Consumer medicine information

Adempas

Riociguat

BRAND INFORMATION

Brand name

Adempas

Active ingredient

Riociguat

Schedule

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Adempas. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Adempas against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT ADEMPAS IS USED FOR

Adempas is used to treat adults with high blood pressure in the lung vessels caused by:

blood clots in the lungs (known as chronic thromboembolic pulmonary hypertension or CTEPH)
narrowing of the vessels that carry blood from the heart to the lungs (known as pulmonary arterial hypertension or PAH)

If the high blood pressure in the lung vessels is caused by CTEPH it can sometimes be treated with surgery. Adempas may be used if surgery is not possible or if there is still high blood pressure in the lung vessels after surgery.

High blood pressure in the lung vessels means that the heart needs to work harder to pump blood through the lungs. This may cause you to feel tired, dizzy and short of breath.

Adempas contains the active substance riociguat. Riociguat is a soluble guanylate cyclase (sGC)-stimulator.

Adempas relaxes the lung vessels making it easier for the heart to pump blood through them. This lowers the pressure in these vessels, relieves the symptoms, and can lead to an improvement in the ability to exercise and perform physical tasks.

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

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

BEFORE YOU TAKE ADEMPAS

When you must not take it

Do not take Adempas if you have an allergy to:

riociguat, the active ingredient in Adempas
any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take this medicine if you are pregnant, think you might be pregnant or if you could become pregnant because you are not using reliable birth control (contraception). It may affect the development of your baby if you take it during pregnancy or if you become pregnant within one month of stopping Adempas.

If you could become pregnant, your doctor will ask you to take a pregnancy test before you start Adempas.

Women must not become pregnant for at least 1 month after stopping treatment with Adempas. Do not use Adempas if you are breast-feeding. If you are breast-feeding, ask your doctor or pharmacist for advice before taking Adempas because it might harm your baby. A decision must be made whether to discontinue breast feeding or to stop therapy with Adempas.

Do not take this medicine if you are taking nitrate medicines which include:

glyceryl trinitrate (also called nitroglycerine)
nicorandil
sodium nitroprusside
isosorbide mononitrate
isosorbide dinitrate
amyl nitrite (also known as ‘poppers’, ‘amyl’ or ‘rush’)

Do not take this medicine if you are taking:

medicines known as PDE-5 inhibitors, such as sildenafil, vardenafil or tadalafil (used to treat high blood pressure in lung vessels in men and women and/or erectile dysfunction in men)
medicines known as non-specific PDE inhibitors, such as dipyridamole or theophylline used in cardiovascular and respiratory conditions
other soluble guanylate cyclase stimulators. Ask your doctor if you are not sure if you are taking a soluble guanylate cyclase stimulator

Do not take this medicine if you have increased pressure in your pulmonary circulation associated with scarring of the lungs, of unknown cause (idiopathic pulmonary pneumonia).

Do not take this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

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

Adempas is not recommended for children or adolescents. The safety and efficacy of Adempas has not been proven in patients less than 18 years of age.

Before you start to take it

Tell your doctor if you have allergies to any medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

recent serious bleeding, especially from the lungs, or if you have undergone treatment to stop coughing up blood (bronchial arterial embolization)
problems with your heart and circulation
low blood pressure
liver disease
kidney disease

Tell your doctor if you are pregnant, or think you might be pregnant or if you could become pregnant because you are not using reliable birth control (contraception).

Women who may become pregnant should have a negative pregnancy test prior to starting treatment with Adempas. If there is a chance that you could become pregnant, use at least two reliable forms of birth control (contraception) while you are taking Adempas. You must continue to use contraception for at least 1 month after stopping Adempas. Speak with a gynaecologist for contraceptive advice if you are unsure of what to do.

Tell your doctor if you are breast-feeding or planning to breast-feed. Adempas should not be used while breast-feeding. If you are breast-feeding, ask your doctor or pharmacist for advice before taking Adempas because it might harm your baby. A decision must be made whether to discontinue breast feeding or to stop therapy with Adempas.

Tell your doctor if you smoke. The metabolism of Adempas is affected by smoking, making it less effective. You should not smoke while taking Adempas.

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

Taking other medicines

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

Do not take this medicine if you are taking:

medicines known as nitrate medicine such as glyceryl trinitrate, isosorbide mononitrate, nicorandil, amyl nitrite (also known as ‘poppers’, ‘amyl’ or ‘rush’) or sodium nitroprusside
medicines known as PDE-5 inhibitors, such as sildenafil, vardenafil or tadalafil (used to treat high blood pressure in lung vessels in men and women and/or erectile dysfunction in men)
medicines known as non-specific PDE inhibitors, such as dipyridamole or theophylline used in cardiovascular and respiratory conditions
soluble guanylate cyclase stimulators

In particular, tell your doctor if you are taking:

medicines known as protease inhibitors for the treatment of HIV infection, such as rilpivirine, abacavir, efavirenz and ritonavir
medicines used to treat fungal infections such as ketoconazole or itraconazole

Also tell your doctor if you are taking:

cancer medicines called tyrosine kinase inhibitors such as erlotinib or gefitinib
cyclosporin, a medicine used to prevent rejection of transplanted organs
epoprostenol, a medicine used to treat pulmonary arterial hypertension
antacids, used to treat heartburn (indigestion)
granisetron, a medicine used to prevent nausea and vomiting
medicines used to treat epilepsy, e.g. phenytoin, carbamazepine, phenobarbitone
anticoagulants, which are medicines used to prevent blood clots
other medicines used to treat blood pressure
clarithromycin, an antibiotic
St. John’s Wort, a herbal treatment for depression

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

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Adempas.

HOW TO TAKE ADEMPAS

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information in this leaflet.

If you do not understand the instructions printed on the label, ask your doctor or pharmacist for help.

How much to take

The recommended starting dose of Adempas is one 1 mg tablet, three times daily for 2 weeks.

Your doctor may advise you to start on a lower dose. Take Adempas exactly as your doctor tells you.

After 2 weeks, your doctor will adjust your dose depending on your blood pressure and your response to the medicine. At the start of treatment your doctor will measure your blood pressure at least every two weeks.

If you have no side effects and your blood pressure is above a certain level, your doctor will increase your dose every 2 weeks. The doctor may increase your dose up to a maximum of 2.5 mg three times a day.

Tell your doctor if you have any side effects as they may need to lower your dose.

How to take it

Swallow the tablet whole with water.

Adempas can be taken with or without food.

When to take it

Take your medicine three times a day at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it. Each dose should be 6 to 8 hours apart. It does not matter if you take this medicine before or after food.

If you are taking an antacid (a medicine to treat stomach disease or heartburn), take it at least 1 hour after taking Adempas.

Transitioning between sildenafil or tadalafil and Adempas

Stop taking sildenafil at least 24 hours before you start taking Adempas.

Stop taking tadalafil at least 48 hours before you start taking Adempas.

Stop taking Adempas at least 24 hours before you start taking sildenafil or tadalafil.

How long to take it

Continue taking Adempas for as long as your doctor tells you. Adempas helps to control your condition, but does not cure it. It is important to keep taking Adempas even if you feel well.

