Uptravi 1,000microgram tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Selexipag
Available from:
Actelion Pharmaceuticals UK Ltd
ATC code:
B01AC27
INN (International Name):
Selexipag
Dosage:
1mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 02050100; GTIN: 7640111931928

Read the complete document

Package leaflet: Information for the patient

Uptravi 200 microgram film-coated tablets

Uptravi 400 microgram film-coated tablets

Uptravi 600 microgram film-coated tablets

Uptravi 800 microgram film-coated tablets

Uptravi 1,000 microgram film-coated tablets

Uptravi 1,200 microgram film-coated tablets

Uptravi 1,400 microgram film-coated tablets

Uptravi 1,600 microgram film-coated tablets

Selexipag

This medicine is subject to additional monitoring. This will allow quick identification of new

safety information. You can help by reporting any side effects you may get. See the end of section 4

for how to report side effects.

Read all of this leaflet carefully before taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you have any side effects, talk to your doctor or nurse. This includes any possible side effects

not listed in this leaflet (see section 4).

What is in this leaflet

What Uptravi is and what it is used for

What you need to know before you take Uptravi

How to take Uptravi

Possible side effects

How to store Uptravi

Contents of the package and other information

1.

What Uptravi is and what it is used for

Uptravi is a medicine that contains the active substance selexipag. It acts on blood vessels in a similar

way to the natural substance prostacyclin, making them relax and widen.

Uptravi is used for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients

insufficiently controlled with other types of medicines for PAH known as endothelin receptor

antagonists and phosphodiesterase type 5 inhibitors. Uptravi can be used on its own if the patient is

not a candidate for these medicines.

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.

By mimicking the action of prostacyclin, 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 of PAH and improves the course of the disease.

2.

What you need to know before you take Uptravi

Do not take Uptravi

if you are allergic to selexipag or any of the other ingredients of this medicine (listed in

section 6).

if you have a heart problem, such as:

poor blood flow to the heart muscles (severe coronary heart disease or unstable angina);

symptoms can include chest pain

heart attack within the last 6 months

weak heart (decompensated cardiac failure) that is not under close medical observation

severe irregular heartbeat

defect of the heart valves (inborn or acquired) that causes the heart to work poorly (not

related to pulmonary hypertension)

if you have had a stroke within the last 3 months, or any other occurrence that reduced the

blood supply to the brain (e.g., transient ischaemic attack)

if you are taking gemfibrozil (medicine used to lower the level of fats [lipids] in the blood)

Warnings and precautions

Talk to your PAH doctor or nurse before taking Uptravi if you

are taking medicines for high blood pressure

have low blood pressure associated with symptoms such as dizziness

have recently experienced significant blood loss or fluid loss such as severe diarrhoea or

vomiting

have problems with your thyroid gland

have severe problems with your kidneys or are undergoing dialysis

have or have had severe problems with your liver not working properly

are taking clopidogrel, deferasirox, or teriflunomide

If you notice any of the above signs or your condition changes, tell your doctor immediately.

Children and adolescents

Do not give this medicine to children under 18 years of age, because Uptravi has not been tested in

children.

Elderly patients

There is limited experience with Uptravi in patients older than 75 years. Uptravi should be used with

caution in this age group.

Other medicines and Uptravi

Tell your doctor if you are taking, have recently taken, or might take any other medicines.

Taking other medicines may affect how Uptravi works.

Talk to your PAH doctor or nurse if you are taking any of the following medicines:

Gemfibrozil (medicine used to lower the level of fats [lipids] in the blood)

Clopidogrel (medicine used to inhibit blood clots in coronary artery disease)

Deferasirox (medicine used to remove iron from the blood stream)

Teriflunomide (medicine used to treat relapsing-remitting multiple sclerosis)

Carbamazepine (medicine used to treat some forms of epilepsy, nerve pain or to help control

serious mood disorders when some other medicines do not work)

Phenytoin (medicine used to treat epilepsy)

Valproic acid (medicine used to treat epilepsy)

Probenecid (medicine used to treat gout)

Fluconazole, rifampicin or rifapentine (antibiotics used to treat infections)

Pregnancy and breast-feeding

Uptravi is not recommended during pregnancy and breast-feeding. 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.

Driving and using machines

Uptravi can cause side effects such as headaches and low blood pressure (see section 4), which may

affect your ability to drive; the symptoms of your condition can also make you less fit to drive.

3.

How to take Uptravi

Uptravi should only be prescribed by a doctor experienced in the treatment of PAH. Always take

Uptravi exactly as your doctor has told you. Check with your doctor if you are not sure or have any

questions.

If you have poor vision or experience any type of blindness, get help from another person when taking

Uptravi during the titration period.

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. Treatment should be initiated in the

evening. Your doctor will instruct you to 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 most appropriate dose. This

will be the highest dose you can tolerate, which may reach the maximum dose of 1,600

micrograms in

the morning and in the evening.

The first pack of tablets you receive will contain the light-yellow 200

microgram tablets.

Your doctor will tell you to increase your dose in steps, usually every week but the interval between

increases could be longer.

With each step, you will add one 200 microgram tablet to your morning dose and another

200 microgram tablet to your evening dose. The first intake of the increased dose should be in the

evening. The diagram below shows the number of tablets to take every morning and every evening

for the first 4 steps.

