YUVANCI 10 MG/40 MG FILM-COATED TABLETS

Introduction

Package Leaflet: Information for the User

Yuvanci 10 mg/20 mg film-coated tablets

Yuvanci 10 mg/40 mg film-coated tablets

macitentan/tadalafil

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What is Yuvanci and what is it used for
2. What you need to know before you take Yuvanci
3. How to take Yuvanci
4. Possible side effects
5. Storage of Yuvanci
6. Contents of the pack and other information

1. What is Yuvanci and what is it used for

Yuvanci contains two active substances: macitentan and tadalafil. Macitentan belongs to a class of medicines called endothelin receptor antagonists (ERAs). Tadalafil belongs to a class of medicines called phosphodiesterase type 5 inhibitors (PDE5i).

Yuvanci is used in adults for the long-term treatment of pulmonary arterial hypertension (PAH) of WHO Functional Class II or III. It is used as an alternative to taking macitentan and tadalafil as separate tablets.

PAH is high blood pressure in the blood vessels that carry blood from the heart to the lungs (pulmonary arteries). In people with PAH, these arteries narrow, so the heart has to work harder to pump blood through them. As a result, patients feel tired and dizzy, and have difficulty breathing. The class reflects the severity of the disease: patients with PAH of WHO Functional Class II have mild limitation of physical activity, while those with Class III have marked limitation of physical activity.

Yuvanci widens the pulmonary arteries, making it easier for the heart to pump blood through them. This reduces blood pressure, alleviates symptoms, increases the ability to perform physical activity, and improves the course of the disease.

2. What you need to know before you take Yuvanci

Do not take Yuvanci if:

• you are allergic to macitentan, tadalafil or any of the other ingredients of this medicine (listed in section 6).
• you have had a heart attack in the last 90 days.
• you are pregnant or may become pregnant because you are not using a reliable method of contraception.
• you are breast-feeding. See section 2 "Pregnancy and breast-feeding".
• you have severe liver disease or if you have very high levels of liver enzymes in your blood. Consult your doctor, who will decide if the medicine is suitable for you.
• you have very low blood pressure (90/50 mmHg).
• you are taking nitrates or riociguat. See section 2 "Other medicines and Yuvanci".
• you have ever had non-arteritic anterior ischemic optic neuropathy (NAION), a condition also known as "eye stroke", a loss of vision due to reduced blood flow to the eye.

If you meet any of the above points, please tell your doctor.

Warnings and precautions

You will need to have blood tests before using Yuvanci and during treatment, as indicated by your doctor:

If you are a woman of childbearing potential, your doctor will ask you to have a pregnancy test before starting Yuvanci and periodically (once a month) during treatment. See section 2 "Pregnancy and breast-feeding".

Your doctor will take blood to determine:

• if your liver is working properly
• if you have anaemia (reduced number of red blood cells)

Yuvanci may cause increases in liver enzymes (proteins), which may be a sign that your liver is not working properly. Other signs that your liver may not be working properly are the following symptoms:

• feeling unwell (nausea)
• vomiting
• fever
• stomach pain (abdomen)
• yellowing of the skin or the whites of the eyes (jaundice)
• dark urine
• itching of the skin
• unusual tiredness or exhaustion (lethargy or fatigue)
• pseudo-flu syndrome (joint or muscle pain with fever)

If you experience any of these signs during treatment with Yuvanci, tell your doctor immediately.

Yuvanci may cause anaemia (low red blood cell count). If you experience any of the following symptoms, which may be symptoms of anaemia, tell your doctor:

• dizziness
• tiredness
• general malaise
• weakness
• rapid heart rate
• palpitations (a strong heartbeat that may be rapid or irregular)
• pallor

Consult your doctor before starting to take the tablets if

• you have any cardiovascular disease (related to the heart and blood vessels) that is not pulmonary hypertension, including:

