Product Information for the User

Kuvan 100 mg Soluble Tablets

dihydrochloride of sapropterin

Read this entire product information carefully before starting to take this medicine, as it contains important information for you.

• Keep this product information, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.

• This medicine has been prescribed only to you, and you must not give it to other people even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this product information. See section 4.

1. What you need to know before starting to take Kuvan
2. How to take Kuvan

1. Possible adverse effects
2. Storage of Kuvan
3. Contents of the pack and additional information

Kuvan contains the active ingredient sapropterin, which is a synthetic copy of a substance found in the body called tetrahydrobiopterin (BH4). BH4 is necessary in the body to convert an amino acid called phenylalanine into another amino acid called tyrosine.

Kuvan is used to treat hyperphenylalaninemia (HPA) or phenylketonuria (PKU) in patients of any age. HPA and PKU are caused by abnormally high levels of phenylalanine in the blood that can be harmful. Kuvan reduces these levels in some patients who respond to BH4 and may help increase the amount of phenylalanine that can be included in the diet.

This medication is also used to treat a hereditary disease called tetrahydrobiopterin deficiency in patients of any age, in which the body cannot produce enough BH4. Because BH4 levels are very low, the body cannot use phenylalanine properly, and levels of this amino acid increase, having harmful effects. By substituting the BH4 that the body cannot produce, Kuvan reduces the damaging excess of phenylalanine in the blood and increases tolerance to phenylalanine in the diet.

Do not take Kuvan

If you are allergic to sapropterin or any of the other components of this medication (listed in section 6).

Warnings and precautions

Consult your doctor or pharmacist before starting to take Kuvan, especially:

• If you are 65 years or older
• If you have kidney or liver problems
• If you are ill. It is recommended to consult with your doctor in case of illness since blood phenylalanine levels may increase

• If you have a predisposition to seizures

When receiving treatment with Kuvan, your doctor will perform blood tests to verify the content of phenylalanine and tyrosine and decide to adjust the dose of Kuvan or the diet as necessary.

You must continue the dietary treatment according to your doctor's recommendations. Do not change your diet without informing your doctor. Even when taking Kuvan, if your blood phenylalanine levels are not well controlled, you may experience severe neurological problems. Your doctor must continue to monitor your blood phenylalanine levels frequently during treatment with Kuvan,to ensure they are not too high or too low.

Use of Kuvan with other medications

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication. In particular, you must inform your doctor if you are using:

• levodopa (to treat Parkinson's disease)
• medications for cancer treatment (e.g. methotrexate)
• medications for bacterial infections (e.g. trimethoprim)
• medications that cause vasodilation (e.g. glyceryl trinitrate [GTN], isosorbide dinitrate [ISDN], sodium nitroprusside [SNP], molsidomine, minoxidil).

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before using this medication.

If you are pregnant, your doctor will instruct you on how to control your phenylalanine levels properly. If they are not strictly controlled before pregnancy or when you become pregnant, it may be harmful to you and your baby. Your doctor will supervise the restriction of phenylalanine intake with diet before and during pregnancy.

If a strict diet does not reduce phenylalanine levels sufficiently in the blood, your doctor will consider whether you should take this medication.

You should not use this medication during breastfeeding.

Driving and operating machinery

Kuvan is not expected to affect your ability to drive and use machines.

Important information about some of the components of Kuvan

This medication contains less than 1 mmol of sodium (23 mg) per tablet; it is essentially “sodium-free”.

Follow exactly the administration instructions of this medication as indicated by your doctor.

In case of doubt, consult your doctor again.

Dosage for PKU

The recommended initial dose of Kuvan in patients with PKU is 10 mg per kg of body weight. Take Kuvan once a day, with a meal to increase absorption, and at the same time every day, preferably in the morning. Your doctor may adjust the dose, generally between 5 and 20 mg daily per kg of weight, according to your condition.

Dosage for BH4 deficiency

The recommended initial dose of Kuvan in patients with BH4 deficiency is 2 to 5 mg per kg of body weight. Take Kuvan with a meal to increase absorption. Divide the total daily dose into 2 or 3 doses administered throughout the day. Your doctor may adjust the dose up to 20 mg daily per kg of weight, according to your condition.

The following table is an example of how to calculate the appropriate dose

Administration form

For patients with PKU, the total daily dose is taken once a day and at the same time every day, preferably in the morning.

For patients with BH4 deficiency, the total daily dose is divided into 2 or 3 doses distributed throughout the day.

Use in all patients

Deposit the prescribed tablets in a medication cup or a glass, exactly as described below, and stir until they dissolve.

The tablets may take a few minutes to dissolve. To dissolve the tablets faster, you can crush them. You may observe small particles in the solution that will not affect the efficacy of the medication. Drink the prepared Kuvan solution with a meal within 15 or 20 minutes after preparation.

Do not ingest the desiccant capsule included in the bottle.

Use in patients with a body weight over 20 kg

Deposit the tablets in a medication cup or a glass (120 to 240 ml) of water and stir until they dissolve.

Use in children up to 20 kg of body weight

The dose is based on body weight, which will change as the child grows. Your doctor will indicate:

the number of Kuvan tablets needed for a dose

the amount of water needed to mix a dose of Kuvan

the amount of solution to administer to the child for the prescribed dose

The child should drink the Kuvan solution with a meal.