If your doctor instructs you to further increase your dose and move to step

5, this may be done by

taking one green 800

microgram tablet and one light-yellow 200

microgram tablet in the morning and

one 800

microgram tablet and one 200

microgram tablet in the evening.

If your doctor tells you to increase your dose further, you will add one 200

microgram tablet to your

morning dose and one 200

microgram tablet to your evening dose with each new step. The first intake

of the increased dose should be in the evening. The maximum dose of Uptravi is 1,600

micrograms in

the morning and 1,600

micrograms in the evening. However, not every patient will reach this dose,

because different patients require different doses.

The diagram below shows the number of tablets to take every morning and every evening at each

step, starting with step 5.

The titration pack also contains a titration guide providing information on the titration process and

allowing you to record the number of tablets you take every day.

Remember to record the number of tablets you take every day in your titration diary.

The titration

steps usually last about 1

week. If your doctor instructs you to prolong each titration step longer than

1 week, there are additional diary pages to allow you to track this. 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, diarrhoea, feeling sick (nausea),

being sick (vomiting), jaw pain, muscle pain, leg pain, joint pain, or reddening of the face (see

section

4). 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. For

example, painkillers such as paracetamol may help treat pain and headache.

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 the number of 200

microgram light-yellow tablets you take

by one in the morning and by one in the evening. The diagram below shows stepping down to a lower

dose. Do this only if instructed to do so by your doctor.

If your side effects are manageable after stepping down your dose, your doctor may decide that you

should stay on that dose. 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.

Your doctor will prescribe a suitable 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 each time.

For a full description of Uptravi tablets, including colours and marking, please see section 6 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 as your

dose may need to be reduced. The doctor may then prescribe you a lower single-tablet strength. Please

remember to dispose of unused tablets (see section 5).

Take Uptravi once in the morning and once in the evening, about 12 hours apart.

Take the tablets with meals as you might tolerate your medicine better. Swallow the tablets whole

with a glass of water. Do not split, crush or chew the tablets.

If you take more Uptravi than you should

If you have taken more tablets than you have been told to take, ask your doctor for advice.

If you forget to take Uptravi

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 6 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

Suddenly stopping your treatment with Uptravi might lead to your symptoms getting worse. Do not

stop taking Uptravi unless your doctor tells you to. Your doctor may tell you to reduce the dose

gradually before stopping completely.

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 doctor or nurse.

4.

Possible side effects

Like all medicines, Uptravi can cause side effects. 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, diarrhoea, feeling sick (nausea), being sick

(vomiting), jaw pain, muscle pain, leg pain, joint pain, or reddening of the face, that you cannot

tolerate or that cannot be treated, you should contact your doctor as the dose you are taking

maybe 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, leg pain

Nasopharyngitis (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

Rashes, including hives, may cause a burning or stinging sensation and skin redness

Uncommon side effects (may affect up to 1 in 100 people)

Increased heart rate

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly (see details below). By reporting side

effects you can help provide more information on the safety of this medicine.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or

Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

5.

How to store Uptravi

Keep this medicine out of the sight and reach of children.

Do not use Uptravi after the expiry date, which is stated on the carton and on the blister after “EXP.”

The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

No special requirements for disposal.

6.

Contents of the pack and other information

What Uptravi contains

The active substance is selexipag.

Uptravi 200 microgram film-coated tablets contain 200 micrograms of selexipag

Uptravi 400 microgram film-coated tablets contain 400 micrograms of selexipag

Uptravi 600 microgram film-coated tablets contain 600 micrograms of selexipag

Uptravi 800 microgram film-coated tablets contain 800 micrograms of selexipag

Uptravi 1,000 microgram film-coated tablets contain 1,000 micrograms of selexipag

Uptravi 1,200 microgram film-coated tablets contain 1,200 micrograms of selexipag

Uptravi 1,400 microgram film-coated tablets contain 1,400 micrograms of selexipag

Uptravi 1,600 microgram film-coated tablets contain 1,600 micrograms of selexipag

The other ingredients are:

In the tablet core:

Mannitol (E421), maize starch, low substituted hydroxypropyl cellulose, hydroxypropyl

cellulose, magnesium stearate.

In the film coat:

Hypromellose, propylene glycol, titanium dioxide (E171), carnauba wax and iron oxides (see

below).

Uptravi 200 microgram film-coated tablets contain iron oxide yellow (E172).

Uptravi 400 microgram film-coated tablets contain iron oxide red (E172).

Uptravi 600 microgram film-coated tablets contain iron oxide red and iron oxide black (E172).

Uptravi 800 microgram film-coated tablets contain iron oxide yellow and iron oxide black

(E172).

Uptravi 1,000 microgram film-coated tablets contain iron oxide red and iron oxide yellow

(E172).

Uptravi 1,200 microgram film-coated tablets contain iron oxide black and iron oxide red

(E172).

Uptravi 1,400 microgram film-coated tablets contain iron oxide yellow (E172).

Uptravi 1,600 microgram film-coated tablets contain iron oxide black, iron oxide red and iron

oxide yellow (E172).

What Uptravi looks like and contents of the pack

Uptravi 200 microgram film-coated tablets: Round, light-yellow, film-coated tablets with “2” marked

on one side.

Uptravi 400 microgram film-coated tablets: Round, red, film-coated tablets with “4” marked on one

side.

Uptravi 600 microgram film-coated tablets: Round, light-violet, film-coated tablets with “6” marked

on one side.

Uptravi 800 microgram film-coated tablets: Round, green, film-coated tablets with “8” marked on one

side.

