Consumer medicine information

Uptravi

Selexipag

BRAND INFORMATION

Brand name

Uptravi

Active ingredient

Selexipag

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Uptravi.

SUMMARY CMI

UPTRAVI®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using UPTRAVI?

UPTRAVI contains the active ingredient selexipag. UPTRAVI is used to treat pulmonary arterial hypertension (PAH) in adults.

For more information, see Section 1. Why am I using UPTRAVI? in the full CMI.

2. What should I know before I use UPTRAVI?

Do not use if you have ever had an allergic reaction to selexipag or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use UPTRAVI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with UPTRAVI and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use UPTRAVI?

  • At the start of treatment, you will take the lowest dose. This is one 200 micrograms tablet in the morning and another 200 micrograms 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 micrograms twice a day.
  • Swallow the tablets whole, do not split, crush or chew the UPTRAVI tablets.

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

5. What should I know while using UPTRAVI?

Things you should do
  • Remind any doctor or pharmacist you visit that you are taking UPTRAVI.
  • Tell your doctor if you become pregnant or are trying to become pregnant.
  • Tell your doctor if, for any reason, you have not used your medicine exactly as prescribed.
  • Keep all of your doctor or clinic appointments.
Things you should not do
  • Do not stop using this medicine unless you have agreed this with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how UPTRAVI affects you. If you are affected, do not drive or operate machinery.
Looking after your medicine
  • Store below 30°C. Protect from moisture.

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

6. Are there any side effects?

The most common side effects are headache, diarrhoea, feeling sick, being sick, jaw pain, muscle pain, pain in hands, arms, legs or feet, flushing, and joint pain. Serious side effects are allergic reaction or anaphylaxis and kidney failure.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

UPTRAVI® (UP-tra-vee)

Active ingredient(s): Selexipag (se-le-xi-pag)

Consumer Medicine Information (CMI)

This leaflet provides important information about using UPTRAVI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using UPTRAVI.

Where to find information in this leaflet:

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

1. Why am I using UPTRAVI?

UPTRAVI contains the active ingredient selexipag. UPTRAVI is a medicine that acts on a receptor that is the target of a natural substance called "prostacyclin".

UPTRAVI is used to treat 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 of PAH and improves the course of the disease.

2. What should I know before I use UPTRAVI?

Warnings

Do not use UPTRAVI if:

  • you are allergic to selexipag, or any of the ingredients listed at the end of this leaflet.
  • you have severe liver problems (Child-Pugh Class C)
  • you have had a stroke within the last 3 months
  • you have severe coronary heart disease or unstable angina
  • you have had a myocardial infarction (heart attack) within the last 6 months
  • you have a weak heart (decompensated cardiac failure) that is not under close medical observation
  • you have severe arrhythmias (irregular heartbeat problem)
  • you have defect of your heart valves (inborn or acquired) that causes the heart to work poorly (not related to pulmonary hypertension)
  • you are taking medicines that are strong inhibitors of CYP2C8 (e.g. gemfibrozil).

Check with your doctor if you:

  • have low blood pressure or experience dizziness or fainting
  • have problems with your liver
  • have severe problem with your kidneys or undergoing dialysis
  • have problems with thyroid gland

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

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

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.

Children and adolescents

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.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

You must tell your doctor if you are taking medicines for high blood pressure.

You must tell your doctor if you are taking:

  • Rifampicin (antibiotic used to treat infections)
  • Sodium valproate or valproic acid (used to treat epilepsy)
  • Gemfibrozil (medicine used to lower the levels of fat in the blood)
  • Lopinavir and ritonavir (antivirals used to treat HIV)
  • Clopidogrel (used to treat heart disease/strokes)
  • Deferasirox (used to treat some blood disorders)
  • Teriflunomide (used to treat nervous system disorders)

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

4. How do I use UPTRAVI?

How much to take

  • Your doctor will decide what dose of UPTRAVI is suitable for you.
  • Always take UPTRAVI exactly as your doctor has told you. Check with your doctor if you are not sure.
  • Tell your doctor if you have problems with your liver or are taking other medications as your doctor may recommend different dose of UPTRAVI.