In case treatment has to be interrupted for 3 days or more, please contact your doctor before restarting Adempas.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Adempas. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING ADEMPAS

Things you must do

If you are about to start on any new medicine, remind your doctor and pharmacist that you are taking Adempas.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Tell your doctor if your shortness of breath is getting worse during treatment with Adempas. This can be caused by a build-up of fluid in the lungs due to another lung vessel disease, known as pulmonary veno-occlusive disease.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If there is a chance you could become pregnant, you should have a negative pregnancy test monthly during treatment and one month after you stop taking Adempas. You should use two reliable forms of contraception while you are taking Adempas. If you become pregnant while taking Adempas, tell your doctor immediately. You must continue to use contraception for at least 1 month after stopping Adempas.

Do not smoke while taking Adempas. Tell your doctor if you stop or start smoking during treatment. Smoking may reduce the effectiveness of Adempas and your doctor may have to adjust your dose if required.

If treatment is interrupted for 3 days or more, contact your doctor before restarting Adempas.

Keep all of your doctor’s appointments so that your progress can be checked. Your doctor will measure your blood pressure and do other tests from time to time to make sure the medicine is working and to check for unwanted side effects.

Things you must not do

Do not take Adempas to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dose without checking with your doctor. If you stop taking it, your condition may worsen.

Things to be careful of

Be careful driving or operating machinery until you know how Adempas affects you. Dizziness is a common side effect of Adempas. If you experience dizziness during treatment, do not drive or operate machinery.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure.

Tell your doctor if you feel dizzy or faint. They may want to check your blood pressure.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Adempas.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

light headedness (hypotension)
dizziness
headache
indigestion
diarrhoea
nausea
vomiting
swelling of extremities (hands, ankles or feet)
tiredness (may be due to decrease in red blood cells)
anaemia (decrease in red blood cells)
fast or irregular heart beats
nosebleed
nasal congestion
heartburn
difficulty in swallowing
constipation
stomach pain
stomach bloating

The above list includes the more common side effects of your medicine.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

coughing up blood

The most serious side effects are coughing up blood and bleeding from the lungs which can be fatal.

You may need urgent medical attention or hospitalisation. These side effects are not common.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

AFTER TAKING ADEMPAS

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep the medicine in a cool dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and damp can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Adempas or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Adempas tablets are round film-coated tablets supplied in blister packs of 21, 42 or 84 tablets (not all pack sizes may be marketed).

Adempas 0.5 mg tablets: White, tablets marked with the Bayer cross on one side and 0.5 and an “R” on the other side.

Adempas 1 mg tablets: Pale yellow, tablets marked with the Bayer cross on one side and 1 and an “R” on the other side.

Adempas 1.5 mg tablets: Yellow-orange, tablets marked with the Bayer cross on one side and 1.5 and an “R” on the other side.

Adempas 2 mg tablets: Pale orange, tablets marked with the Bayer cross on one side and 2 and an “R” on the other side.

Adempas 2.5 mg tablets: Red-orange, tablets marked with the Bayer cross on one side and 2.5 and an “R” on the other side.

Ingredients

Active ingredients:

Adempas 0.5 mg contains 0.5 mg of riociguat
Adempas 1 mg contains 1 mg of riociguat
Adempas 1.5 mg contains 1.5 mg of riociguat
Adempas 2 mg contains 2 mg of riociguat
Adempas 2.5 mg contains 2.5 mg of riociguat

Inactive ingredients:

cellulose microcrystalline
crospovidone
hypromellose
lactose monohydrate
magnesium stearate
sodium lauryl sulfate
hyprolose
propylene glycol
titanium dioxide
iron oxide yellow (1 mg, 1.5 mg, 2 mg and 2.5 mg)
iron oxide red (2 mg and 2.5 mg)

Suppliers

Made in Germany for:

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

www.bayer.com.au

Australian registration number

Adempas 0.5 mg
- AUST R 207595

Adempas 1 mg
- AUST R 207599

Adempas 1.5 mg
- AUST R 207597

Adempas 2 mg
- AUST R 207598

Adempas 2.5 mg
- AUST R 207596

Date of preparation

June 2022

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered Trademark of the Bayer Group, Germany

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Adempas

Active ingredient

Riociguat

Schedule

1 Name of Medicine

Riociguat.

2 Qualitative and Quantitative Composition

Adempas 0.5 mg: Each film-coated tablet for oral administration contains 0.5 mg of riociguat.
Adempas 1 mg: Each film-coated tablet for oral administration contains 1 mg of riociguat.
Adempas 1.5 mg: Each film-coated tablet for oral administration contains 1.5 mg of riociguat.
Adempas 2 mg: Each film-coated tablet for oral administration contains 2 mg of riociguat.
Adempas 2.5 mg: Each film-coated tablet for oral administration contains 2.5 mg of riociguat.

Excipients with known effect.

Sugars as lactose.
Each 0.5 mg film-coated tablet contains 39.8 mg lactose monohydrate.
Each 1 mg film-coated tablet contains 39.2 mg lactose monohydrate.
Each 1.5 mg film-coated tablet contains 38.7 mg lactose monohydrate.
Each 2 mg film-coated tablet contains 38.2 mg lactose monohydrate.
Each 2.5 mg film-coated tablet contains 37.7 mg lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Adempas is a film-coated tablet.
0.5 mg film-coated tablet: White, round, biconvex tablets marked with the Bayer cross on one side and 0.5 and an "R" on the other side.
1 mg film-coated tablet: Pale yellow, round, biconvex tablets marked with the Bayer cross on one side and 1 and an "R" on the other side.
1.5 mg film-coated tablet: Yellow orange, round, biconvex tablets marked with the Bayer cross on one side and 1.5 and an "R" on the other side.
2 mg film-coated tablet: Pale orange, round, biconvex tablets marked with the Bayer cross on one side and 2 and an "R" on the other side.
2.5 mg film-coated tablet: Red orange, round, biconvex tablets marked with the Bayer cross on one side and 2.5 and an "R" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Pulmonary arterial hypertension.

Adempas, as monotherapy or in combination with approved PAH treatments (endothelin receptor antagonists or inhaled or subcutaneous prostanoids), is indicated for the treatment of:
idiopathic pulmonary arterial hypertension;
heritable pulmonary arterial hypertension;
pulmonary arterial hypertension associated with connective tissue diseases; or
pulmonary arterial hypertension associated with congenital heart disease in adult patients with WHO functional class II, III or IV symptoms.

Chronic thromboembolic pulmonary hypertension.

Adempas is indicated for the treatment of:
persistent or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment; or
inoperable CTEPH.
In adult 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 CTEPH or PAH.
Tablets should be taken three times daily approximately 6 to 8 hours apart. Adempas can be taken with or without food.
Antacids, if required, should be taken at least 1 hour after Adempas (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacokinetic interactions).

Adults.

Treatment initiation.

The recommended starting dose is 1.0 mg three times daily for 2 weeks. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg taken three times a day. Dosage should be increased in 2 week intervals by 0.5 mg increments to a maximum of 2.5 mg three times daily, if systolic blood pressure is ≥ 95 mmHg and the patient has no signs or symptoms of hypotension. During the up titration phase:
if systolic blood pressure is ≥ 95 mmHg and the patient has signs or symptoms of hypotension, the dosage should be decreased by 0.5 mg TDS;
if systolic blood pressure is < 95 mmHg and the patient has no signs or symptoms of hypotension, the dosage should be maintained;
if systolic blood pressure is < 95 mmHg and the patient has signs or symptoms of hypotension, the dosage should be decreased by 0.5 mg TDS.

Maintenance dose.

The established individual dose should be maintained unless signs and symptoms of hypotension occur. The maximum total daily dose of Adempas is 7.5 mg. If a dose is missed, treatment should be continued with the next dose as planned.
If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day.

Treatment discontinuation.

In case treatment has to be interrupted for 3 days or more, restart treatment at 1 mg three times daily for 2 weeks, and continue treatment with the dose titration regimen as described above.

Special populations.

Individual dose titration at treatment initiation allows to adjust the dose to the patient's needs.

Transitioning to and from Adempas.

Discontinue sildenafil at least 24 hours prior to administering Adempas (see Section 4.3 Contraindications, Pharmacodynamic interactions, Clinical trials). Monitor for signs and symptoms of hypotension on initiation of Adempas after discontinuing sildenafil.
Discontinue tadalafil at least 48 hours prior to administering Adempas. It is recommended to monitor for signs and symptoms of hypotension on initiation (see Section 4.3 Contraindications, Pharmacodynamic interactions, Clinical trials).
Discontinue Adempas at least 24 hours prior to administering a PDE5 inhibitor. It is recommended to monitor for signs and symptoms of hypotension on initiation (see Section 4.3 Contraindications, Pharmacodynamic interactions, Clinical trials).

Hepatic impairment.

Patients (non-smokers) with mild hepatic impairment (Child Pugh A) had an increased exposure of riociguat by 35% compared to healthy controls which is within the day to day variability. Patients with moderate hepatic impairment (Child Pugh B) showed a higher exposure to Adempas (see Section 5.2 Pharmacokinetic Properties). Particular care should be exercised during individual dose titration.
Patients with severe hepatic impairment (Child Pugh C) have not been studied and therefore use of Adempas is not recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Patients on stable doses of strong multi pathway CYP/ P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors.

Coadministration of Adempas with strong multi pathway CYP and P-gp/BCRP inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) increases exposure to Adempas (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). When initiating Adempas in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg, three times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment. Consider a dose reduction for patients on Adempas doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Smoking status.

Current smokers should be advised to stop smoking. Plasma concentrations of riociguat in smokers are reduced compared to non-smokers. Dose adjustment of Adempas may be required in patients who stop or start smoking during treatment (see Section 4.4 Special Warnings and Precautions for Use, Additional information on special populations).

Pregnancy.

Adempas is contraindicated during pregnancy (see Section 4.3 Contraindications). Women of child-bearing potential should be tested for pregnancy prior to initiating treatment, at regular intervals during treatment and one month after discontinuation of treatment with Adempas.

4.3 Contraindications

Adempas is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.
Adempas is contraindicated during pregnancy and lactation (see Boxed Warnings; see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
Women of childbearing potential who may become pregnant and not using reliable contraception (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Women must not become pregnant for at least 1 month after stopping treatment with Adempas.
Coadministration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacodynamic interactions).
Coadministration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacodynamic interactions).
Adempas is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP). (See Section 5.1 Pharmacodynamic Properties).
Co-administration of Adempas with other soluble guanylate cyclase stimulators is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacodynamic interactions).

4.4 Special Warnings and Precautions for Use

Additional information on special populations.

Studies with riociguat have been mainly performed in PAH and CTEPH patients classified as WHO functional class II and III. Riociguat has only been studied in a limited number of patients with WHO functional class IV.
The efficacy and safety of riociguat when coadministered with epoprostenol has not been established.
In cigarette smokers riociguat exposure is reduced by 50-60%. Therefore patients are advised to stop smoking (see Section 4.2 Dose and Method of Administration, Special populations).

Hypotension.

Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischaemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong multipathway CYP and P-gp/BCRP inhibitors.
While the risk of hypotension is greater during titration it may occur during maintenance therapy. Dose reduction should be considered if the patient develops signs or symptoms of hypotension.
Patients with systolic blood pressure < 95 mmHg at treatment initiation have not been studied and therefore the use of Adempas is not recommended. See Section 5.1 Pharmacodynamic Properties, Clinical trials for information of patients excluded from the trials where caution is advised.

Pulmonary veno-occlusive disease.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to these patients is not recommended. Should signs of pulmonary oedema occur, the possibility of associated PVOD should be considered and treatment with Adempas should be discontinued.

Bleeding.

In patients with pulmonary hypertension, there is increased likelihood for respiratory tract bleeding, particularly among patients receiving anticoagulation therapy.
Bleeding risk should be carefully evaluated before initiating Adempas therapy, and patients should be monitored periodically, particularly in patients taking anticoagulants. The prescriber should regularly assess the benefit/ risk with each individual patient.
The risk of serious and fatal bleeding, including respiratory tract bleeding may be further increased under treatment with Adempas, especially in the presence of risk factors, such as recent episodes of serious haemoptysis including those managed by bronchial arterial embolization. Riociguat should be avoided in patients with a history of serious haemoptysis or who have previously undergone bronchial arterial embolization.
In the placebo controlled clinical trials program, serious bleeding occurred in 2.4% (12/490) of patients taking Adempas compared to 0% (0/214) of placebo patients. Serious haemoptysis occurred in 1% (5/490) patients taking Adempas compared to 0% (0/214) placebo patients, including one event with fatal outcome. Serious haemorrhagic events also included 2 patients with vaginal haemorrhage, 2 with catheter site haemorrhage, and 1 each with subdural haematoma, haematemesis, and intra-abdominal haemorrhage.

Concomitant use with other medicinal products.

The concomitant use of Adempas with strong multipathway CYP and P-glycoprotein (P-gp)/ breast cancer resistance protein (BCRP) inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) results in a pronounced increase in riociguat exposure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacokinetic interactions).
Assess the benefit-risk for each patient individually before prescribing Adempas in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors. Consider a starting dose of 0.5 mg Adempas, three times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment and consider a dose reduction for patients on Adempas doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In patients on stable doses of Adempas, the initiation of strong multi pathway CYP and P-gp/BCRP inhibitors is not recommended as no dosage recommendation can be given due to limited data. Alternative treatments should be considered.
The concomitant use of Adempas with strong CYP1A1 inhibitors, such as the tyrosine kinase inhibitor erlotinib, and strong P-gp/BCRP inhibitors, such as the immunosuppressive agent cyclosporin, may increase riociguat exposure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacokinetic interactions).
These medicines may increase riociguat exposure which may cause hypotension. Therefore, they should be used with caution. Blood pressure should be monitored and dose reduction of riociguat considered.

Food and dairy products.

No clinically relevant interaction with food was observed (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Adempas have not yet been studied in patients below 18 years. No data are available. Therefore, Adempas is not recommended for use in paediatric patients.

Use in the elderly.

In elderly patients (≥ 65 years) particular care should be exercised during individual dose titration (see Section 5.2 Pharmacokinetic Properties). Of the total number of subjects in the Phase III clinical program, 23% were 65 and over and 6% were 75 and over. The incidence of hypotension in patients between 65 and 75 treated with Adempas was 16.4% versus 5.2% for the placebo group. The incidence of hypotension in patients 75 years and older treated with Adempas was 15.9% versus 0.0% in the placebo group. The incidence of hypotension in patients < 65 was 7.1% in the Adempas-treated group versus 3.4% in the placebo group. Particular care should be exercised during individual dose titration in elderly patients.

Use in renal impairment.

Patients with mild, moderate or severe renal impairment (stage 2-4 CKD, creatinine clearance 80-15 mL/min) showed a higher exposure to Adempas and its active main metabolite (see Section 5.2 Pharmacokinetic Properties). There is a higher risk of hypotension in these patients, particular care should be exercised during individual dose titration. Additionally, kidney function during treatment with Adempas should be regularly checked in patients with renal impairment.
Adempas has not been sufficiently studied in patients with pulmonary hypertension who have a creatinine clearance below < 30 mL/min (stage 4 CKD). Patients with creatinine clearance < 15 mL/min or on dialysis (stage 5 CKD) have not been studied and therefore use of Adempas is not recommended in these patients.

Use in hepatic impairment.

Adempas has not been studied in patients with severe hepatic impairment (Child-Pugh C); moderate hepatic impairment results in increased exposure. Adempas is not recommended for use in patients with severe hepatic impairment and should be used with caution in patients with moderate hepatic impairment.

Effect on laboratory tests.

In the phase III studies with Adempas in patients with CTEPH and PAH, mean changes in laboratory tests from baseline to end of study were clinically insignificant for the majority of the chemistry parameters tested.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

Effects of other substances on Adempas.

Riociguat is cleared mainly via cytochrome P450 mediated (CYP1A1, CYP3A4, CYP2C8, CYP2J2) oxidative metabolism, direct biliary/ faecal excretion of the unchanged drug, and renal excretion of the unchanged drug via glomerular filtration. Based on in vitro studies, riociguat was found to be a substrate for the membrane transport proteins P-gp/BCRP. Inhibitors or inducers of these enzymes or transporters may affect riociguat exposure.
Concomitant use with strong multi pathway CYP and P-gp/BCRP inhibitors.

Antifungals.

In vitro, ketoconazole, classified as a strong CYP3A4 and P-gp inhibitor, has been shown to be a 'multipathway CYP and P-gp/BCRP inhibitor' for riociguat metabolism and excretion. Concomitant administration of ketoconazole 400 mg once daily led to a 150% (range up to 370%) increase in riociguat mean AUC and a 46% increase in mean C_max. Terminal half-life increased from 7.3 to 9.2 hours and total body clearance decreased from 6.1 to 2.4 L/h.
When initiating Adempas therapy in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, e.g. ketoconazole or itraconazole, consider a starting dose of 0.5 mg riociguat, three times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment. Consider a dose reduction for patients on Adempas doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
In patients on stable doses of Adempas, the initiation of strong multi pathway CYP and P-gp/BCRP inhibitors is not recommended as no dosage recommendation can be given due to limited data. Alternative treatments should be considered.

Highly active antiretroviral therapy (HAART).

In vitro, rilpivirine, abacavir, efavirenz, ritonavir, cobicistat and elvitegravir inhibited CYP1A1 and the metabolism of riociguat in the order listed with rilpivirine as the strongest inhibitor. Cobicistat, ritonavir, atazanavir and darunavir are additionally classified as CYP3A inhibitors. In addition, ritonavir showed inhibition of P-gp.
The impact of HAART (including different combinations of abacavir, atazanavir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, rilpivirine, ritonavir, and tenofovir) on riociguat exposure was investigated in a dedicated study in HIV patients. Concomitant administration of HAART combinations led to an increase in riociguat mean AUC of up to about 160% and up to an approximate 30% increase in mean C_max. The safety profile observed in HIV patients taking a single dose of 0.5 mg riociguat together with different combinations of HIV drugs used in HAART was generally comparable to other patient populations.
When initiating Adempas treatment in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, e.g. as contained in HAART therapy, consider a starting dose of 0.5 mg riociguat, three times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment. Consider a dose reduction for patients on Adempas doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
In patients on stable doses of Adempas, the initiation of strong multi pathway CYP and P-gp/BCRP inhibitors is not recommended as no dosage recommendation can be given due to limited data. Alternative treatments should be considered.
Concomitant use with other CYP and P-gp/BCRP inhibitors. Medicines strongly inhibiting P-gp/BCRP such as the immunosuppressive agent cyclosporin, should be used with caution (see Section 4.4 Special Warnings and Precautions for Use, Concomitant use with other medicinal products).
From the recombinant CYP isoforms investigated in vitro, CYP1A1 most effectively catalysed formation of the riociguat main metabolite. The class of tyrosine kinase inhibitors was identified as potent inhibitors of CYP1A1, with erlotinib and gefitinib exhibiting the highest inhibitory potency in vitro. Therefore, drug-drug interactions by inhibition of CYP1A1 (see Section 5.2 Pharmacokinetic Properties) could result in increased riociguat exposure, especially in smokers. Therefore, strong CYP1A1 inhibitors should be used with caution (see Section 4.4 Special Warnings and Precautions for Use, Concomitant use with other medicinal products).
Coadministration of clarithromycin (500 mg twice daily), classified as a strong and selective CYP3A4 inhibitor and also reported to be a weak to moderate P-gp inhibitor, increased riociguat mean AUC by 41% without significant change in C_max.
Concomitant use with drugs increasing gastric pH. Riociguat exhibits a reduced solubility at neutral pH vs. acidic medium. Comedication of medicines increasing the upper gastrointestinal pH may lead to lower oral bioavailability.
Pretreatment and cotreatment with the proton pump inhibitor omeprazole (40 mg once daily) reduced riociguat mean AUC by 26% and mean C_max by 35%. This is not considered clinically relevant.
Coadministration of the antacid aluminium hydroxide/ magnesium hydroxide reduced riociguat mean AUC by 34% and mean C_max by 56% (see Section 4.2 Dose and Method of Administration). Antacids should be taken at least 1 hour after Adempas.
Concomitant use with CYP3A4 inducers. Bosentan, reported to be a moderate inducer of CYP3A4, led to a decrease of riociguat steady-state plasma concentrations in PAH patients by 27% without compromising the efficacy of the combination (see Section 4.1 Therapeutic Indications; Section 5.1 Pharmacodynamic Properties, Clinical trials, Treatment of pulmonary arterial hypertension (PAH)).
The concomitant use of Adempas with strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. John's wort) may also lead to decreased riociguat plasma concentration.

Effects of Adempas on other substances.

Riociguat and its main metabolite are neither inhibitors nor inducers of major CYP isoforms (including CYP3A4) or transporters (e.g. P-gp/BCRP) in vitro at therapeutic plasma concentrations.
Lack of mutual pharmacokinetic interactions between riociguat and the CYP3A4 probe substrate midazolam was demonstrated in vivo.
Patients must not get pregnant during Adempas therapy (see Section 4.3 Contraindications). Riociguat (2.5 mg three times per day) did not have a clinically meaningful effect on the exposure of combined oral contraceptives containing levonorgestrel (150 mg) and ethinylestradiol (30 microgram) when concomitantly administered to healthy female subjects.
Based on this study and as riociguat is not an inducer of any of the relevant metabolic enzymes, also no pharmacokinetic interaction is expected with other hormonal contraceptives.
Riociguat and its main metabolite revealed to be strong inhibitors of CYP1A1 in vitro. Therefore, clinically relevant drug-drug interactions with comedications which are significantly cleared by CYP1A1 mediated biotransformation, such as erlotinib or granisetron, cannot be ruled out.

Pharmacodynamic interactions.

Nitrates.

Adempas 2.5 mg tablets potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after Adempas. Therefore coadministration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated (see Section 4.3 Contraindications).

PDE inhibitors.

Riociguat and PDE-5 inhibitors are modulators of intracellular cGMP through different modes of action, but both act as vasodilators clinically. When cGMP is elevated by combining both principles, an additive effect on systemic blood pressure is anticipated (see Section 4.3 Contraindications).
Preclinical studies in animal models showed additive systemic blood pressure lowering effect when riociguat was combined with either sildenafil or vardenafil. With increased doses, over additive effects on systemic blood pressure were observed in some cases.
In some patients, concomitant use of these two medicine classes can lower blood pressure significantly leading to symptomatic hypotension (see Section 4.3 Contraindications).
In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg three times daily) and single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive haemodynamic effects. Doses above 1 mg riociguat were not investigated in this study.
A 12 week combination study in 18 patients with PAH on stable sildenafil treatment (20 mg three times daily) and riociguat (1.0 mg-2.5 mg three times daily) compared to sildenafil alone was performed. In the long-term extension part (noncontrolled) the concomitant use of sildenafil and riociguat resulted in a high rate of discontinuation, predominately due to hypotension. There was no evidence of a favourable clinical effect of the combination in the population studied.
Concomitant administration of Adempas with PDE-5 inhibitors (such as sildenafil, tadalafil, vardenafil) or nonspecific PDE inhibitors (such as dypyridamole or theophylline) is contraindicated (see Section 4.3 Contraindications).

Soluble guanylate cyclase stimulators.

Co-administration of Adempas with other soluble guanylate cyclase stimulators is contraindicated (see Section 4.3 Contraindications).

Warfarin/phenprocoumon.

Concomitant treatment of riociguat and warfarin did not alter prothrombin time induced by the anticoagulant. The concomitant use of Adempas with other coumarin derivates (e.g. phenprocoumon) is also not expected to alter prothrombin time.
Lack of mutual pharmacokinetic interactions between riociguat and the CYP2C9 substrate warfarin was demonstrated in vivo.

Acetylsalicylic acid.

Adempas neither potentiated the bleeding time caused by acetylsalicylic acid nor affected the platelet aggregation in humans.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No specific studies with Adempas in humans have been conducted to evaluate effects on fertility. No effects on fertility were seen in a study on male and female rats at a relative exposure (unbound AUC) of approximately 5 to 7-fold higher than observed in patients with pulmonary hypertension.
(Category X)
Adempas has not been studied in pregnant women. Studies in animals have shown reproductive toxicity. Adempas was teratogenic in rats. Therefore, Adempas is contraindicated during pregnancy (see Section 4.3 Contraindications). Women of childbearing potential have to use effective contraception during treatment with Adempas.

Pregnancy testing.

Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with Adempas, monthly during treatment, and one month after discontinuation of treatment with Adempas. Women with childbearing potential must use two reliable methods of contraception during treatment with Adempas and for 1 month after treatment with Adempas.
If there is any doubt about risk to the foetus or what contraceptive advice should be given to the individual patient, consultation with a gynaecologist is recommended. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk of harm to the foetus.
No specific studies on riociguat in semen have been conducted. It has been shown in the quantitative autoradiography that riociguat related radioactivity was in the testes and in the accessory sex glands. Thus it can be assumed that it is in the semen. Riociguat is nongenotoxic (see Section 5.3 Preclinical Safety Data, Genotoxicity), thus no effect on DNA of sperm is expected.
Developmental toxicity studies in rats and rabbits have shown reproductive toxicity of riociguat. In rats, an increased rate of cardiac malformation was observed as well as a reduced gestation rate due to early resorption at maternal systemic exposure of about 7 times the maximum anticipated human exposure (MAHE; based on 2.5 mg three times daily), with an NOAEL at ~2 times MAHE. In rabbits, abortion and foetal toxicity were seen starting at systemic exposure of about 3 times MAHE, with an NOAEL similar to the MAHE.
No data on the use of Adempas in breastfeeding women are available. Data from animals indicate that riociguat is secreted into milk.
Because of the potential for serious adverse reactions in nursing infants, Adempas is contraindicated during breastfeeding. A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from therapy, taking into account the importance of the medicine for the mother.

4.7 Effects on Ability to Drive and Use Machines

Dizziness has been reported and may affect the ability to drive and use machines (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be aware of how they react to Adempas, before driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

The safety of Adempas has been evaluated in phase III trials of more than 650 patients with CTEPH or PAH receiving at least one dose of riociguat (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The safety profile of Adempas in CTEPH and PAH appeared to be similar, therefore adverse drug reactions (ADRs) identified from placebo controlled 12 and 16 week clinical trials are presented as pooled frequency in Table 2.
Most of the undesirable effects are caused by relaxation of smooth muscle cells in the vasculature or gastrointestinal tract.
The most commonly reported adverse reactions, occurring in ≥ 10% of patients on Adempas treatment (up to 2.5 mg TDS), were headache, dizziness, dyspepsia, peripheral oedema, nausea, diarrhoea and vomiting.
With longer observation in uncontrolled long-term extension studies, the safety profile was similar to that observed in the placebo controlled phase III trials.
Serious haemoptysis and pulmonary haemorrhage, including cases with fatal outcome have been observed in patients with CTEPH or PAH treated with Adempas (see Section 4.4 Special Warnings and Precautions for Use, Bleeding).
The overall rates of discontinuation due to an adverse event (AE) in the pivotal placebo controlled trials were low in all treatment arms (pooled data: 2.9% for Adempas and 5.1% for placebo). The adverse events observed with Adempas at a cut off of 5% are represented in Table 1. Adverse drug reactions at a cut off of 1% are listed in Table 2, they are classified according to system organ class (MedDRA version 15.0). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Less frequent adverse drug reactions < 1% in the phase III studies.

Respiratory, thoracic and mediastinal disorders.

Pulmonary haemorrhage*.
*Fatal pulmonary haemorrhage was reported in uncontrolled long-term extension studies.

Abnormal haematologic and clinical chemistry findings.

Treatment emergent values below the lower limit of normal for erythrocytes, haematocrit, and haemoglobin were observed more frequently in the riociguat group than in the placebo group.
In a pooled analysis of placebo controlled phase III studies in subjects with CTEPH or PAH, changes from baseline in mean haemoglobin (-0.58 g/dL vs. 0.13 g/dL) and haematocrit (-1.66% vs. 0.45%) were observed in patients receiving Adempas or placebo, respectively. Decreases in haemoglobin (24.1% vs. 9.1%) and haematocrit (13.3% vs. 4.9%) were observed in patients receiving Adempas and placebo, respectively. Anaemia had a higher rate in the Adempas group (6.7%) compared to placebo (2.3%).
Mean changes in group values from baseline were small for most of the clinical chemistry parameters in the pooled controlled phase III studies.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Inadvertent overdosing with total daily doses of Adempas 9-25 mg for periods 2-32 days has been reported. Adverse reactions were similar to those seen at lower doses (see Section 4.8 Adverse Effects (Undesirable Effects)).
No specific antidote is available. In case of overdose, standard supportive measures should be adopted as required. In case of pronounced hypotension, active cardiovascular support may be required. Based on the high plasma protein binding riociguat is not expected to be dialysable.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme found in most tissues and the receptor for nitric oxide (NO).
When NO binds to sGC, the enzyme catalyses synthesis of the signalling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation.
Pulmonary hypertension (PH) is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway.
Riociguat has a dual mode of action. It sensitises sGC to endogenous NO by stabilising the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO.
Riociguat restores the NO-sGC-cGMP pathway and leads to increased generation of cGMP.

Clinical trials.

Treatment of chronic thromboembolic pulmonary hypertension (CTEPH).

CHEST. A randomised, double blind, multinational, multicentre, placebo controlled phase III study (CHEST-1) was conducted in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Patients were included if they:
were technically inoperable for pulmonary endarterectomy, with pulmonary vascular resistance (PVR) > 300 dyn*sec*cm^-5 and mean pulmonary artery pressure > 25 mmHg measured at least 90 days after the start of full anticoagulation; or
had recurrent or persisting pulmonary hypertension defined as PVR > 300 dyn*sec*cm^-5 measured at least 180 days following pulmonary endarterectomy.
The patient population included male and female patients between the age of 18 and 80, of which 72% of patients had inoperable CTEPH and 28% had recurrent or persisting CTEPH following pulmonary endarterectomy.
Patients had a World Health Organization (WHO) functional class I (1%) or II (31%) or III (64%) or IV (4%) at baseline. The mean baseline six minute walking distance (6MWD) was 347 m. All patients were treatment naïve (patients on PAH specific medication were excluded). Patients with systolic blood pressure < 95 mmHg were excluded from the study. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues, specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example dipyridamole or theophylline).
CHEST-1 included 261 patients treated and valid for safety analysis randomised to one of two treatment groups: Adempas individual dose titration (IDT) up to 2.5 mg TDS (n = 173, referred to as riociguat group), or placebo (n = 88). During an 8 week titration phase, the dose of Adempas was titrated every 2 weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension. An individualised dose was reached at the end of the titration. 77% of patients were titrated to the maximum dose of 2.5 mg TDS and 13%, 6%, 4%, and 1% of patients received Adempas 2 mg, 1.5 mg, 1 mg, and 0.5 mg TDS, respectively.

Statistical analysis of efficacy endpoints.

All p-values are based on stratified Wilcoxon test (unless a different test is mentioned). All 95% confidence interval (CI) and treatment effects are based on analysis of covariance (ANCOVA).

Primary endpoint.

The primary endpoint was the change from baseline at week 16 (last visit) in 6MWD compared to placebo. Results of the 6MWD at 16 weeks are shown in Table 3 and Figure 1.
Improvements in walking distance were apparent from week 2 onward, and at week 16 (n = 261) the mean increase in 6MWD within the riociguat group was 46 m (95% CI: 25 m to 67 m; p < 0.0001) compared to placebo (ITT analysis, see Table 3). Improvements of riociguat over placebo were observed in all subgroups evaluated. Inoperable patients (n = 189) demonstrated an increase in 6MWD of 54 m (95% CI: 29 m to 79 m), and patients with recurrent or persisting CTEPH following pulmonary endarterectomy (n = 72) demonstrated an increase in 6MWD of 27 m (95% CI: -10 m to 63 m).

Secondary endpoints.

No statistically significant (below threshold of hierarchical testing¹) result was found for:
Time to clinical worsening, Borg CR 10 scale, European quality of life (EQ-5D) and Living with Pulmonary Hypertension (LPH) questionnaire;
A trend towards lower incidence of clinical worsening events by week 16 (last visit) in patients treated with riociguat (2.3%) compared to placebo (5.7%) was observed (p = 0.1724, stratified log-rank test).
¹All subsequent endpoints cannot be considered statistically significant in a formal sense because statistical significance was not achieved for time to clinical worsening in the hierarchical testing of the secondary efficacy variables.

Haemodynamic parameters.

Right heart catheterisation was performed at the beginning and the end of the placebo controlled study period in 233/261 (89%) patients to generate a comprehensive set of cardiopulmonary haemodynamic data (see Table 5).
A statistically significant reduction of PVR (see above) was shown in the riociguat group vs. placebo. The improvement seen for PVR was also observed in other relevant haemodynamic parameters including mean pulmonary artery pressure (PAP_mean) (-5.0 mmHg) and an increase in cardiac index (0.47 L/min/m²).

Long-term treatment of CTEPH. An open label extension study (CHEST-2) included 237 patients who had completed CHEST-1. In the interim analysis, the mean treatment duration at the cut off date was 1077 days with a median duration of 1071 days (range 15 to 1953 days) and a total riociguat exposure of 699 patient years.
The safety profile in CHEST-2 was similar to that observed in pivotal trials. The probabilities of survival at 1 and 2 years were 97% and 93% respectively. Without a control group, these data must be interpreted cautiously.

Treatment of pulmonary arterial hypertension (PAH).

PATENT. A randomised, double blind, multinational, multicentre, placebo controlled, phase III study (PATENT-1) was conducted in patients with pulmonary arterial hypertension (PAH) who were either treatment naïve or pretreated with an endothelin receptor antagonist (ERA) or a prostacyclin analogue (inhaled, oral or subcutaneous).
The overall patient population included male (21%) and female (79%) patients who were between the age of 18 and 80 years (mean age = 50.6 years) and had been diagnosed with either idiopathic PAH (61%), familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or associated PAH due to anorexigen or amphetamine (1%) use.
Unspecific treatments which may also be used for the treatment of PH such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation were permitted in the study. Patients with systolic blood pressure of < 95 mmHg at initiation were excluded.
In addition, patients with cardiovascular diseases including clinically significant cardiovascular disease, uncontrolled hypertension, atrial flutter, atrial fibrillation, left heart failure, symptomatic atherosclerotic disease and severe coronary artery disease were excluded.
Patients had a WHO functional class I (3%) or II (42%) or III (54%), or IV (1%) at baseline, with 50% of patients treatment naïve, 44% pretreated with ERAs and 7% with prostacyclin analogues (of which, 32% by oral, 45% by inhalation and 23% by subcutaneous administration, intravenous prostanoids were not studied). The overall mean baseline 6MWD was 363 m.
PATENT-1 included 443 patients treated and valid for safety analysis, randomised to one of three treatment groups: Adempas individual dose titration up to 2.5 mg TDS (n = 254); placebo (n = 126); and a "capped" Adempas dose titration up to 1.5 mg TDS (n = 63; exploratory dose arm, no statistical testing performed). Adempas was added in combination in patients pretreated with an ERA or a prostacyclin analogue.
Patients were initiated on treatment at 1 mg TDS. During an 8 week titration phase, the dose of Adempas was titrated every 2 weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension. An individualised dose was reached at the end of the titration. Approximately 75% of patients were up titrated to receive the maximum dose of 2.5 mg TDS by week 12 and 15%, 6%, 3%, and 2% received 2 mg, 1.5 mg, 1 mg, and 0.5 mg respectively.

Statistical analysis of efficacy endpoints.

The prespecified primary analysis is with the Adempas 2.5 mg treatment arm (referred to as riociguat group) compared to placebo. All p-values are based on stratified Wilcoxon test (unless a different test is mentioned). All 95% CI and treatment effects are based on analysis of covariance (ANCOVA).

Primary endpoint.

The primary endpoint was the change from baseline at week 12 (last visit) in 6MWD compared to placebo. Results of the 6MWD at 12 weeks are shown in Table 6 and Figure 2.
Improvements in walking distance were apparent from week 2 onward, and at week 12 for the riociguat group was 36 m (95% CI: 20 m to 52 m; p < 0.0001) compared to placebo (ITT analysis, see Table 6). Improvements of riociguat over placebo were observed in all subgroups evaluated. Treatment naïve patients (n = 189) demonstrated an increased 6MWD of 38 m (95% CI: 14 m to 62 m).
Pretreated patients (n = 191) demonstrated an increased 6MWD of 36 m (95% CI: 15 m to 56 m). Further subgroup analysis of patients pretreated with ERAs (n = 167) revealed a treatment effect estimate of 26 m, (95% CI: 5 m to 46 m). In patients pretreated with prostacyclin analogues² (n = 27), the estimated treatment effect was 101 m, (95% CI: 27 m to 176 m).
²Three patients were pretreated with an ERA and prostacyclin analogue at the same time.

Last visit = last observed value, not including follow-up, for patients who completed the study or withdrew, except imputed worst value (zero) in case of death or clinical worsening without a termination visit or a measurement at that termination visit.
There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day.
A post hoc analysis was conducted in patients with PAH associated with congenital heart disease who underwent surgical correction for their atrial septal defect or ventricle septal defect. A placebo corrected treatment response of 41 m (95% CI -0.5 to 82.6) in the 6MWD was observed.

Secondary endpoints.

Improvements in walking distance were complemented with consistent improvements in clinically relevant secondary endpoints.
A statistically significant improvement for the riociguat group over placebo was shown for the following secondary efficacy variables:
Pulmonary vascular resistance (PVR): significantly reduced PVR (placebo corrected mean change from baseline of -226 dyn*s*cm^-5; 95% CI -281 to -170; p < 0.0001; see Table 9);
NT-proBNP: significantly reduced NT-proBNP (placebo corrected mean change from baseline - 432 nanogram/L, 95% CI -782 to -82; p < 0.0001; see Table 9);
WHO functional class: significant improvement of at least one functional class in the riociguat group at week 12 (last visit) of 21% vs. 14% in the placebo group and a deterioration of at least one functional class was observed in 4% of patients in the riociguat group vs. 14% in the placebo group (p = 0.0033; see Table 7 and Table 9). Functional class was unchanged in 76% of patients in the riociguat group vs. 71% in the placebo group;
Time to clinical worsening: riociguat treated patients experienced a significant delay in time to clinical worsening versus placebo treated patients (p = 0.0046; stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with riociguat (1.2%) compared to placebo (6.3%) (see Table 8 and Table 9);
Borg CR 10 scale: significant improvement in Borg CR 10 scale (-0.4 for riociguat vs. +0.1 for placebo, p = 0.0022; see Table 9).
No statistically significant (below threshold of hierarchical testing³) result was found for the European quality of life (EQ-5D) and Living with Pulmonary Hypertension (LPH) questionnaires (see Table 9).
³All subsequent endpoints cannot be considered statistically significant in a formal sense because statistical significance was not achieved for EQ-5D in the hierarchical testing of the secondary efficacy variables.

Haemodynamic parameters.

Right heart catheterisation was performed at the beginning and at the end of the placebo controlled study period in 339/380 (89%) patients to generate a comprehensive set of cardiopulmonary haemodynamic data (see Table 10).
A statistically significant reduction of PVR (see above) was shown in the riociguat group vs. placebo. The improvement seen for PVR was also observed in other relevant haemodynamic parameters including mean pulmonary artery pressure (PAP_mean) (-3.83 mmHg) and an increase in cardiac index (0.56 L/min/m²).

Long-term treatment of PAH. An open label extension study (PATENT-2) included 363 patients who had completed PATENT-1. The mean treatment duration in PATENT-2 at the cut off date was 438 days with a median duration of 441 days (range 1 to 1078 days) and a total riociguat exposure of 436 patient years.
The safety profile in PATENT-2 was similar to that observed in pivotal trials.
The probabilities of survival at 1 and 2 years were 97% and 93% respectively. Without a control group, these data must be interpreted cautiously.
RESPITE.

Study in PAH patients transitioned from PDE-5 inhibitors to Adempas.

A 24-week, uncontrolled study was conducted in 61 adult PAH patients stable on sildenafil (n=40) or tadalafil (n=21) for at least 90 days; all patients were WHO Functional Class III and 82% were pretreated with an endothelin receptor antagonist at baseline and continued this treatment during the study. All patients in the study were transitioned from sildenafil or tadalafil to Adempas (median treatment-free time of 1 day for sildenafil and 3 days for tadalafil) (see Section 4.3 Contraindications).
Fifty-one patients (84%) completed the study and 92% of completers were receiving treatment with 2.5 mg 3 times daily at Week 24. Six patients (10%) experienced at least one clinical worsening event during the study, including 2 deaths unrelated to study drug. No serious adverse events were reported during the transition period. Overall, the safety profile observed in the study was comparable with that observed in the pivotal trials.

Adverse effects in pulmonary hypertension associated with idiopathic interstitial pneumonias (WHO group 3).

A randomised, double-blind, placebo-controlled study in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP, WHO Group 3) compared riociguat (73) to placebo (74). The objective of the study was to evaluate the efficacy and safety of 26 weeks treatment with riociguat vs. placebo in patients with symptomatic pulmonary hypertension (PH) associated with idiopathic interstitial pneumonia (IIP). The study was terminated prematurely due to increased risk of mortality and serious adverse events in patients treated with riociguat and a lack of efficacy. More patients taking riociguat died (11% vs. 4%) and had serious adverse events (37% vs. 23%) during the main phase. In the long-term extension, more patients who switched from the placebo group to riociguat (21%) died than those who continued in the riociguat group (3%). Riociguat is therefore contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (see Section 4.3 Contraindications).

5.2 Pharmacokinetic Properties

Absorption.

The absolute bioavailability of riociguat is high (94%). Riociguat is rapidly absorbed with maximum concentrations (C_max) appearing 1-1.5 hours after tablet intake.
Intake with food does not affect riociguat area under the concentration curve (AUC) or C_max to a clinically relevant extent. Riociguat can be taken with or without food.

Distribution.

Plasma protein binding in humans is high at approximately 95%, with serum albumin and α1-acidic glycoprotein being the main binding components.
The volume of distribution is moderate with volume of distribution at steady state being approximately 30 L.

Metabolism.

N-demethylation, catalysed by CYP1A1, CYP3A4, CYP2C8 and CYP2J2, is the major biotransformation pathway of riociguat leading to its major circulating active metabolite (pharmacological activity: 1/10 to 1/3 of riociguat) which is further metabolised to the pharmacologically inactive N-glucuronide.
CYP1A1 catalyses the formation of riociguat's main metabolite in liver, lungs and intestines and is known to be inducible by polycyclic aromatic hydrocarbons, for instance, present in cigarette smoke.

Excretion.

Total riociguat (parent compound and metabolites) is excreted via both renal (33-45%) and biliary/ faecal routes (48-59%). Approximately 4 to 19% of the administered dose is excreted as unchanged riociguat via the kidneys. Approximately 9-44% of the administered dose is excreted as unchanged riociguat in faeces.
Based on in vitro data, riociguat and its main metabolite are substrates of the transporter proteins P-gp (P-glycoprotein) and BCRP (breast cancer resistance protein).
With a systemic clearance of about 3-6 L/h, riociguat can be classified as a low clearance drug. Elimination half-life is about 7 hours in healthy subjects and about 13 hours in patients.

Linearity.

Riociguat pharmacokinetics are linear from 0.5 to 2.5 mg.
Interindividual variability (CV%) of riociguat exposure (AUC) across all doses is approximately 60%.

Use in the elderly.

Elderly patients (≥ 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 40% higher in elderly, mainly due to reduced (apparent) total and renal clearance (see Section 4.2 Dose and Method of Administration, Special populations).

Use in hepatic impairment.

In cirrhotic patients (non-smokers) with mild hepatic impairment (classified as Child-Pugh A) riociguat mean AUC was increased by 35% compared to healthy controls, which is within normal intraindividual variability. In cirrhotic patients (non-smokers) with moderate hepatic impairment (classified as Child-Pugh B), riociguat mean AUC was increased by 51% compared to healthy controls. (See Section 4.2 Dose and Method of Administration, Special populations.)
There are no data in patients with pulmonary hypertension with severe hepatic impairment (classified as Child-Pugh C), patients with ALT > 3 x ULN and bilirubin > 2 x ULN were not studied. Therefore use of Adempas is not recommended in these patients (see Section 4.2 Dose and Method of Administration, Special populations; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Use in renal impairment.

Overall, mean dose and weight normalised exposure values for riociguat were higher in subjects with renal impairment compared to subjects with normal renal function.
Corresponding values for the main metabolite were higher in subjects with renal impairment compared to healthy subjects. In non-smoking individuals with mild (stage 2 chronic kidney disease (CKD), creatinine clearance 50-80 mL/min), moderate (stage 3 CKD, creatinine clearance 30-49 mL/min) or severe (stage 4 CKD, creatinine clearance 15-29 mL/min) renal impairment, riociguat plasma concentrations (AUC) were increased by 53%, 139% or 54%, respectively (see Section 4.2 Dose and Method of Administration, Special populations).
There are no data in patients with pulmonary hypertension with creatinine clearance < 15 mL/min or on dialysis (stage 5 CKD). Therefore use is not recommended in patients with creatinine clearance < 15 mL/min or on dialysis (see Section 4.2 Dose and Method of Administration, Special populations; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Due to the high plasma protein binding riociguat is not expected to be dialysable.

Gender, inter-ethnic differences, weight categories.

Pharmacokinetic data reveal no relevant differences due to gender, ethnicity or weight in the exposure to riociguat.

Pharmacokinetic/pharmacodynamic relationships.

There is a direct relationship between riociguat plasma concentration and haemodynamic parameters such as systemic and pulmonary vascular resistance, systolic blood pressure and cardiac output.

5.3 Preclinical Safety Data

Genotoxicity.

Riociguat showed no genotoxicity potential in bacterial mutagenicity tests, chromosomal aberration assays in Chinese hamster cells or in an in vivo mouse micronucleus assay.

Carcinogenicity.

In rats, at systemic exposure corresponding up to 7-fold the human exposure, Adempas was noncarcinogenic.
In the carcinogenicity study in mice, at exposure levels close to the human therapeutic exposure, impaired gastrointestinal motility, dysbiosis and chronic inflammation followed by mucosal degeneration and reactive hyperplasia as well as a statistically non-significant increase in intestinal tumours were seen. This sequence of events is a typical reaction in mice to a stimulus like inflammation or degeneration and therefore these tumours are not considered as relevant for humans.

Paediatric use.

In fast growing adolescent rats effects on bone formation (i.e. an increase in overall bone mass) were seen. No such effects were observed after administration of riociguat to adult rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients in the tablet core are cellulose microcrystalline, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate. The film coating contains the excipients hyprolose, hypromellose, propylene glycol, titanium dioxide. Adempas 1 mg, 1.5 mg, 2 mg and 2.5 mg tablets also contain iron oxide yellow and Adempas 2 mg and 2.5 mg tablets also contain iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Store in original container.

6.5 Nature and Contents of Container

Adempas 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg film-coated tablets are supplied in polypropylene/ aluminium blister packs: 21, 42 and 84 tablet packs (not all pack sizes may be marketed).

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

Chemical structure.

The chemical formula for riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)- 1H-pyrazolo [3,4-b]pyridine-3-yl]- 5-pyrimidinyl(methyl)carbamate.
Riociguat has the following structural formula:

C₂₀H₁₉FN₈O₂.
Riociguat is a white to yellowish, crystalline, non-hygroscopic substance with a relative molecular mass of 422.42 g/mol. In solid form it is stable to temperature, light and humidity.
The solubility at 25°C in water: 4 mg/L, in ethanol: 800 mg/L, in 0.1 HCl (pH 1): 250 mg/L and in buffer (phosphate) pH 7: 3 mg/L. In the pH range of 2 to 4 the solubility showed strong pH dependency. Solubility increases at lower pH values.

CAS number.

625115-55-1.

7 Medicine Schedule (Poisons Standard)

S4-Prescription Only Medicine.

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Adempas

Riociguat

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