Uptravi 1,000 microgram film-coated tablets: Round, orange, film-coated tablets with “10” marked on

one side.

Uptravi 1,200 microgram film-coated tablets: Round, dark-violet, film-coated tablets with “12”

marked on one side.

Uptravi 1,400 microgram film-coated tablets: Round, dark-yellow, film-coated tablets with “14”

marked on one side.

Uptravi 1,600 microgram film-coated tablets: Round, brown, film-coated tablets with “16” marked on

one side.

Uptravi 200 microgram film-coated tablets are supplied in blister packs of 10 or 60 tablets and 60 or

140 tablets (titration packs).

Uptravi 400 microgram, 600 microgram, 800 microgram, 1,000 microgram, 1,200 microgram,

1,400 microgram, and 1,600 microgram film-coated tablets are supplied in blister packs of 60 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Actelion Registration Ltd

Chiswick Tower 13

Floor

389 Chiswick High Road

London W4 4AL

United Kingdom

Tel: +44 20 8987 3320

Manufacturer

Actelion Manufacturing GmbH

Emil-Barell-Strasse 7

79639 Grenzach-Wyhlen

Germany

Actelion Pharmaceuticals Belgium NV

Bedrijvenlaan 1

2800 Mechelen

Belgium

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

België/Belgique/Belgien

Actelion Pharmaceuticals Belgium N.V.

Tél/Tel: +32-(0)15 284 777

Lietuva

Biocodex UAB

Tel: +370 37 40 86 81

България

Аквахим AД

Teл.: +359 2 807 50 00

Luxembourg/Luxemburg

Actelion Pharmaceuticals Belgium N.V.

Tél/Tel: +32-(0)15 284 777

Česká republika

Actelion Pharmaceuticals CZ, s.r.o.

Tel: +420 221 968 006

Magyarország

Actelion Pharmaceuticals Hungaria Kft.

Tel: +36-1-413-3270

Danmark

Actelion Danmark,

Filial af Actelion Pharmaceuticals Sverige AB,

Sverige

Tlf: +45 3694 45 95

Malta

Actelion Pharmaceuticals Ltd

Tel: +44 208 987 3333

Deutschland

Actelion Pharmaceuticals Deutschland GmbH

Tel: +49 761 45 64 0

Nederland

Actelion Pharmaceuticals Nederland B.V.

Tel: +31 (0)348 435950

Eesti

Biocodex OÜ

Tel: +372 605 6014

Norge

Actelion Pharmaceuticals Sverige AB,

Filial Norge

Tlf: +47 22480370

Ελλάδα

Actelion Pharmaceuticals Eλλάς Α.Ε.

Τηλ: +30 210 675 25 00

Österreich

Actelion Pharmaceuticals Austria GmbH

Tel: +43 1 505 4527

España

Actelion Pharmaceuticals España S.L.

Tel: +34 93 366 43 99

Polska

Actelion Pharma Polska Sp. z o.o.

Tel: +48 (22) 262 31 00

France

Actelion Pharmaceuticals France SAS

Tél: +33 1 58 62 32 32

Portugal

Actelion Pharmaceuticals Portugal Lda.

Tel: +351 21 358 6120

Hrvatska

Medis Adria d.o.o.

Tel: + 385 (0) 1 2303 446

România

Geneva Romfarm International SRL

Tel: + 40 (021) 231 3561

Ireland

Actelion Pharmaceuticals UK Ltd

Tel: +44 208 987 3333

Slovenija

Medis d.o.o.

Tel: +386-(0)1 589 69 00

Ísland

Actelion Pharmaceuticals Sverige AB

Sími: +46 (0)8 544 982 50

Slovenská republika

Actelion Pharmaceuticals SK, s.r.o.

Tel: +420 221 968 006

Italia

Actelion Pharmaceuticals Italia S.r.l.

Tel: +39 0542 64 87 40

Suomi/Finland

Actelion Pharmaceuticals Sverige AB,

Filial Finland

Puh/Tel: +358 9 2510 7720

Κύπρος

Actelion Pharmaceuticals Eλλάς Α.Ε.

Τηλ: +30 210 675 25 00

Sverige

Actelion Pharmaceuticals Sverige AB

Tel: +46 8 544 982 50

Latvija

Biocodex SIA

Tel: +371 6761 9365

United Kingdom

Actelion Pharmaceuticals UK Ltd

Tel: +44 208 987 3333

This leaflet was last revised in April 2018

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu.

Read the complete document

Object 1

Uptravi

Summary of Product Characteristics Updated 18-Apr-2018 | Actelion Pharmaceuticals UK Ltd

This medicinal product is subject to additional monitoring. This will allow quick identification of

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See

section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Uptravi 200 microgram film-coated tablets.

Uptravi 400 microgram film-coated tablets.

Uptravi 600 microgram film-coated tablets.

Uptravi 800 microgram film-coated tablets.

Uptravi 1,000 microgram film-coated tablets.

Uptravi 1,200 microgram film-coated tablets.

Uptravi 1,400 microgram film-coated tablets.

Uptravi 1,600 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 1,000 microgram film-coated tablets

Each film-coated tablet contains 1,000 micrograms of selexipag.

Uptravi 1,200 microgram film-coated tablets

Each film-coated tablet contains 1,200 micrograms of selexipag.

Uptravi 1,400 microgram film-coated tablets

Each film-coated tablet contains 1,400 micrograms of selexipag.

Uptravi 1,600 microgram film-coated tablets

Each film-coated tablet contains 1,600 micrograms of selexipag.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet

Uptravi 200 microgram film-coated tablets

Round, light-yellow, film-coated tablets with “2” debossed on one side.

Uptravi 400 microgram film-coated tablets

Round, red, film-coated tablets with “4” debossed on one side.

Uptravi 600 microgram film-coated tablets

Round, light-violet, film-coated tablets with “6” debossed on one side.

Uptravi 800 microgram film-coated tablets

Round, green, film-coated tablets with “8” debossed on one side.

Uptravi 1,000 microgram film-coated tablets

Round, orange, film-coated tablets with “10” debossed on one side.

Uptravi 1,200 microgram film-coated tablets

Round, dark-violet, film-coated tablets with “12” debossed on one side.

Uptravi 1,400 microgram film-coated tablets

Round, dark-yellow, film-coated tablets with “14” debossed on one side.

Uptravi 1,600 microgram film-coated tablets

Round, brown, film-coated tablets with “16” debossed on one side.

4. Clinical particulars

4.1 Therapeutic indications

Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult

patients with WHO functional class (FC) II–III, either as combination therapy in patients insufficiently

controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5)

inhibitor, or as monotherapy in patients who are not candidates for these therapies.

Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated

with connective tissue disorders, and PAH associated with corrected simple congenital heart disease (see

section 5.1).

4.2 Posology and method of administration

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

Posology

Individualised dose titration

Each patient should be up-titrated to the highest individually tolerated dose, which can range from 200

micrograms given twice daily to 1,600 micrograms given twice daily (individualised maintenance dose).

The recommended starting dose 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. At the

beginning of treatment and at each up-titration step it is recommended to take the first dose in the

evening. During dose titration some adverse reactions, reflecting the mode of action of Uptravi (such as

headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia, and flushing),

may occur. They are usually transient or manageable with symptomatic treatment (see section 4.8).

However, if a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous

dose level.

In patients in whom up-titration was limited by reasons other than adverse reactions reflecting the mode

of action of Uptravi, a second attempt to continue up-titration to the highest individually tolerated dose up

to a maximum dose of 1,600 micrograms twice daily may be considered.

Individualised maintenance dose

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

less tolerated at a given dose, symptomatic treatment and/or a dose reduction to the next lower dose

should be considered.

Interruptions and discontinuations

If a dose is missed, it should be taken as soon as possible. The missed dose should not be taken if the next

scheduled dose is within approximately 6 hours.

If treatment is missed for 3 days or more, Uptravi should be restarted at a lower dose and then up-titrated.

There is limited experience with abrupt discontinuation of Uptravi in patients with PAH. No evidence for

acute rebound has been observed.

However, if the decision to withdraw Uptravi is taken, it should be done gradually while an alternative

therapy is introduced.

Elderly (≥ 65 years)

No adjustment to the dose regimen is needed in elderly people (see section 5.2). There is limited clinical

experience in patients over the age of 75 years, therefore Uptravi should be used with caution in this

population (see section 4.4).

Hepatic impairment

Uptravi should not be administered in patients with severe liver impairment (Child-Pugh class C; see

section 4.4). For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of

Uptravi should be 200 micrograms once daily, and increased at weekly intervals by increments of 200

micrograms given once daily until adverse reactions, reflecting the mode of action of selexipag, that

cannot be tolerated or medically managed are experienced. No adjustment to the dose regimen is needed

in patients with mild hepatic impairment (Child-Pugh class A).

Renal impairment

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

change in starting dose is required in patients with severe renal impairment (estimated glomerular

filtration rate [eGFR] < 30 mL/min/1.73 m

); dose titration should be done with caution in these patients

(see section 4.4).

Paediatric population (< 18 years)

The safety and efficacy of Uptravi in children aged 0 to less than 18 years have not yet been established.

No data are available. Administration of selexipag in the paediatric population is not recommended.

Animal studies indicated an increased risk of intussusception, but the clinical relevance of these findings

is unknown (see section 5.3).

Method of administration

Oral use.

The film-coated tablets are to be taken orally in the morning and in the evening. To improve tolerability,

it is recommended to take Uptravi with food and, at the beginning of each up-titration phase, to take the

first increased dose in the evening.

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

Patients who have poor vision or are blind must be instructed to get assistance from another person when

taking Uptravi during the titration period.

4.3 Contraindications

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

Severe coronary heart disease or unstable angina.

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; see section 4.5).

4.4 Special warnings and precautions for use

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).

Hyperthyroidism

Hyperthyroidism has been observed with Uptravi. Thyroid function tests are recommended as clinically

indicated in the presence of signs or symptoms of hyperthyroidism.

Pulmonary veno-occlusive disease

Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in

patients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occur when

Uptravi is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should

be considered. If confirmed, treatment with Uptravi should be discontinued.

Moderate inhibitors of CYP2C8

Concomitant administration of selexipag with moderate inhibitors of CYP2C8 (e.g. clopidogrel,

deferasirox, teriflunomide) may increase the exposure to selexipag and its main active metabolite. An

adjustment of the dose of selexipag should be considered in case a moderate inhibitor of CYP2C8 is

coadministered or discontinued.

Elderly (≥ 65 years)

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 (see section 4.2).