Finding the right dose for you

  • At the start of treatment, you will take the lowest dose. This is one 200 micrograms tablet in the morning and another 200 micrograms tablet in the evening. It is recommended to take the first dose 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 micrograms twice a day.
  • During titration, you will receive a titration pack containing light yellow UPTRAVI 200 micrograms 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 micrograms tablet to your morning and evening doses. The first intake of the increased dose should be in the evening. 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 micrograms tablet and adding one light-yellow 200 micrograms tablet. For this, you will receive a pack containing green UPTRAVI 800 micrograms tablets (with an “8” stamped on one side) and a titration pack containing light yellow UPTRAVI 200 micrograms 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 micrograms tablet to your morning and evening doses. The first intake of the increased dose should be in the evening. 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 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 micrograms 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.

  • 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 colour 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 details 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.

When to take UPTRAVI

  • Take UPTRAVI in the morning and in the evening, consistently either with or without meals. You might tolerate the medicine better when you take it with meals.

How to take UPTRAVI

  • Swallow the tablets whole, do not split, crush or chew the UPTRAVI tablets.

If you forget to use UPTRAVI

UPTRAVI should be used regularly at the same time each day. If you miss your dose at the usual time, take a dose as soon as you remember, then continue to take your tablets at the usual times.

If it is almost time for your next dose (within six hours before you would normally take it), skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

  • 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 use too much UPTRAVI

If you think that you have used too much UPTRAVI, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (in Australia telephone 13 11 26 and in New Zealand telephone 0800 POISON or 0800 764 766), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using UPTRAVI?

Things you should 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.

Remind any doctor or pharmacist you visit that you are taking UPTRAVI.

Things you should not do

  • Do not stop using this medicine unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use UPTRAVI to treat any other complaints unless your doctor says to.

Driving or using machines

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

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. If you are affected, do not drive or operate machinery.

Looking after your medicine

  • Store below 30°C. Protect from moisture.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date. The expiry date refers to the last day of that month.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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 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 may be too high for you and may need to be reduced.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Headache
  • Flushing (reddening of the face)
  • Nausea and vomiting (feeling sick and being sick)
  • Diarrhoea
  • Jaw pain, muscle pain, joint pain
  • Rash
  • Stuffy nose
  • Anaemia (low red blood cell levels)
  • Hyperthyroidism (overactive thyroid gland)
  • Decreased appetite
  • Weight loss
  • Hypotension (low blood pressure)
  • Stomach pain, including indigestion
  • Pain in hands, arms, legs or feet
  • Changes in some blood test results including those measuring blood cell counts or your thyroid function
  • Increased heart rate
  • Eye pain
  • Fever
  • Burning sensation
  • Feeling very tired
  • Flu like symptoms
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of an allergic reaction such as:
  • wheezing, shortness of breath, difficulty breathing, or a tight feeling in your chest
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching, hives or flushed red skin
  • dizziness or light-headedness.
Signs of kidney failure such as:
  • decreased urine output
  • swelling in the ankles or feet
  • tiredness or weakness
  • shortness of breath
  • confusion
  • irregular heartbeat
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online in Australia at www.tga.gov.au/reporting-problems or in New Zealand at pophealth.my.site.com/carmreportnz/s/. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What UPTRAVI contains

Active ingredient
(main ingredient)		selexipag
Other ingredients
(inactive ingredients)		Tablet core:
mannitol, maize starch, hyprolose, magnesium stearate
Film coat:
200 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide yellow, carnauba wax.
400 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide red, carnauba wax.
600 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide red, iron oxide black, carnauba wax.
800 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide yellow, iron oxide black, carnauba wax.
1000 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide red, iron oxide yellow, carnauba wax.
1200 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide black, iron oxide red, carnauba wax.
1400 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide yellow, carnauba wax
1600 micrograms:
hypromellose, propylene glycol, titanium dioxide, iron oxide black, iron oxide red, iron oxide yellow, carnauba wax.
Potential allergensn/a

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

What UPTRAVI looks like

UPTRAVI 200 micrograms film-coated tablets are: Round, light yellow, film-coated tablets with “2” marked on one side. (AUST R 234161).