Administer the child the prescribed amount of solution within 15 or 20 minutes after dissolution. If you cannot administer the dose to the child within 15 or 20 minutes after dissolution of the tablets, you will have to prepare a new solution, as the unused solution should not be used once 20 minutes have passed.

Materials needed to prepare and administer the child's Kuvan dose

• The number of Kuvan tablets needed for a dose

• A medication cup with graduation marks corresponding to 20, 40, 60, and 80 ml

• A glass or cup

• A spoon or a clean utensil to stir
• A oral syringe (graduated in 1 ml divisions; a 10 ml syringe for administering volumes ≤10 ml or a 20 ml syringe for administering volumes >10 ml)

Ask your doctor for the medication cup to dissolve the tablets and the oral syringe of 10 ml or 20 ml if you do not have these materials.

Steps for preparation and taking the dose:

• Deposit the prescribed tablets in the medication cup. Pour the indicated amount of water into the medication cup (e.g., your doctor told you to use 20 ml to dissolve a Kuvan tablet). Check that the amount of liquid aligns (with the graduation mark corresponding to the amount indicated by your doctor) with the amount indicated by your doctor. Stir with the spoon or clean utensil until the tablets dissolve.
• If your doctor told you to administer only a part of the solution, insert the tip of the oral syringe into the medication cup. Pull the plunger back slowly to extract the indicated amount.
• Next, transfer the solution to a glass or a dosing cup by pushing the plunger slowly until all the solution previously introduced into the oral syringe is inside (e.g., if your doctor told you to dissolve two Kuvan tablets in 40 ml of water and administer 30 ml to the child, you will have to use the 20 ml oral syringe twice to extract the 30 ml (e.g., 20 ml + 10 ml) of solution and transfer it to a glass or cup for administration). Use a 10 ml oral syringe for administering volumes ≤10 ml or a 20 ml oral syringe for administering volumes >10 ml.

• If the baby is too small to drink from a glass or cup, you can administer the solution using the oral syringe. Extract the prescribed volume of prepared solution from the dosing cup and insert the tip of the oral syringe into the baby's mouth. Point the tip of the oral syringe towards one cheek. Push the plunger slowly, releasing a small amount at a time, until you administer all the solution contained in the oral syringe.

• Discard any remaining solution. Extract the plunger from the body of the oral syringe. Wash both parts of the oral syringe and the dosing cup with warm water and let them air dry. When the oral syringe is dry, reinsert the plunger into the body of the oral syringe. Store the oral syringe and medication cup for the next use.

If you take more Kuvan than you should

If you take more Kuvan than prescribed, you may experience adverse effects that may include headaches and dizziness. If you take more Kuvan than prescribed, inform your doctor or pharmacist immediately.

If you forget to take Kuvan

Do not take a double dose to compensate for the missed doses. Take the next dose at the usual time.

If you interrupt treatment with Kuvan

Do not interrupt treatment with Kuvan without previously discussing it with your doctor, as it may increase blood phenylalanine levels.

If you have any other doubts about the use of this medication, ask your doctor or pharmacist.

Like all medications, this medication may produce adverse effects, although not all people will experience them.

Few cases of allergic reactions (such as skin rashes and severe reactions) have been reported.

Its frequency is unknown (the frequency cannot be estimated from the available data).

If you have inflamed, red, and intensely itchy areas (urticaria), nasal discharge, rapid or irregular pulse, tongue or throat inflammation, sneezing, hissing while breathing, severe respiratory difficulty, or dizziness, you may be experiencing a severe allergic reaction to the medication. If you experience these symptoms, consult your doctor immediately.

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

Headache and nasal discharge.

Common Adverse Effects(may affect up to 1 in 10 people)

Sore throat, congestion or nasal blockage, cough, diarrhea, vomiting, stomach pain, low phenylalanine levels in blood tests, indigestion, and general discomfort (nausea) (see section 2: "Warnings and Precautions").

Unknown Adverse Effects(cannot be estimated from the available data)

Gastritis (inflammation of the stomach lining), esophagitis (inflammation of the esophagus lining).

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this prospectus. You can also report them directly through thenational notification system included in theAppendix V.By reporting adverse effects, you can contribute to providing more information about the safety of this medication.

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

Do not use this medication after the expiration date that appears on the bottle and on the packaging after CAD. The expiration date is the last day of the month indicated.

Store below 25 °C.

Keep the bottle perfectly closed to protect it from moisture.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. In this way, you will help protect the environment.

Composition of Kuvan

• The active ingredient is dihydrochloride of sapropterin. Each tablet contains 100 mg of dihydrochloride of sapropterin (equivalent to 77 mg of sapropterin).
• The other components are mannitol (E421), anhydrous calcium hydrogen phosphate, crospovidone type A, ascorbic acid (E300), sodium stearate fumarate, and riboflavin (E101).

Appearance of the product and contents of the packaging

Kuvan 100 mg soluble tablets are white to light yellow in color with "177" marked on one side.

They are presented in child-resistant safety closures with 30, 120, or 240 soluble tablets. Each container contains a small plastic tube with a desiccant (silica gel).

Only some packaging sizes may be commercially available.

Marketing Authorization Holder

BioMarin International Limited

Shanbally, Ringaskiddy

County Cork

Ireland

Responsible for Manufacturing

BioMarin International Limited

Shanbally, Ringaskiddy

County Cork

Ireland

Last review date of this leaflet: {MM/AAAA} Other sources of information

Detailed information about this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu There are also links to other websites about rare diseases and orphan medicines.