Hepatic impairment

There is no clinical experience with selexipag in patients with severe liver impairment (Child-Pugh class

C), therefore Uptravi should not be administered in these patients. The exposure to selexipag and its

active metabolite is increased in subjects with moderate hepatic impairment (Child-Pugh class B; see

section 5.2). In patients with moderate hepatic impairment, Uptravi should be dosed once daily (see

section 4.2).

Renal impairment

In patients with severe renal impairment (eGFR < 30 mL/min/1.73 m

), caution should be exercised

during dose titration. There is no experience with Uptravi in patients undergoing dialysis (see section

5.2), therefore Uptravi should not be used in these patients.

Women of childbearing potential

Women of childbearing potential should practise effective contraception while taking selexipag.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on selexipag

Selexipag is hydrolysed to its active metabolite by carboxylesterases (see section 5.2). 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 weak substrate of the

P-gp efflux pump. The active metabolite is a weak substrate of the breast cancer resistance protein

(BCRP).

The pharmacokinetics of selexipag and its active metabolite are not affected by warfarin.

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, the major contributor to

efficacy, increased approximately 11-fold. Concomitant administration of Uptravi with strong inhibitors

of CYP2C8 (e.g., gemfibrozil) is contraindicated (see section 4.3).

The effect of moderate inhibitors of CYP2C8 (e.g., clopidogrel, deferasirox, teriflunomide) on the

exposure to selexipag and its active metabolite has not been studied. An adjustment of the dose of Uptravi

should be considered in case a moderate inhibitor of CYP2C8 is coadministered or discontinued. A

potential pharmacokinetic interaction with moderate inhibitors of CYP2C8 cannot be excluded (see

section 4.4).

Inducers of CYP2C8

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 selexipag may be required with concomitant administration of inducers of CYP2C8

(e.g., rifampicin, carbamazepine, phenytoin).

Inhibitors of UGT1A3 and UGT2B7

The effect of strong inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) on

the exposure to selexipag and its active metabolite has not been studied. Caution is required when

administering these medicinal products concomitantly with Uptravi. A potential pharmacokinetic

interaction with strong inhibitors of UGT1A3 and UGT2B7 cannot be excluded.

Inhibitors and inducers of CYP3A4

In the presence of 400/100 mg lopinavir/ritonavir twice daily, a strong CYP3A4 inhibitor, exposure to

selexipag increased approximately 2-fold, whereas the exposure to the active metabolite of selexipag did

not change. Given the 37-fold higher potency of the active metabolite, this effect is not clinically relevant.

Since a strong inhibitor of CYP3A4 did not affect the pharmacokinetics of the active metabolite,

indicating that the CYP3A4 pathway is not important in the elimination of the active metabolite, no effect

of inducers of CYP3A4 on the pharmacokinetics of the active metabolite is expected.

PAH-specific therapies

In the Phase 3 placebo-controlled trial in patients with PAH, the use of selexipag in combination with

both an ERA and a PDE-5 inhibitor resulted in a 30% lower exposure to the active metabolite.

Transporter inhibitors (lopinavir/ritonavir)

In the presence of 400/100 mg lopinavir/ritonavir twice daily, a strong 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. Given that the majority of the pharmacological effect is

driven by the active metabolite, this effect is not clinically relevant.

Effect of selexipag on other medicinal products

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

proteins at clinically relevant concentrations.

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 daily) 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.

Midazolam

At steady state after up-titration to 1,600 µg selexipag twice a day, no clinically relevant 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.

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 to the

CYP2C9 substrate S-warfarin, reduced efficacy of hormonal contraceptives is not expected.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should practise effective contraception while taking selexipag.

Pregnancy

There are no data from the use of selexipag in pregnant women. Animal studies do not indicate direct or

indirect harmful effects with respect to reproductive toxicity. Selexipag and its main metabolite showed

20- to 80-times lower prostacyclin (IP) receptor potency in vitro for animal species used in reproductive

toxicity testing compared to humans. Therefore, safety margins for potential IP receptor-mediated effects

on reproduction are accordingly lower than for non-IP-related effects (see section 5.3).

Uptravi is not recommended during pregnancy and in women of childbearing potential not using

contraception.

Breast-feeding

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

metabolites are excreted in milk (see section 5.3). A risk to the suckling child cannot be excluded. Uptravi

should not be used during breast-feeding.

Fertility

There are no clinical data available. In rat studies, selexipag at high doses caused transient disturbances in

oestrus cycles that did not affect fertility (see section 5.3). The relevance for humans is not known.

4.7 Effects on ability to drive and use machines

Uptravi has 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.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are headache, diarrhoea, nausea and vomiting, jaw pain,

myalgia, pain in extremity, arthralgia, and flushing. These reactions are more frequent during the up-

titration phase. The majority of these reactions are of mild to moderate intensity.

Tabulated list of adverse reactions

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

1,156 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.

Adverse reactions obtained from the pivotal clinical study are tabulated below. Within each frequency

grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Blood and lymphatic

disorders

Anaemia

Haemoglobin decreased

Endocrine disorders

Hyperthyroidism

Thyroid-stimulating Hormone

decreased (see section 4.4)

Metabolism and nutrition

disorders

Decreased appetite

Weight decrease

Nervous system disorders Headache*

Cardiac disorders

Sinus tachycardia (see

section 4.4)

Vascular disorders

Flushing*

Hypotension (see section 4.4)

Respiratory, thoracic and

mediastinal disorders

Nasopharyngitis (of

non-infectious origin)

Nasal congestion

Gastro-intestinal

disorders

Diarrhoea*

Vomiting *

Nausea*

Abdominal pain

Skin and subcutaneous

tissue disorders

Rash

Urticaria

Erythema

Musculoskeletal and

connective tissue

disorders

Jaw pain*

Myalgia*

Arthralgia*

Pain in extremity*

General disorders and

administration site

conditions

Pain

* See section Description of selected adverse reactions.

Description of selected adverse reactions

Pharmacological effects associated with titration and maintenance treatment

Adverse reactions associated with the mode of action of selexipag have been observed frequently, in

particular during the phase of individualised dose titration, and are tabulated below:

Prostacyclin-like associated

adverse reactions

Titration

Maintenance

Selexipag

Placebo

Selexipag

Placebo

Headache

Diarrhoea

Nausea

Pain in jaw

Myalgia

Pain in extremity

Vomiting

Flushing

Arthralgia

These effects are usually transient or manageable with symptomatic treatment. 7.5% of patients on

selexipag discontinued treatment due to these adverse reactions. The approximate rate of adverse

reactions that were serious was 2.3% in the selexipag group and 0.5% in the placebo group. In clinical

practice, gastro-intestinal events have been observed to respond to anti-diarrhoeal, anti-emetic, and anti-

nauseant medicinal products and/or medicinal products for functional gastro-intestinal disorders. Pain-

associated events have frequently been treated with analgesics (such as paracetamol).

Haemoglobin decrease

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

regular visits compared to baseline ranged from -0.34 to -0.02 g/dL in the selexipag group compared to

-0.05 to 0.25 g/dL in the placebo group. A decrease from baseline in haemoglobin concentration to below

10 g/dL was reported in 8.6% of selexipag-treated patients and 5.0% of placebo-treated patients.

Thyroid function tests

In a Phase 3 placebo-controlled study in patients with PAH, hyperthyroidism was reported for 1.6% of

patients in the selexipag group, compared to no case in the placebo group (see section 4.4). A reduction

(up to -0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone 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.

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. Electrocardiogram investigations showed sinus tachycardia

in 11.3% of patients in the selexipag group compared to 8.8% in the placebo group (see also sections 4.4

and 5.1).

Reporting of suspected adverse reactions

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

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

asked to report any suspected adverse reactions via the national reporting system listed below.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple

App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email

protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9 Overdose

Isolated cases of overdose up to 3,200 micrograms 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin,

ATC code: B01AC27

Mechanism of action

Selexipag is a selective IP receptor agonist 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

–EP

, DP, FP, and TP).

Selectivity against EP

, EP

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

receptors in the gastro-intestinal tract and blood vessels. Selectivity against EP

, EP

, and DP

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 prevents cardiac and pulmonary remodelling in a rat

model of PAH and causes proportional decreases in pulmonary and peripheral pressures, indicating that

peripheral vasodilation reflects pulmonary pharmacodynamic efficacy. Selexipag does not cause IP

receptor desensitisation in vitro nor tachyphylaxis in a rat model.

Pharmacodynamic effects

Cardiac electrophysiology

In a thorough QT study in healthy subjects, repeated doses of 800 and 1,600 micrograms of selexipag

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

interval) or conduction (PR and QRS

intervals) and had a mild accelerating effect on heart rate (the placebo-corrected, baseline-adjusted

increase in heart rate reached 6–7 bpm at 1.5 to 3 h after dosing with 800 micrograms selexipag and 9-10

bpm at the same timepoints after 1,600 micrograms selexipag).

Coagulation factors

In Phase 1 and 2 studies a slight decrease in plasma levels of von Willebrand factor (vWF) was observed

with selexipag; the vWF values remained above the lower limit of the normal range.

Pulmonary haemodynamics

A Phase 2 double-blind, placebo-controlled clinical study assessed haemodynamic variables after 17

weeks of treatment in patients with PAH WHO FC II–III and concomitantly receiving ERAs and/or PDE-

5 inhibitors. 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% confidence interval [CI]: -44.7%, -12.2%; p = 0.0045)

and an increase in cardiac index (mean treatment effect) of 0.48 L/min/m

(95% CI: 0.13, 0.83) compared

to placebo (N = 10).

Clinical efficacy and safety

Efficacy in patients with PAH

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

duration of exposure approximately 4.2 years), double-blind, placebo-controlled, parallel-group, event-

driven Phase 3 study in 1,156 patients with symptomatic (WHO FC I–IV) PAH. Patients were

randomised to either placebo (N = 582) or selexipag (N = 574) twice daily. The dose was increased at

weekly intervals by increments of 200 micrograms given twice daily to determine the individualised

maintenance dose (200–1,600 micrograms twice daily).

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 WHO FC

II or III at baseline) confirmed by a decrease in 6-minute walk distance (6MWD) from baseline (≥ 15%)

and worsening of WHO FC or (patients in WHO FC III or IV at baseline) confirmed by a decrease in

6MWD from baseline (≥ 15%) and need for additional PAH-specific therapy.

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%). 17.9% of patients were ≥ 65 and 1.1% ≥ 75 years of age. 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 simple corrected congenital heart

disease (10%), and PAH associated with other aetiologies (drugs and toxins [2%] and HIV [1%]).

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

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

(33%).

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

weeks for the selexipag group. 23% of patients on selexipag achieved maintenance doses in the range of

200–400 micrograms, 31% achieved doses in the range of 600–1,000 micrograms, and 43% achieved

doses in the range of 1,200–1,600 micrograms.

Treatment with selexipag 200–1,600 micrograms twice daily resulted in a 40% reduction (hazard ratio

[HR] 0.60; 99% CI: 0.46, 0.78; one-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 1).

Figure 1 Kaplan-Meier estimates of the first morbidity-mortality event

Table 1 Summary of outcome events

Endpoints &

statistics

Patients with an event

Treatment comparison: selexipag vs placebo

Placebo

(N=582)

Selexipag

(N=574)

Absolute risk

reduction

Relative risk

reduction (99%

CI)

HR

(99% CI)

p-value

Morbidity-

mortality event

a

58.2%

41.7%

16.5%

(22%; 54%)

0.60

(0.46; 0.78)

< 0.0001

Hospitalisation due

to PAH

b

n (%)

(18.7%)

(13.6%)

5.1%

(2%; 54%)

0.67

(0.46; 0.98)

0.04

Disease progression

b

n (%)

(17.2%)

(6.6%)

10.6%

(41%; 78%)

0.36

(0.22; 0.59)

< 0.0001

i.v./s.c.

Prostanoid

initiation or oxygen

therapy

b c

n (%)

(2.6%)

(1.9%)

0.7%

(-90%; 76%)

0.68

(0.24; 1.90)

0.53

Death up to EOT +

7 days

d

n (%)

(6.4%)

(8.0%)

-1.7%

-17%

(-107%;34%)

1.17

(0.66, 2.07)

0.77

Death up to study

closure

d

n (%)

(18.0%)

(17.4%)

0.6%

(-39%; 32%)

0.97

(0.68; 1.39)

0.42

CI = confidence interval; EOT = end of treatment; HR = hazard ratio; i.v. = intravenous; PAH =

pulmonary arterial hypertension; s.c. = subcutaneous.

(a) % of patients with an event at 36 months = 100 × (1 – Kaplan-Meier estimate); hazard ratio estimated

using Cox's proportional hazard model; unstratified one-sided log-rank p-value

(b) % of patients with an event as part of the primary endpoint up to EOT + 7 days; hazard ratio estimated

using Aalen Johansen method; 2-sided p-value using Gray's test

(c) Includes 'Need for lung transplantation or atrial septostomy' (1 patient on selexipag and 2 on placebo)

(d) % of patients with an event up to EOT + 7 days or up to study closure; hazard ratio estimated using

Cox's proportional hazard model; unstratified one-sided log-rank p-value

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 imbalance in deaths is consistent with the

assumption of a neutral effect on PAH mortality and reduction of non-fatal events.

The observed effect of selexipag versus placebo on the primary endpoint was consistent across

individualised maintenance dose as shown by the hazard ratio for the three pre-defined categories (0.60

for 200–400 micrograms twice daily, 0.53 for 600–1,000 micrograms twice daily, and 0.64 for 1,200–

1,600 micrograms twice daily), which was consistent with the overall treatment effect (0.60).

The efficacy of selexipag on the primary endpoint was consistent across subgroups of age, sex, race,

aetiology, geographical region, WHO FC, and as monotherapy or in combination with an ERA or a PDE-

5 inhibitor or triple combination with both an ERA and a PDE-5 inhibitor.

Time to PAH-related death or hospitalisation for PAH was assessed as a secondary endpoint. The risk of

an event for this endpoint was reduced by 30% in patients receiving selexipag compared to placebo (HR

0.70, 99% CI: 0.50, 0.98; one-sided log-rank p = 0.0031). The percentages of patients with an event at

Month 36 were 28.9% and 41.3% in the selexipag and placebo groups, respectively, with an absolute risk

reduction of 12.4%.

The number of patients who experienced, as a first event, death due to PAH or hospitalisation for PAH up

to end of treatment was 102 (17.8%) in the selexipag group and 137 (23.5%) in the placebo group. Death

due to PAH as a component of the endpoint was observed in 16 (2.8%) patients on selexipag and 14

(2.4%) on placebo. Hospitalisation for PAH was observed in 86 (15.0%) patients on selexipag and 123

(21.1%) patients on placebo. Selexipag reduced the risk of hospitalisation for PAH as a first outcome

event compared to placebo (HR 0.67, 99% CI: 0.46, 0.98; one-sided log-rank p = 0.04).

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

105 (18.0%) for the placebo group (HR 0.97, 99% CI: 0.68, 1.39). The number of deaths due to PAH up

to study closure was 70 (12.2%) for the selexipag group and 83 (14.3%) for the placebo group.

Symptomatic endpoints

Exercise capacity was evaluated as a secondary endpoint. Median 6MWD at baseline was 376 m (range:

90–482 m) and 369 m (range: 50–515 m) in selexipag patients and placebo patients, respectively.

Treatment with selexipag resulted in a placebo-corrected median effect on 6MWD measured at trough

(i.e., approximately 12 h post-dose) of 12 m at Week 26 (99% CI: 1, 24 m; one-sided p value = 0.0027).

In patients without concurrent PAH-specific therapy, the placebo-corrected treatment effect measured at

trough was 34 m (99% CI: 10, 63 m).

Quality of life was assessed in a subset of patients in the GRIPHON study using the Cambridge

Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire. There was no significant

treatment effect from baseline to Week 26.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Uptravi

in one or more subsets of the paediatric population for treatment of pulmonary hypertension, (see section

4.2 for information on paediatric use).