UPTRAVI 400 micrograms film-coated tablets are: Round, red, film-coated tablets with “4” marked on one side. (AUST R 234160)

UPTRAVI 600 micrograms film-coated tablets are: Round, light violet, film-coated tablets with “6” marked on one side. (AUST R 234159)

UPTRAVI 800 micrograms film-coated tablets are: Round, green, film-coated tablets with “8” marked on one side. (AUST R 234166)

UPTRAVI 1000 micrograms film-coated tablets are: Round, orange, film-coated tablets with “10” marked on one side. (AUST R 234162)

UPTRAVI 1200 micrograms film-coated tablets are: Round, dark violet, film-coated tablets with “12” marked on one side. (AUST R 234163)

UPTRAVI 1400 micrograms film-coated tablets are: Round, dark yellow, film-coated tablets with “14” marked on one side. (AUST R 234165)

UPTRAVI 1600 micrograms film-coated tablets are: Round, brown, film-coated tablets with “16” marked on one side. (AUST R 234164)

Who distributes UPTRAVI

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 on 13 January 2025.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Uptravi

Active ingredient

Selexipag

Schedule

S4

 

1 Name of Medicine

Uptravi selexipag.

2 Qualitative and Quantitative Composition

Selexipag is a pale yellow crystalline powder that is practically insoluble in water. In the solid state, selexipag is very stable, is not hygroscopic, and is not light sensitive.
Each round film-coated tablet contains 200 microgram or multiples thereof (respectively 400, 600, 800, 1000, 1200, 1400, or 1600 microgram) selexipag. The film-coated tablets are not light sensitive.
See Section 6.1 List of Excipients.

3 Pharmaceutical Form

Uptravi 200 microgram, light yellow, debossed with '2', round, film-coated tablet.
Uptravi 400 microgram, red, debossed with '4', round, film-coated tablet.
Uptravi 600 microgram, light violet, debossed with '6', round, film-coated tablet.
Uptravi 800 microgram, green, debossed with '8', round, film-coated tablet.
Uptravi 1000 microgram, orange, debossed with '10', round, film-coated tablet.
Uptravi 1200 microgram, dark violet, debossed with '12', round, film-coated tablet.
Uptravi 1400 microgram, dark yellow, debossed with '14', round, film-coated tablet.
Uptravi 1600 microgram, brown, debossed with '16', round, film-coated tablet.
See Section 6.5 Nature and Contents of Container.

4 Clinical Particulars

4.1 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.

4.2 Dose and Method of Administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension (PAH).
Selexipag can be used in 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.

Method of administration.

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.

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 microgram given twice daily, approximately 12 hours apart. The dose is increased in increments of 200 microgram 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 microgram twice daily is reached. 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, it is recommended not to discontinue treatment in the event of expected pharmacological side effects since they are usually transient or manageable with symptomatic treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 restarted at a lower dose and then titrated.

Dosage adjustment in elderly patients.

Elderly (≥ 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. Avoid use of Uptravi in patients with severe hepatic impairment (Child-Pugh class C, see Section 4.3 Contraindications).

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.

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 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, In vivo studies, Inhibitors of CYP2C8.)

4.3 Contraindications

Uptravi is contraindicated in patients with:
Known hypersensitivity to the active substance selexipag 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.
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 administration of strong inhibitors of CYP2C8 (e.g. gemfibrozil; see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 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 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). 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, other PAH therapy or with resting hypotension, hypovolaemia, severe left ventricular outflow obstruction or autonomic dysfunction). Monitoring of blood pressure is recommended in such patients as clinically indicated.

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.

Use in the 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 use.

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

Use in 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 population. There is no clinical experience with Uptravi in patients with severe hepatic impairment (Child-Pugh class C). Avoid use of Uptravi in patients with severe hepatic impairment (see Section 4.3 Contraindications).

Use in 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 clinical experience with Uptravi in patients undergoing dialysis or in patients with estimated glomerular filtration rates < 15 mL/min/1.73 m2.

Effects on laboratory tests.

Please see Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro studies.

Selexipag is hydrolysed to its active metabolite by carboxylesterases [see Section 5.2 Pharmacokinetic Properties]. Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent 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.

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. Patients on combination PAH therapy experienced a greater number of adverse events including anaemia in some patients.

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 microgram 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.

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 with concomitant administration of inducers of CYP2C8 (e.g. rifampicin).

Midazolam.

At steady state after up-titration to 1600 microgram 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.

Inhibitors of UGT1A3 and UGT2B7.

