Macitentan and Tadalafil

For female patients:

Do not take macitentan and tadalafil if you are pregnant or plan to become pregnant. There is a high risk that macitentan and tadalafil will cause harm to the fetus.

Because of the risk of fetal harm, a program called Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) has been set up to make sure that pregnant women do not take macitentan and tadalafil, and that women do not become pregnant while taking macitentan and tadalafil. All females, including females who are not able to get pregnant, can only receive macitentan and tadalafil if they are registered with Macitentan-Containing Products REMS, have a prescription from a doctor who is registered with Macitentan-Containing Products REMS, and fill the prescription at a pharmacy that is registered with Macitentan-Containing Products REMS. Your doctor will register you in Macitentan-Containing Products REMS.

Your doctor will tell you about the risks of macitentan and tadalafil, especially the risks of serious birth defects if taken while pregnant. You must sign an informed consent sheet stating that you understand this information in order for your doctor to register you. Your doctor will also determine if you are able to become pregnant. If you have reached puberty (when child's body becomes physically mature and capable of having a child), have a uterus, and have not yet gone through menopause ('change in life' end of monthly menstrual periods), you are considered to be a female who is able to become pregnant, and you will have to follow certain additional rules in order to receive macitentan and tadalafil. For females who are able to become pregnant: You must use reliable birth control throughout your treatment with macitentan, and for 1 month after your final dose. Your doctor will tell you which forms of birth control are acceptable, and will give your written information about birth control. In most cases you will be required to use two forms of birth control in order to prevent pregnancy while taking macitentan and tadalafil.

You will have to take a pregnancy test before starting treatment, every month during treatment, and 1 month after your final dose in order to be able to receive macitentan and tadalafil. Your doctor will order the pregnancy tests for you. The pharmacy will not dispense macitentan and tadalafil to you until they have confirmed that you have taken your required pregnancy tests. You must not have unprotected sex while taking macitentan and tadalafil. Call your doctor right away if you have had unprotected sex, think your birth control failed, missed your period, or think you may be pregnant for any reason. He or she will discuss your medical options with you. Do not wait until your next appointment to discuss this with your doctor. Tell your doctor if you do not understand everything you were told about birth control, or if you do not think you will be able to use acceptable forms of birth control at all times during your treatment. If you are a parent or guardian of a female who had not yet reached puberty, check your child regularly to see if she is developing any signs of puberty (breast buds, pubic hair) and let her doctor know about any changes.

For all patients: Macitentan and tadalafil is not available at retail pharmacies. Your medication will be mailed to you from a specialty pharmacy that is registered with Macitentan-Containing Products REMS. If you are a female who has not reached puberty or a female who is able to become pregnant, you will only receive a 30-day supply at a time.

Ask your doctor if you have any questions about how you will receive your medication. Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with macitentan and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website ( https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm ) or the manufacturer's website to obtain the Medication Guide.

Macitentan and tadalafil is used to treat certain types of pulmonary arterial hypertension (PAH; high blood pressure in the vessels that carry blood to the lungs) in adults. Macitentan is in a class of medications called endothelin receptor antagonists. It works by stopping the action of endothelin, a natural substance that causes blood vessels to narrow and prevents normal blood flow in people who have PAH. Tadalafil is in a class of medications called phosphodiesterase (PDE) inhibitors. It works by relaxing the blood vessels in the lungs to allow blood to flow more easily.

Macitentan and tadalafil comes as a tablet to take by mouth. It is usually taken with or without food once a day. Take macitentan and tadalafil at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take macitentan and tadalafil exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

Your doctor may start you on a low dose of macitentan and tadalafil and gradually increase your dose after a week.

Macitentan and tadalafil controls PAH but does not cure it. Continue to take macitentan and tadalafil even if you feel well. Do not stop taking macitentan and tadalafil without talking to your doctor.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Before taking macitentan and tadalafil,

• tell your doctor and pharmacist if you are allergic to macitentan, tadalafil, any other medications, or any of the ingredients in macitentan and tadalafil tablet. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• some medications should not be taken with macitentan and tadalafil. Other medications may cause dosing changes or extra monitoring when taken with macitentan and tadalafil. Make sure you have discussed any medications you are currently taking or plan to take before starting macitentan and tadalafil with your doctor and pharmacist. Before starting, stopping, or changing any medications while taking macitentan and tadalafil, please get the advice of your doctor or pharmacist.
• tell your doctor what herbal products you are taking, especially St. John's Wort.
• tell your doctor if you have or have ever had liver disease, low blood pressure, heart disease or heart failure, anemia (low red blood cell count), pulmonary veno-occlusive disease (PVOD; blockage of veins in the lungs), angina (chest pain), stroke, any condition that affects the shape of the penis; blood circulation problems; blood cell problems such as sickle cell anemia (a disease of the red blood cells), multiple myeloma (cancer of the plasma cells), or leukemia (cancer of the white blood cells); or kidney disease.
• you should not breastfeed while receiving macitentan and tadalafil.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking macitentan and tadalafil.
• ask your doctor about the safe use of alcoholic beverages while you are taking macitentan and tadalafil. Alcohol can make the side effects from macitentan and tadalafil, such as dizziness, headache and changes in blood pressure, worse.
• you should know that macitentan and tadalafil may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• you should know that macitentan and tadalafil has caused decrease in sperm count, which may impact fertility (ability to get your partner pregnant) in men.

Unless your doctor tells you otherwise, continue your normal diet.

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Macitentan and tadalafil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• swelling in face, arms or legs
• headache
• abdominal pain

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• nausea or vomiting, stomach or belly pain, tiredness, loss of appetite, yellowing of skin or whites of eye, dark urine, itching
• low blood pressure which may cause symptoms such as dizziness or lightheadedness
• tiredness, pale skin color, cold hands or feet, difficulty concentrating
• unusual weight gain, trouble breathing or swelling of ankles or legs
• erection that lasts longer than 4 hours with or without pain

Some patients experienced a sudden loss of some or all of their vision after they took tadalafil. The vision loss was permanent in some cases. It is not known if the vision loss was caused by the medication. If you experience a sudden loss of vision while you are taking tadalafil, call your doctor immediately or get emergency medical treatment.

Some patients experienced a sudden decrease or loss of hearing after they took tadalafil. The hearing loss usually involved only one ear and did not always improve when the medication was stopped. It is not known if the hearing loss was caused by the medication. If you experience a sudden loss of hearing, sometimes with ringing in the ears or dizziness, while you are taking tadalafil, call your doctor immediately.

Macitentan and tadalafil may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (https://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. https://www.upandaway.org

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (https://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.

Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check your body's response to macitentan and tadalafil.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Opsynvi^®