% (34)

3% (19)

Musculoskeletal and connective

tissue disorders

Jaw pain*

26% (148)

6% (33)

Pain in extremity*

17% (97)

8% (44)

Myalgia*

16% (92)

6% (34)

Arthralgia*

11% (62)

8% (44)

Musculoskeletal pain

3% (18)

2% (12)

Vascular disorders

Flushing*

12% (70)

5% (28)

Hypotension

5% (29)

3% (18)

Skin and subcutaneous tissue

disorders

Rash

11% (64)

8% (48)

General disorders and

administration site conditions

Asthenia

5% (31)

4% (24)

Pyrexia

4% (23)

3% (17)

Pain

3% (18)

1% (3)

Investigation

Weight decrease

3% (17)

1% (8)

UPTRAVI NEW ZEALAND DATA SHEET

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reported by 3% more in the active group vs placebo and/or if confirmed by laboratory findings (as appropriate) and/if the

adverse event is consistent with the pharmacology of the drug and hence a causal relationship was deemed at least as

possible.

* see section

Description of selected adverse reactions.

Table 3 presents adverse reactions occurring in selexipag-treated subjects at an incidence < 3 %

respectively and with a placebo-corrected difference ≥ 1 % (during treatment and up to 7 days after

treatment discontinuation). Adverse reactions are listed by system organ class and frequency

category, using the convention: common (≥ 1/100 and < 1/10). Frequency determination does not

account for other factors including varying study duration, pre-existing conditions, and baseline

patient characteristics.

U

Table 3

Adverse reactions occurring in selexipag-treated subjects at an incidence < 3 % and

with a placebo-corrected difference ≥ 1

U

%

P

System Organ Class

Common ≥ 1/100 and ˂ 1/10

Cardiac disorder*

Sinus tachycardia

Nervous system disorders

Burning sensation

Eye disorders

Eye pain

Vascular disorders

Hot flush

Musculoskeletal and connective

tissue disorders

Neck pain, bone pain

Endocrine disorders

Hyperthyroidism

Thyroid-stimulating

Hormone decreased

reported by < 3% in the active group vs placebo and/or if confirmed by laboratory findings (as

appropriate) and/if the adverse event is consistent with the pharmacology of the drug and hence a

causal relationship was deemed at least as possible.

Description of selected adverse reactions

Pharmacological effects associated with titration and maintenance treatment

Adverse reactions associated with the pharmacological action of selexipag have been observed

frequently, in particular during the phase of individualised dose titration (Table 4). These effects

usually are transient or manageable with symptomatic treatment.

Table 4

Adverse reactions associated with pharmacological action of selexipag during

titration and maintenance phase (> 3% placebo-corrected incidence in decreasing

order)

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Selexipag

Adverse reaction

Titration phase (≤

12 weeks)

N = 509

Maintenance phase

(> 12 weeks)

N = 509

Headache

Diarrhoea

Jaw pain

Nausea

Myalgia

Vomiting

Pain in extremity

Flushing

Arthralgia

Increase in heart rate:

In the Phase 3 placebo-controlled study in patients with PAH a transient increase in mean heart rate

of 3–4 bpm at 2-4 hours post-dose was observed. ECG investigations showed sinus tachycardia in

11.3% of patients in the selexipag group compared to 8.8% in the placebo group.

Laboratory abnormalities

Haemoglobin

In a Phase 3 placebo-controlled study in patients with PAH, mean absolute changes in haemoglobin

at regular visits compared to baseline ranged from −3.4 to −0.2 g/L in the selexipag group compared

to −0.5 to 2.5 g/L in the placebo group. A decrease from baseline in haemoglobin concentration to

below 100 g/L was reported in 8.6% of patients treated with selexipag and 5.0% of placebo-treated

patients.

Thyroid function tests

In a Phase 3 placebo-controlled study in patients with PAH, a reduction (up to −0.3 MU/L from a

baseline median of 2.5 MU/L) in median thyroid-stimulating hormone (TSH) was observed at most

visits in the selexipag group. In the placebo group, little change in median values was apparent.

There were no mean changes in triiodothyronine or thyroxine in either group.

Postmarketing data

In addition to the adverse reactions reported during clinical studies and listed above, the following

adverse reactions have been reported during postmarketing experience (Table 5). Because these

reactions were reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure. In the table, the

frequencies are provided according to the following convention:

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Very common

≥ 1/10 (≥ 10%)

Common

≥ 1/100 and < 1/10 (≥ 1% and < 10%)

Uncommon

≥ 1/1000 and < 1/100 (≥ 0.1% and < 1%)

Rare

≥ 1/10000 and < 1/1000 (≥0.01 and < 0.1%)

Very rare

< 1/10000, including isolated reports (< 0.01%)

Not known

Cannot be estimated from the available data

Table 5 Adverse reactions identified during postmarketing experience with selexipag

System Organ Class Adverse Reaction

Frequency category calculated from clinical

trials with selexipag

Immune system disorders

Hypersensitivity reactions

Common

Skin and subcutaneous tissue disorders

Urticaria

Common

Angioedema

Common

Overdose

Isolated cases of overdose up to 3200 µg were reported. Mild, transient nausea was the only

reported consequence. In the event of overdose, supportive measures must be taken as required.

Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein

bound.

Contact the Poisons Information Centre on 13 11 26 for advice on management of overdose. Contact

the NZ National Poisons Centre on 0800 POISON (0800 764766) for advice on management of

overdose.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic agents, platelet aggregation inhibitors excluding

herapin, ACT code: B01AC27

Mechanism of Action

The vasculo-protective effects of prostacyclin (PGI

) are mediated by the prostacyclin receptor (IP

receptor). Decreased expression of IP receptors and decreased synthesis of prostacyclin contribute

to the pathophysiology of pulmonary arterial hypertension (PAH).

Selexipag is an oral, selective, IP prostacyclin receptor agonist, and is structurally and

pharmacologically distinct from prostacyclin and its analogues. Selexipag is hydrolysed by

carboxylesterases) to yield its active metabolite, which is approximately 37-fold more potent than

selexipag. Selexipag and the active metabolite are high affinity IP receptor agonists with a high

selectivity for the IP receptor versus other prostanoid receptors (EP

, DP, FP and TP). Selectivity

against EP

, EP

, FP and TP is important because these are well-described contractile receptors in

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gastro-intestinal tract and blood vessels. Selectivity against EP

, EP

and DP

is important because

these receptors mediate immune depressive effects.

Stimulation of the IP receptor by selexipag and the active metabolite leads to vasodilatory as well as

anti-proliferative and anti-fibrotic effects. Selexipag improves haemodynamic parameters and

prevents cardiac and pulmonary remodeling in a rat model of PAH. In these PAH rats, pulmonary and

peripheral vasodilation in response to selexipag correlate, indicating that peripheral vasodilation

reflects pulmonary pharmacodynamic efficacy. Selexipag does not cause IP receptor desensitisation

in vitro nor tachyphylaxis in a rat model.

PAH patients have variable degrees of IP receptor expression. Differences in maintenance dose of

selexipag between individuals may be related to differences in IP receptor expression levels.

Pharmacodynamics

Cardiac electrophysiology:

In a thorough QT study in healthy subjects, repeated doses of 800 and 1600 micrograms of selexipag

twice daily did not show an effect on cardiac repolarisation (the QT

interval) or conduction (PR and

QRS intervals) and had a mild accelerating effect on heart rate. The placebo-corrected increase from

time-matched baseline heart rate 1.5 to 3 hours post-dose was 6–7 bpm at 800 μg twice daily and 9–

10 bpm at 1600 μg twice daily.

Pulmonary Haemodynamics:

A Phase 2 double-blind, placebo-controlled clinical study assessed haemodynamic parameters after

17 weeks of treatment in patients with PAH WHO functional classes II–III and concomitantly

receiving ERAs and/or PDE-5 inhibitor. Patients titrating selexipag to an individually tolerated dose

(200 micrograms twice daily increments up to 800 micrograms twice daily; N=33) achieved a

statistically significant mean reduction in pulmonary vascular resistance of 30.3% (95% CL −44.7%,

−12.2%; P = 0.0045) and an increase in cardiac index (mean treatment effect) 0.48 L/min/m

, 95% CL

0.13, 0.83 compared to placebo (N=10).

Clinical Efficacy and Safety

Efficacy in Patients with Pulmonary Arterial Hypertension

The effect of selexipag on progression of PAH was demonstrated in a multi-centre, long-term (mean

duration of exposure approximately 1.5 years up to maximum of 4.2 years), double-blind, placebo-

controlled, parallel group, event-driven Phase 3 study (GRIPHON) in 1156 patients with symptomatic

[WHO FC I–IV] PAH. Patients were randomised to either placebo (N=582), or selexipag (N=574) twice

a day. The dose was increased in weekly intervals by increments of 200 micrograms given twice a

day to determine the individualised maintenance dose (200 - 1600 micrograms twice a day).

The primary study endpoint was the time to first occurrence of a morbidity or mortality event up to

end of treatment defined as a composite of death (all-causes); or hospitalisation for PAH; or

progression of PAH resulting in need for lung transplantation or balloon atrial septostomy; or

initiation of parenteral prostanoid therapy or chronic oxygen therapy; or other disease progression

events (patients in modified NYHA/WHO FC II or III at baseline) confirmed by decrease in 6MWD

from baseline (≥ 15%) and worsening of NYHA/WHO FC or (patients in modified NYHA/WHO FC III or

IV at baseline) confirmed by decrease in 6MWD from baseline (≥ 15%) and need for additional PAH

specific therapy.

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All events were confirmed by an independent adjudication committee, blinded to treatment

allocation.

The mean age was 48.1 years (range 18–80 years of age) with the majority of subjects being

Caucasian (65.0%) and female (79.8%). Approximately 1%, 46%, 53%, and 1% of patients were in

WHO FC I, II, III, and IV, respectively, at baseline.

Idiopathic or heritable PAH was the most common aetiology in the study population (58%) followed

by PAH due to connective tissue disorders (29%), PAH associated with congenital heart disease with

repaired shunts (10%), and PAH associated with other aetiologies (drugs and toxins [2%] and HIV

[1%]). Patients with left ventricular dysfunction, moderate or severe obstructive or restrictive lung

disease, moderate or severe hepatic impairment, or severe renal insufficiency were excluded from

the study.

At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of specific

therapy for PAH, either with an ERA (15%) or with a PDE-5 inhibitor (32%) or both an ERA and a PDE-

5 inhibitor (33%).

Patients on selexipag achieved doses within the following groups: 200–400 micrograms (23%), 600–

1000 micrograms (31%) and 1200–1600 micrograms (43%).

The overall median double-blind treatment duration was 63.7 weeks for placebo group and 70.7

weeks for the group on selexipag.

Treatment with selexipag 200–1600 micrograms twice a day resulted in a 40% reduction (99%

confidence interval [CI] 22 to 54%; two-sided log rank p-value <0.0001) of the occurrence of

morbidity or mortality events up to 7 days after last dose compared to placebo (Figure 1). The

beneficial effect of selexipag was primarily attributable to a reduction in hospitalisation for PAH and

a reduction in other disease progression events (Table 6).

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Figure 1

Kaplan-Meier estimates of the first morbidity-mortality event in GRIPHON

Table 6

Primary Endpoint and Related Components in GRIPHON

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UPTRAVI

N=574

Placebo

N=582

Hazard Ratio

(99% CI)

p-value

Primary endpoint events up to the end of treatment

All primary endpoint events

As first event:

27.0

41.6

0.60 [0.46,0.78]

<0.0001

Hospitalisation for PAH

Other disease Progression

(Decrease in 6MWD plus

worsening functional class or

need for other therapy)

Death

13.6

18.7

17.2

Parenteral prostanoid or

chronic oxygen therapy

PAH worsening resulting in

need for lung transplantation

or balloon atrial septostomy

The observed benefit of selexipag was similar regardless of the dose achieved when patients are

titrated to their highest tolerated dose (see Dosage and Administration). This was shown by the

hazard ratio for the 3 pre-defined categories (0.60 for 200–400 micrograms twice daily, 0.53 for

600–1000 micrograms twice daily, and 0.64 for 1200–1600 micrograms twice daily), which was

consistent with the overall treatment effect (0.60).

The numerical increase in deaths up to end of treatment + 7 days but not up to study closure was

further investigated by mathematical modelling, showing that the most likely explanation for this

phenomenon is a reduction of non-fatal events by selexipag and a neutral effect on PAH mortality.

Figures 2A, B and C show time to first event analyses for primary endpoint components of

hospitalisation for PAH (A), other disease progression (B), and death (C)—all censored 7 days after

any primary end point event (because many patients on placebo transitioned to open-label UPTRAVI

at this point).

Figure 2A

Hospitalisation for PAH as the First Endpoint in GRIPHON

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Figure 2B

Disease Progression as the First Endpoint in GRIPHON

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Figure 2C

Death as the First Endpoint in GRIPHON

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The total number of deaths of all causes up to study closure was 100 (17.4%) for the UPTRAVI group

and 105 (18.0%) for the placebo group (HR 0.97, 99% CI: 0.68–1.39) (Figure 3).

Figure 3

Kaplan-Meier estimates of the occurrence of death up to study closure

The number of deaths due to PAH up to study closure was 70 (12.2%) for the UPTRAVI group and 83

(14.3%) for the placebo group.

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Subgroup analyses indicated consistent treatment effect across subgroups of age, sex, race,

aetiology, geographical region, WHO Functional Class, and by monotherapy or in combination with

ERA, PDE-5 inhibitors or triple combination with both an ERA and a PDE-5 inhibitor (Figure 4).

Figure 4

Sub-group analyses of the primary endpoint in the GRIPHON study

CI = confidence interval; EP = number of placebo patients with events; EU = number of Uptravi patients with events;

HR = hazard ratio; NP = number of patients randomised to placebo; NU = number of patients randomised to Uptravi; RRR =

relative risk reduction.

The size of the square represents the number of patients in the subgroup.

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all were pre-

specified. The 99% confidence limits that are shown do not take into account how many comparisons were made, nor do

they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity

among groups should not be over-interpreted.

Symptomatic endpoint

Exercise capacity was evaluated as a secondary endpoint. Treatment with UPTRAVI resulted in a

placebo-corrected median increase in 6MWD measured at trough (i.e., approximately 12 hours post-

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dose) of 12 metres at Week 26 (99% CI: 1 - 24, two-sided p-value: 0.005). In patients without

concurrent PAH-specific therapy, the treatment effect measured at trough was 34 metres (99% CI:

10.0 -,63.0 one sided p-value:0.0002).

Long-Term Treatment of PAH

Patients enrolled into the pivotal study (GRIPHON) were eligible to enter a long-term open-label

extension study. A total of 574 patients were treated with UPTRAVI in the GRIPHON study; of these,

330 patients continued UPTRAVI treatment in the open-label extension study. Kaplan-Meier

estimates of survival of these patients across the GRIPHON and the long-term extension study at 1,

2, 5 and 7 years were 92%, 85%, 71%, and 63%, respectively (Figure 5). The median follow-up

duration was 4.5 years and the median exposure to UPTRAVI was 3 years. Most patients were WHO

FC II or III (47.6% and 51.2%, respectively); less than 1% of patients were in FC I (0.7%) or IV (0.5%) at

baseline. The Kaplan-Meier estimates of survival at 1, 2, 5, and 7 years for patients of WHO FC I-II at

baseline of the pivotal study were 97%, 91%, 81% and 70%, respectively, and for patients of WHO FC

III-IV at baseline were 88%, 80%, 61% and 56%, respectively.

Figure 5

Kaplan-Meier estimates of time to death (all-causes) in long-term follow-up of

UPTRAVI treatment

Pharmacokinetic properties

The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy

subjects. The pharmacokinetics of selexipag and the active metabolite, both after single- and

multiple-dose administration, were dose-proportional up to a single dose of 800 micrograms and

multiple doses of up to 1800 micrograms twice a day. After multiple-dose administration, steady-

state conditions of selexipag and active metabolite were reached within 3 days. No accumulation in

plasma, either of parent compound or active metabolite, occurred after multiple-dose

administration.

Censoring Times

UPTRAVI (n/N=152/574)

Number of subjects at risk

UPTRAVI

574 558 543 527 5

Cumulative number of events

UPTRAVI

9 21 34 45

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In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval)

at steady-state was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject

variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively.

Exposure to selexipag and the active metabolite at steady-state was 30% and 20% higher,

respectively, in PAH patients compared to healthy subjects. The pharmacokinetics of selexipag and

the active metabolite in PAH patients were not influenced by the severity of the disease and did not

change with time.

Absorption

Selexipag is rapidly absorbed and is hydrolysed by carboxylesterases to its active metabolite.

The absolute bioavailability is of selexipag is approximately 49%.

Maximum observed plasma concentrations of selexipag and its active metabolite after oral

administration are reached within 1–3 h and 3–4 h, respectively.

In the presence of food, the exposure to selexipag after a single dose of 400 micrograms was

increased by 10% in Caucasian subjects and decreased by 15% in Japanese subjects, whereas

exposure to the active metabolite was decreased by 27% (Caucasian subjects) and 12% (Japanese

subjects). More subjects reported adverse events after administration in the fasted than in the fed

state.

Distribution

Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total

and to the same extent to albumin and alpha1-acid glycoprotein).

The volume of distribution of selexipag at steady state is 11.7L.

Biotransformation

Selexipag is hydrolysed to its active metabolite in the liver and in the intestine by carboxylesterases.

Oxidative metabolism catalysed mainly by CYP2C8 and to a smaller extent by CYP3A4 leads to the

formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the

glucuronidation of the active metabolite. Except for the active metabolite, none of the circulating

metabolites in human plasma exceeds 3% of the total drug-related material. Both in healthy subjects

and PAH patients, after oral administration, exposure at steady-state to the active metabolite is

approximately 3- to 4-fold higher than to the parent compound.

Elimination

Elimination of selexipag is predominantly via metabolism with a mean terminal half-life of 0.8-2.5 h.

The active metabolite has a half-life of 6.2-13.5h. The total body clearance of selexipag is 17.9 L/h.

Excretion in healthy subjects was complete 5 days after administration and occurred primarily via

faeces (accounting for 93% of the administered dose) compared to 12% in urine.

Special populations

No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag

and its active metabolite have been observed in healthy subjects or PAH patients. In PAH patients,

the exposure to selexipag and ACT-333679 decreased 9% and 4%, respectively, with increasing age

from 23 to 72 years. PAH patients with body weights of 51 (96) kg showed 30% higher (20% lower)

exposure to selexipag and 20% higher (10% lower) exposure to ACT-333679 compared to patients of

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70 kg body weight. PAH male patients showed 13% lower exposure to ACT-333679 than female

patients. These differences are smaller than the intersubject variability, which is larger than 30%.

Renal impairment

The AUC

0-∞

values of selexipag and ACT-333679 were increased 1.73-fold and 1.61-fold, respectively,

in subjects with severe renal function impairment (SRFI) compared to healthy subjects, and the t1/2

of ACT-333679 was prolonged 1.61-fold in patients with SRFI.

Hepatic impairment

In subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, after a single

dose administration of 400 micrograms of selexipag exposure to selexipag was 2- and 4-fold higher,

respectively, when compared to healthy subjects. Exposure to the active metabolite remained

almost unchanged in subjects with mild hepatic impairment and was doubled in subjects with

moderate hepatic impairment. Only two subjects with severe (Child-Pugh C) hepatic impairment

were dosed with selexipag. Exposure to selexipag and its active metabolite in these two subjects was

similar to that in subjects with moderate (Child-Pugh B) hepatic impairment.

Based on pharmacokinetic modelling of data from a study in subjects with hepatic impairment, the

exposure to the active metabolite at steady state in subjects with moderate hepatic impairment

(Child-Pugh class B) after a once-daily regimen is expected to be similar to that in healthy subjects

receiving a twice-daily regimen. The exposure to selexipag at steady state in subjects with moderate

hepatic impairment during a once-daily regimen is predicted to be approximately 2-fold that seen in

healthy subjects receiving a twice-daily regimen.

Preclinical safety data

In the repeated-dose toxicity studies in rodents, strong blood pressure decrease as a result of

exaggerated pharmacology induced transient clinical signs and reduced food consumption and body-

weight gain. In adult and juvenile dogs, intestine and bone / bone marrow were identified as the

main target organs after treatment with selexipag. In dogs less than 1 year of age, intussusception

due to prostacyclin-related effects on intestinal motility was observed sporadically. The effect

occurred at 5-fold the human exposure (i.e., corrected for potency; 415-fold based on total

exposure) (active metabolite). Safety margins based on no-observed-adverse-effect levels for the

active metabolite, corrected for difference in receptor potency between human and dog, were 2-

fold (i.e., corrected for potency; 180-fold based on total exposure) in relation to human exposure at

a dose of 1600 micrograms of selexipag twice a day. The finding did not occur in mouse or rat

toxicity studies. Because of the species-specific sensitivity of dogs to develop intussusception and

the safety margin, this finding is considered not relevant for adult humans.

Increased bone ossification and related changes in the bone marrow in dog studies are considered to

be due to the activation of EP4 receptors in dogs. As human EP4 receptors are not activated by

selexipag or its active metabolite, this effect is species-specific and, therefore, not relevant to

humans.

Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of

conducted genotoxicity studies.

In the 2-year carcinogenicity studies, selexipag caused an increased incidence of thyroid adenomas

in mice and Leydig cell adenomas in rats. The mechanisms are rodent-specific. The findings were

observed at exposures that were more than 25-fold above human exposure and are, therefore, not

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CCDS210413 Page 26 of 28 UPTRAVI (210531) ADS

relevant for humans. Tortuosity of retinal arterioles was noted after 2 years of treatment only in

rats. Mechanistically, the effect is considered to be induced by life-long vasodilation and subsequent

changes in ocular haemodynamics. The finding is considered to be species-specific.

Selexipag was not teratogenic in rats and rabbits, and had no effect on fertility of male and female

rats. In the rat pre- and post-natal development study, selexipag induced no effects on maternal and

pup reproductive function.

Selexipag and its active metabolite were phototoxic in vitro. A dedicated clinical study did not

indicate a phototoxic potential of selexipag in humans.

6 PHARMACEUTICAL PARTICULARS

List of excipients

Tablet cores

D-Mannitol,

Maize starch,

Low substituted hydroxypropyl cellulose,

Hydroxypropyl cellulose,

Magnesium stearate.

Film coating

UPTRAVI 200 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide yellow (E172),

Carnauba wax.

UPTRAVI 400 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide red (E172),

Carnauba wax.

UPTRAVI 600 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide red (E172),

Iron oxide black (E172),

Carnauba wax.

UPTRAVI 800 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide yellow (E172),

Iron oxide black (E172),

UPTRAVI NEW ZEALAND DATA SHEET

CCDS210413 Page 27 of 28 UPTRAVI (210531) ADS

Carnauba wax.

UPTRAVI 1000 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide red (E172),

Iron oxide yellow (E172),

Carnauba wax.

UPTRAVI 1200 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide black (E172),

Iron oxide red (E172),

Carnauba wax.

UPTRAVI 1400 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide yellow (E172),

Carnauba wax.

UPTRAVI 1600 microgram film coated tablet:

Hypromellose,

Propylene glycol,

Titanium dioxide (E171),

Iron oxide black (E172),

Iron oxide red (E172),

Iron oxide yellow (E172),

Carnauba wax.

Incompatibilities

Not applicable.

Shelf life

3 years

Special precautions for storage

Store at or below 30°C. Protect from moisture.

Nature and contents of container

Uptravi 200 microgram film-coated tablets

Polyamide / aluminium / high-density polyethylene / polyethylene with an embedded desiccant

agent / high-density polyethylene blister sealed with an aluminium foil (Alu/Alu blister with

desiccant) in cartons of either 60 or 140 (titration pack) film-coated tablets.

UPTRAVI NEW ZEALAND DATA SHEET

CCDS210413 Page 28 of 28 UPTRAVI (210531) ADS

Uptravi 400, 600, 800, 1000, 1200, 1400, and 1600 microgram film-coated tablets

Polyamide / aluminium / high-density polyethylene / polyethylene with an embedded desiccant

agent / high-density polyethylene blister sealed with an aluminium foil (Alu/Alu blister with

desiccant) in cartons of 60 film-coated tablets.

Special precautions for disposal

No special requirements for disposal.

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

requirements.

7 MEDICINE SCHEDULE

Prescription Only Medicine

8 SPONSOR

Janssen-Cilag (New Zealand) Ltd

Auckland, NEW ZEALAND

Telephone: 0800 800 806

Fax: (09) 588 1398

Email: medinfo@janau.jnj.com

9 DATE OF FIRST APPROVAL

17 March 2016

10 DATE OF REVISION OF THE TEXT

31 May 2021

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

4.8 Undesirable effects

Addition of postmarketing data.

5.1 Pharmacodynamic

properties

Update to reflect the results of GRIPHON open-label extension

study.

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