The effect of strong inhibitors of UGT1A3 and UGT2B7 (such as valproic acid), on the exposure to selexipag or its active metabolite has not been studied. Caution is recommended when administering these drugs concomitantly with selexipag. Concomitant administration may result in a significant exposure to selexipag 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 but 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 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. Although multiple-dose treatment with selexipag did not affect the exposure to the CYP3A4 substrates midazolam and r-warfarin or the CYP2C9 substrate s-warfarin and no reduced efficacy of hormonal contraceptives is expected, caution should be exercised (see Section 4.6 Fertility, Pregnancy and Lactation).

Pharmacodynamic interactions.

Reductions in blood pressure may occur when Uptravi is administered with diuretics, antihypertensive agents, or other vasodilators.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Selexipag had no effect on fertility of male and female rats. In the rat pre- and postnatal development study, selexipag induced no effects on maternal and pup reproductive function.
(Category B1)
Use in pregnancy should be avoided. Pregnant women were excluded from the trial and there is no data in human pregnancy. Selexipag was not teratogenic in rats and rabbits.
 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.

4.7 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.

4.8 Adverse Effects (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 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 2 presents adverse drug reactions occurring 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). 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.

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 3). These effects are usually transient or manageable with symptomatic treatment.

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 postdose was observed. ECG investigations showed sinus tachycardia in 11.3% of patients in the selexipag group compared to 8.8% in the placebo group.

Eye disorders.

Eye disorders in the selexipag and placebo groups occurred in 11.0% and 7.8%, respectively (mostly eye pain at 1.6% vs. 0.3%) and retinal disorders in 3.5% vs. 1.9%. Tortuosity and dilation of retinal arterioles were seen in rats after 2 years of treatment with very high doses (more than 25-fold above human exposure).

Malignancies.

Malignancies occurred in 1.9% (n = 11) in the selexipag group and 0.7% (n = 4) in the placebo group, mainly due to cutaneous malignancies and blood and lymphatic system malignancies (see Section 5.3, Genotoxicity, Carcinogenicity).

Laboratory abnormalities.

Haemoglobin/anaemia.

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. Median haemoglobin concentrations decreased over the first 3 months of treatment and stabilised thereafter.
Adverse events of anaemia were more frequent in selexipag patients who were taking concomitant treatment for PAH: ERA monotherapy: 14.9% and 9.2% with selexipag and placebo, respectively; PDE-5i monotherapy: 11.1% and 5.4%; ERA and PDE-5i: 11.2% and 10.7%. The incidence of anaemia AEs in patients who received no concomitant PAH specific therapies were 4.5% in the selexipag group and 6.7% in the placebo group.

Thyroid function tests.

In a phase 3 placebo controlled study in patients with PAH, a reduction in median thyroid stimulating hormone (TSH) (up to -0.3 MU/L from a baseline median of 2.5 MU/L) 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.

Long-term safety.

Of the 1,156 patients who participated in the pivotal study, 709 patients entered a long-term open label extension study (330 patients who continued on selexipag from the GRIPHON study and 379 patients who received placebo in GRIPHON and crossed over to selexipag). Long-term follow up of patients treated with selexipag for a median treatment duration of 31.7 months and for a maximum of up to 126 months showed a safety profile that was similar to that observed in the pivotal clinical study described above.

Combination treatment of selexipag with macitentan and tadalafil in newly diagnosed PAH patients.

Safety of triple combination treatment (selexipag, macitentan and tadalafil) versus double combination (macitentan, tadalafil and placebo) in newly diagnosed PAH patients was evaluated in the double-blind, placebo-controlled TRITON clinical study. The median duration of exposure to selexipag/ placebo was 90 weeks.
The adverse reactions that occurred in at least 10% of patients in triple therapy group and ≥ 5% more commonly on selexipag, macitentan and tadalafil than on placebo, macitentan, and tadalafil are shown in Table 4. Adverse reactions are listed by system organ class and frequency category is defined using the convention: very common (≥ 10%).

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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Isolated cases of overdose up to 3200 microgram 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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The vasculoprotective effects of prostacyclin (PGI2) 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 (EP1-EP4, DP, FP and TP). Selectivity against EP1, EP3, FP and TP is important because these are well described contractile receptors in gastrointestinal tract and blood vessels. Selectivity against EP2, EP4 and DP1 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 antiproliferative and antifibrotic 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 microgram of selexipag twice daily did not show an effect on cardiac repolarisation (the QTc 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 postdose was 6-7 bpm at 800 microgram twice daily and 9-10 bpm at 1600 microgram 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 microgram twice daily increments up to 800 microgram 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/m2, 95% Cl 0.13, 0.83 compared to placebo (N = 10).