• aortic and mitral valve disease (problems with the heart valves that can affect blood flow)
• constrictive pericarditis (a disease in which the sac that surrounds the heart - the pericardium - becomes rigid, affecting the heart's ability to function)
• restrictive or congestive cardiomyopathy (a disease in which the heart muscle becomes rigid or weakened, causing problems with pumping blood effectively)
• left ventricular dysfunction (a disease in which the left side of the heart has difficulty pumping blood effectively to the rest of the body)
• arrhythmias (abnormal heart rhythm)
• coronary artery disease (heart disease caused by narrowing or blockage of the blood vessels that supply the heart muscle)
• uncontrolled high blood pressure

• you have blood pressure problems, such as significant drops in blood pressure when standing up or when blood pressure is consistently lower than normal
• you have any inherited disease that causes damage to the retina (the light-sensitive membrane at the back of the eye)
• you have severe liver disease
• you have severe kidney disease

If you have kidney problems, talk to your doctor before using Yuvanci. During treatment with Yuvanci, there may be a higher risk of low blood pressure and anaemia.

The use of medicines for the treatment of PAH, including Yuvanci, in patients with pulmonary veno-occlusive disease (obstruction of the pulmonary veins) may cause pulmonary oedema (fluid accumulation in the lungs). Tell your doctor immediatelyif you experience signs of pulmonary oedema during treatment with Yuvanci, such as:

• a sudden and significant increase in shortness of breath
• cough
• tiredness after exertion
• difficulty breathing when lying down

Before taking Yuvanci, tell your doctorif you have any penile deformity, such as:

• angulation, a condition in which the penis is curved, possibly due to cavernosal fibrosis (scarring of certain tissues of the penis).
• Peyronie's disease, a disease that affects adult men, in which a "plate" of scar tissue forms, which can be felt, accompanied by curvature of the penis.
• a disease that may predispose you to priapism (a prolonged and painful erection that can occur without sexual stimulation), such as sickle cell anaemia, multiple myeloma, or leukaemia.

If you experience an erection that lasts for 4 hours or more during treatment with Yuvanci, go to your doctor immediately.

Visual disturbances and sudden loss of vision have been reported with the use of tadalafil and PDE5 inhibitors. If you experience a reduction or sudden loss of vision or your vision is distorted or blurred during treatment, stop taking Yuvanci and contact your doctor immediately.

In some patients treated with tadalafil, a decrease or sudden loss of hearing has been observed. Although it is not known if the event is directly related to tadalafil, if you experience a decrease or sudden loss of hearing, contact your doctor immediately.

Children and adolescents

Do not give this medicine to children and adolescents under 18 years old, as Yuvanci has not been tested in children.

Other medicines and Yuvanci

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

Do not take Yuvanci if you are taking any of the following medicines:

• riociguat (a medicine used to treat PAH and chronic thromboembolic pulmonary hypertension)
• nitrates such as nitroglycerin, isosorbide, and amyl nitrate (for chest pain)

Tell your doctor or pharmacist if you are taking any of the following medicines:

Medicines that may decrease the effectiveness of Yuvanci by decreasing the amount of Yuvanci in the blood, including:

• St. John's Wort (a herbal medicine used to treat depression)
• phenytoin or carbamazepine (medicines used to treat epilepsy)
• rifampicin (an antibiotic used to treat infections)

Medicines that may increase the risk of side effects of Yuvanci, including:

• clarithromycin, telithromycin, ciprofloxacin, erythromycin (antibiotics used to treat infections)
• ritonavir, saquinavir (used to treat HIV infection)
• doxazosin (used to treat high blood pressure or prostate problems)
• nefazodone (used to treat depression)
• ketoconazole (except when used as a shampoo), fluconazole, itraconazole, miconazole, voriconazole (medicines used to treat fungal infections)
• amiodarone (to control heartbeats)
• cyclosporin (used to prevent organ rejection after a transplant),
• diltiazem, verapamil (to treat high blood pressure or specific heart problems)
• prostacyclin-like medicines, such as epoprostenol and iloprost (used to treat PAH, pulmonary fibrosis, and obstruction of the pulmonary arteries)

Yuvanci with food and alcohol

If you are taking piperine as a dietary supplement, this may alter the way the body responds to some medicines like Yuvanci. Talk to your doctor or pharmacist if this is the case.

Drinking alcohol may temporarily lower blood pressure. If you have taken or are going to take Yuvanci, avoid excessive alcohol consumption (more than 5 units of alcohol), as this may increase the risk of dizziness when standing up.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Yuvanci should not be taken during pregnancy, as it may harm the foetus. See section 2 "Do not take Yuvanci".

• If you can become pregnant, use a reliable method of contraception while taking Yuvanci. Talk to your doctor about contraception.
• Do not take Yuvanci if you are pregnant or planning to become pregnant.
• If you become pregnant or think you may have become pregnant during treatment with Yuvanci, or shortly after stopping treatment (up to 1 month), go to your doctor immediately.

If you are a woman of childbearing potential, your doctor will ask you to have a pregnancy test before starting Yuvanci and periodically (once a month) during treatment.

It is not known if Yuvanci passes into breast milk. Do not breast-feed during treatment with Yuvanci. Talk to your doctor if you are planning to breast-feed. See section 2 "Do not take Yuvanci"

Fertility

Yuvanci may cause a reduction in sperm count in men. Talk to your doctor if you are planning to have children.

Driving and using machines

Yuvanci may cause side effects such as headaches and low blood pressure (indicated in section 4), and the symptoms of PAH may also make you less fit to drive. Check carefully how you react to Yuvanci before driving or using machines.

Yuvanci contains lactose monohydrate and sodium

• Yuvanci contains lactose monohydrate. If your doctor has told you that you have an intolerance to some sugars, consult them before taking this medicine.
• This medicine contains less than 1 mmol of sodium (23 mg) per tablet; this is essentially "sodium-free".

3. How to take Yuvanci

Follow exactly the administration instructions of this medicine given by your doctor. If you are unsure, ask your doctor or pharmacist.

The recommended dose of Yuvanci is one 10 mg/40 mg tablet once a day. In some situations, your doctor may decide to start with a lower dose of 10 mg/20 mg once a day, this allows your body to adapt to the new medicine. If you tolerate it, your doctor will then increase the dose to one 10 mg/40 mg tablet once a day.

Swallow the tablet whole with a glass of water. Do not chew or break the tablet. You can take Yuvanci with or without food. It is best to take the tablet at the same time each day.

If you take more Yuvanci than you should

Tell your doctor or pharmacist immediately. You may experience any of the side effects described in section 4.

If you forget to take Yuvanci

If you forget to take Yuvanci, take a dose as soon as you remember and then continue to take the tablets at the usual times. Do not take a double dose to make up for forgotten doses.

If you stop taking Yuvanci

Yuvanci is a treatment that you should continue to take to control PAH. Do not stop taking Yuvanci unless you have agreed this with your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

The adverse effects listed below have been observed with Yuvanci or have been previously reported with the active substances (macitentan or tadalafil) of Yuvanci and may also occur with Yuvanci.

If you experience any of the following adverse effects, stop using the medicine and seek immediate medical attention:

• severe allergic reactions (may affect up to 1 in 10 people).

• symptoms include swelling around the eyes, face, lips, tongue, or throat, which can be potentially fatal if throat swelling blocks the airways. If you experience any of these symptoms during treatment with Yuvanci, seek immediate medical attention.

• chest pain (may affect up to 1 in 10 people).

• priapism, a prolonged and potentially painful erection that can occur without sexual stimulation (may affect up to 1 in 100 people).

• sudden loss of vision or distorted, blurred, or diminished central vision, or sudden reduction in vision. (The frequency with which these side effects may appear in people is unknown).

Other Adverse Effects

Very Common(may affect more than 1 in 10 people)

• Edema/fluid retention (swelling), especially in ankles and feet
• Headache
• Anemia (low red blood cell count) or reduced hemoglobin (the protein in red blood cells that carries oxygen throughout the body)
• Nausea (feeling of discomfort)
• Dyspepsia (indigestion)
• Abdominal pain (stomach pain)
• Abdominal discomfort
• Nasopharyngitis (inflammation of the throat and nose)
• Bronchitis (inflammation of the airways)
• Myalgia (muscle pain)
• Back pain
• Pain in arms and legs
• Rubefaction (redness of the skin)

Common(may affect up to 1 in 10 people)

• Vomiting (discomfort)
• Gastroesophageal reflux disease (acid reflux)
• Syncope (fainting)
• Migraine
• Flu
• Urinary tract infection (infection of the parts of the body that collect and expel urine)
• Respiratory tract infection (infection of the respiratory system, chest or nose, sinuses or throat, a cold)
• Pharyngitis (inflammation of the throat)
• Epistaxis (nosebleed)
• Palpitations (a strong heartbeat that can be rapid or irregular)
• Tachycardia (rapid heartbeats)
• Increased levels of liver enzymes, according to blood tests
• Leukopenia (low levels of white blood cells in the blood)
• Thrombocytopenia (low levels of platelets in the blood, components that help blood clotting)
• Hypotension (low blood pressure)
• Blurred vision (blurred vision)
• Increased uterine bleeding (related to the uterus)
• Rash
• Hypersensitivity (allergic reactions), including itching

Uncommon(may affect up to 1 in 100 people)

• Epileptic seizures
• Transient amnesia (passing memory loss)
• Sudden cardiac death (the heart stops beating unexpectedly, causing loss of consciousness and death)
• Urticaria (hives)
• Hyperhidrosis (excessive sweating)
• Penile hemorrhage (penile bleeding)
• Hematospermia (blood in semen and/or urine)
• Tinnitus (ringing in the ears)
• Hematuria (blood in urine)

Frequency Not Known(cannot be estimated)

• Stroke
• Myocardial infarction (heart attack)
• Unstable angina (chest pain)
• Ventricular arrhythmia (abnormal heart rhythm originating in the lower chambers of the heart)
• Stevens-Johnson syndrome (severe rash with blisters and peeling of the skin, especially around the mouth, nose, eyes, and genitals)
• Exfoliative dermatitis (peeling of the skin)
• Retinal vascular occlusion (blood clot in the blood vessels of the eye, which can cause blurred vision or blindness)
• Visual field defect
• Sudden hearing loss

Reporting Adverse Effects

If you experience any adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Yuvanci

Keep this medicine out of sight and reach of children.

Do not use Yuvanci after the expiration date stated on the carton and blister after "EXP". The expiration date is the last day of the month indicated.

Store in the original packaging to protect it from moisture.

This medicine does not require any special storage temperature.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Yuvanci

The active substances are macitentan and tadalafil.

Each 10 mg/20 mg film-coated tablet contains 10 mg of macitentan and 20 mg of tadalafil.

Each 10 mg/40 mg film-coated tablet contains 10 mg of macitentan and 40 mg of tadalafil.

The other components are:

Tablet core

Hydroxypropylcellulose

Hydroxypropylcellulose of low substitution (E463a)

Lactose monohydrate (see section 2, Yuvanci contains lactose)

Magnesium stearate (E470b)

Microcrystalline cellulose (E460i)

Polysorbate 80 (E433)

Povidone (E1201)

Sodium starch glycolate (see section 2, Yuvanci contains sodium)

Sodium lauryl sulfate

Film coating

Hypromellose

Lactose monohydrate

Titanium dioxide (E171)

Triacetin (E1518)

Talc (E553b)

Yuvanci 10 mg/20 mg film-coated tablets also contain red iron oxide (E172) and yellow iron oxide (E172).

Appearance of the Product and Package Contents

Yuvanci 10 mg/20 mg film-coated tablets are pink, oblong, with the inscription "MT" on one side and "1020" on the other. Yuvanci 10 mg/20 mg is presented in 30 × 1 film-coated tablets in single-dose aluminum blisters with integrated desiccant.

Yuvanci 10 mg/40 mg film-coated tablets are white to almost white, oblong, with the inscription "MT" on one side and "1040" on the other. Yuvanci 10 mg/40 mg is presented in 30 × 1 film-coated tablets in single-dose aluminum blisters with integrated desiccant.

Marketing Authorization Holder

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

Manufacturer

Janssen Pharmaceutica NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Prospectus:

Detailed information on this medicine is available on the European Medicines Agency website: https://www.ema.europa.eu