5.2 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 1,800 micrograms twice daily. After multiple-dose administration, steady state conditions of

selexipag and the active metabolite were reached within 3 days. No accumulation in plasma, either of

parent compound or active metabolite, occurred after multiple-dose administration.

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 in PAH patients and healthy subjects was

similar. 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.

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

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

The absolute bioavailability of selexipag in humans is approximately 49%. This is most probably due to a

first-pass effect of selexipag, as plasma concentrations of the active metabolite are similar after the same

oral and intravenous dose administration.

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 11.7 L.

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 exceed 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 6.2–13.5 h. 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.

Renal impairment

A 1.4- to 1.7-fold increase in exposure (maximum plasma concentration and area under the plasma

concentration-time curve) to selexipag and its active metabolite was observed in subjects with severe

renal impairment (eGFR < 30 mL/min/1.73 m

Hepatic impairment

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

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 class 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 class B)

hepatic impairment.

Based on modelling and simulation data from a study in subjects with hepatic impairment, the exposure to

selexipag at steady state in subjects with moderate hepatic impairment (Child-Pugh class B) after a once-

daily regimen is predicted to be approximately 2-fold higher than that in healthy subjects during a twice-

daily regimen. The exposure to the active metabolite at steady state in these patients during a once-daily

regimen is predicted to be similar to that in healthy subjects during a twice-daily regimen. Subjects with

severe hepatic impairment (Child-Pugh class C) showed similar predicted exposure at steady state as

subjects with moderate hepatic impairment during a once-daily regimen.

5.3 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. A delay in the closure of the femoral and/or tibial epiphyseal growth plate was

observed in juvenile dogs. A no-observed-adverse-effect level was not established. In juvenile dogs,

intussusception due to prostacyclin-related effects on intestinal motility was observed sporadically. Safety

margins adapted for IP receptor potency for the active metabolite were 2-fold (based on total exposure) in

relation to human therapeutic exposure. The finding did not occur in mouse or rat toxicity studies.

Because of the species-specific sensitivity of dogs to develop intussusception, 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 EP

receptors in dogs. As human EP

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. 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. Additional

histopathological findings of selexipag were observed only at exposures sufficiently in excess of the

maximum human exposure, indicating little relevance to humans.

In a fertility study performed in rats, a prolongation of oestrus cycles resulting in increases in days until

copulation was observed at exposures 173-fold above therapeutic exposures (based on total exposures),

the no-observed-effect level being 30-fold above therapeutic exposures. Otherwise, fertility parameters

were not affected.

Selexipag was not teratogenic in rats and rabbits (exposure margins above therapeutic exposure of 13-fold

for selexipag and 43-fold for the active metabolite, based on total exposure). Safety margins for potential

IP receptor-related effects on reproduction were 20 for fertility and 5 and 1 (based on free exposure) for

embryo-foetal development in rats and rabbits, respectively, when adapted for differences in receptor

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

reproductive function.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Mannitol (E421),

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),

carnauba wax.

Uptravi 1,000 microgram film-coated tablet

Hypromellose,

propylene glycol,

titanium dioxide (E171),

iron oxide red (E172),

iron oxide yellow (E172),

carnauba wax.

Uptravi 1,200 microgram film-coated tablet

Hypromellose,

propylene glycol,

titanium dioxide (E171),

iron oxide black (E172),

iron oxide red (E172),

carnauba wax.

Uptravi 1,400 microgram film-coated tablet

Hypromellose,

propylene glycol,

titanium dioxide (E171),

iron oxide yellow (E172),

carnauba wax.

Uptravi 1,600 microgram film-coated tablet

Hypromellose,

propylene glycol,

titanium dioxide (E171),

iron oxide black (E172),

iron oxide red (E172),

iron oxide yellow (E172),

carnauba wax.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Polyamide / aluminium / HDPE / PE with an embedded desiccant agent / HDPE blister sealed with an

aluminium foil.

Uptravi 200 microgram film-coated tablets

Cartons of 10 or 60 film-coated tablets, and 60 or 140 film-coated tablets (titration packs).

Uptravi 400 microgram, 600 microgram, 800 microgram, 1,000 microgram, 1,200 microgram, 1,400

microgram, and 1,600 microgram film-coated tablets

Cartons of 60 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. Marketing authorisation holder

Actelion Registration Ltd

Chiswick Tower 13

Floor

389 Chiswick High Road

London W4 4AL

United Kingdom

8. Marketing authorisation number(s)

EU/1/15/1083/001

EU/1/15/1083/002

EU/1/15/1083/003

EU/1/15/1083/004

EU/1/15/1083/005

EU/1/15/1083/006

EU/1/15/1083/007

EU/1/15/1083/008

EU/1/15/1083/009

EU/1/15/1083/010

EU/1/15/1083/011

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 12 May 2016

10. Date of revision of the text

April 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

Company Contact Details

Actelion Pharmaceuticals UK Ltd

Address

Chiswick Tower 13th Floor, 389 Chiswick High Road, Chiswick, London, W4 4AL

Telephone

+44 (0)208 987 3333

Medical Information Direct Line

+44 (0)208 987 3333

http://www.actelion.com

+44 (0)208 987 3322

Medical Information e-mail

[email

protected]

Similar products

Search alerts related to this product

View documents history

Share this information