Clinical trials.

Efficacy in patients with pulmonary arterial hypertension. The effect of selexipag on progression of PAH was demonstrated in a multicentre, long-term (mean duration of exposure was approximately 1.5 years up to a maximum of 4.2 years), double blind, placebo controlled, parallel group, event driven phase 3 study (GRIPHON) in 1156 patients with symptomatic [WHO functional class (FC) I-IV] PAH. Patients were randomised to either placebo (N = 582), or selexipag (N = 574) twice a day in multiples of 200 microgram. The dose was increased in weekly intervals by increments of 200 microgram given twice a day to determine the individualised maintenance dose (200-1600 microgram 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.
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 of whom three patients in WHO FC IV received selexipag.
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 microgram (23%), 600-1000 microgram (31%) and 1200-1600 microgram (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 microgram 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).
The observed benefit of selexipag was similar regardless of the dose achieved when patients are titrated to their highest tolerated dose (see Section 4.2 Dose and Method of Administration). This was shown by the hazard ratio for the 3 predefined categories (0.60 for 200-400 microgram twice daily, 0.53 for 600-1000 microgram twice daily, and 0.64 for 1200-1600 microgram twice daily), which was consistent with the overall treatment effect (0.60).
It is not known if the excess number of deaths in the selexipag group is drug related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON. Figures 2, 3 and 4 show time to first event analyses for primary endpoint components of hospitalisation for PAH (Figure 2), other disease progression (Figure 3), and death (Figure 4), all censored 7 days after any primary endpoint event (because many patients on placebo transitioned to open label Uptravi at this point).
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).
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.
Subgroup analyses were performed 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. The treatment effect of Uptravi on time to first primary event was consistent irrespective of background PAH therapy (i.e. in combination with ERA, PDE-5 inhibitors, or both, or without background therapy) (Figure 5).

Note.

Figure 5 presents effects in various subgroups all of which are baseline characteristics and all were prespecified. 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 postdose) 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.

In long-term follow-up of patients who were treated with Uptravi in the pivotal study and the open-label extension (N=574), Kaplan-Meier estimates of survival of these patients across the GRIPHON study and the long-term extension study at 1, 2, 5, 7 and 9 years were 92%, 85%, 71%, 63% and 57%, respectively. The median follow-up time was 4.5 years and the median exposure to Uptravi was 3 years. Additional PAH treatments were initiated in 38% of patients during the follow-up period. These uncontrolled observations do not allow comparison with a control group not given Uptravi and cannot be used to determine the long-term effect of Uptravi on mortality.

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 microgram and multiple doses of up to 1800 microgram 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.
In healthy subjects, intersubject 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. Intrasubject 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.
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 is approximately 49%.
In the presence of food, the exposure to selexipag after a single dose of 400 microgram 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 yield 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 6.2-13.5 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 bodyweight 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 bodyweights 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 70 kg bodyweight. 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 AUC0-∞ 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 microgram 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.

5.3 Preclinical Safety Data

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.

Carcinogenicity.

In 2 year carcinogenicity studies, selexipag produced possible increases in the incidences of thyroid adenomas in mice and Leydig cell adenomas in rats. The induction of such tumours is thought to reflect unique aspects of rodent biology that are not relevant to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets include the following inactive ingredients: mannitol, maize starch, hyprolose, and magnesium stearate.
The tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, and carnauba wax. In addition, tablets may contain iron oxide red, iron oxide yellow, or iron oxide black.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store Uptravi below 30°C, protect from moisture.

6.5 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 10, 60 or 140 film-coated tablets.

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.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Active: selexipag.
Uptravi (selexipag) is a selective non-prostanoid prostacyclin IP receptor agonist. The chemical name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide.
The molecular formula: C26H32N4O4S.
The molecular weight: 496.62 mg/mol.
Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin.
ATC code: B01AC27.

Chemical structure.


CAS number.

475086-01-2.
See Section 2 Qualitative and Quantitative Composition.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes