Kuvan

Patient Information Leaflet

Kuvan 100 mg dispersible tablets

Sapropterin dihydrochloride
Please 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 questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Kuvan is and what it is used for

Kuvan contains the active substance sapropterin, which is a synthetic copy of a substance naturally present in
our body called tetrahydrobiopterin (BH4). The role of the BH4 molecule is to help
the body process an amino acid called phenylalanine by converting it 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,
which 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 medicine is also used to treat an inherited disorder called BH4 deficiency, in
patients of any age, in which the body does not produce enough BH4. Due to very
low levels of BH4, phenylalanine is not properly metabolized and its levels
increase, leading to harmful effects. By replacing the BH4 that the body does not produce,
Kuvan reduces the harmful effects of excess phenylalanine in the blood and increases
phenylalanine tolerance in the diet.

2. What you need to know before taking Kuvan

Do not take Kuvan
If you are allergic to sapropterin or to any of the other ingredients of this medicine (listed in
section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Kuvan, especially:

• if you are over 65 years old
• if you have problems with your kidneys or liver
• if you are ill. You should consult your doctor, as phenylalanine levels may increase during illness
• if you are prone to seizures

During treatment with Kuvan, your doctor will carry out blood tests to monitor the levels of phenylalanine and tyrosine in your blood and may decide, if necessary, to adjust your Kuvan dosage or your diet.
You must continue your dietary treatment as recommended by your doctor. Do not change your diet without contacting your doctor. Serious neurological problems may still occur even while taking Kuvan if phenylalanine levels are not properly controlled. During treatment with Kuvan, your doctor must continue to monitor your blood phenylalanine levels frequently, to ensure they are not too high or too low.

Other medicines and Kuvan
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. In particular, you must inform your doctor if you are taking:

• levodopa (used to treat Parkinson's disease)
• medicines used to treat cancer (e.g. methotrexate)
• medicines used to treat bacterial infections (e.g. trimethoprim)
• medicines that cause blood vessel dilation (such as glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomine, minoxidil).

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
If you are pregnant, your doctor will advise you on how to properly control your phenylalanine levels. Poorly controlled phenylalanine levels before or during pregnancy may harm both you and your baby. Your doctor will monitor your dietary phenylalanine intake before and during pregnancy.
If a strict diet does not sufficiently reduce phenylalanine levels in the blood, your doctor will decide whether you should take this medicine.
You must not take this medicine during breastfeeding.

Driving and using machines
Kuvan is not expected to affect your ability to drive or operate machinery.

Important information about some of the excipients in Kuvan
This medicine contains less than 1 mmol of sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.

3. How to take Kuvan

Take this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor.

Dosage for PKU
The recommended starting dose of Kuvan in patients with PKU is 10 mg per kg of body weight. Take Kuvan once daily with meals to enhance its absorption, always at the same time, preferably in the morning. Your doctor may adjust your dose, usually between 5 and 20 mg per kg of body weight per day, depending on your individual needs.

Dosage for BH4 deficiency
The recommended starting dose of Kuvan in patients with BH4 deficiency ranges from 2 to 5 mg per kg of body weight. Take Kuvan with meals to enhance its absorption. Divide the total daily dose into 2 or 3 doses taken throughout the day. Your doctor may adjust your dose up to 20 mg per kg of body weight per day, depending on your individual needs.

The table below is an example of how an appropriate dose is calculated.

Administration method
For patients with PKU, the total daily dose should be taken once daily, always at the same time, preferably in the morning.
For patients with BH4 deficiency, the total daily dose is divided into 2 or 3 doses throughout the day.

Use in all patients
Transfer the prescribed number of tablets into a glass or cup of water, as described in detail below, and stir until dissolved.
The tablets may take several minutes to dissolve. To speed up dissolution, the tablets may be crushed. Small particles may be visible in the solution, but they will not affect the efficacy of the medicine. Drink the dissolved Kuvan preparation with a meal, within 15 to 20 minutes after preparation.
Do not swallow the desiccant capsule contained in the bottle.

Use in patients with body weight above 20 kg
Place the tablets in a glass or cup of water (120–240 mL) and stir until dissolved.

Use in children with body weight up to 20 kg
The dose depends on body weight, which changes as your child grows. Your doctor will inform you:

• the number of Kuvan tablets required for one dose
• the amount of water needed to prepare one dose of Kuvan
• the volume of solution to administer to your child for the prescribed dose.

Your child must drink the solution with a meal.
Give your child the prescribed volume of solution within 15 or 20 minutes after dissolution. If you cannot administer the dose to your child within 15 or 20 minutes after the tablets have dissolved, you must prepare a new solution, as the unused solution must not be used after 20 minutes have elapsed.

Materials required to prepare and administer the dose of Kuvan

• The number of Kuvan tablets required for one dose
• A graduated measuring cup with markings at 20, 40, 60 and 80 mL
• A glass or cup
• A teaspoon or clean stirring utensil
• An oral dosing syringe (with 1 mL markings) (10 mL syringe for administering volumes ≤10 mL or 20 mL syringe for administering volumes >10 mL)

If you do not have the graduated measuring cup for dissolving the tablets and the 10 mL or 20 mL syringe, please request them from your doctor.

Steps for preparing and administering the dose:

• Transfer the prescribed number of tablets into the graduated measuring cup. Add the amount of water indicated by your doctor (for example, your doctor instructed you to use 20 mL to dissolve one Kuvan tablet). Ensure the liquid volume corresponds to the amount indicated by your doctor. Stir with a teaspoon or clean utensil until the tablets are completely dissolved.
• If your doctor instructed you to administer only a portion of the solution, immerse the tip of the oral dosing syringe into the measuring cup. Slowly pull back the plunger to withdraw the volume indicated by your doctor.
• Transfer the solution by slowly pushing the plunger to empty the entire contents of the oral dosing syringe into a glass or cup for administration (for example, if your doctor instructed you to dissolve two Kuvan tablets in 40 mL of water and to give 30 mL to your child, you will need to use the 20 mL oral dosing syringe twice to withdraw 30 mL (e.g., 20 mL + 10 mL) of solution and transfer it into a glass or cup for administration). Use a 10 mL oral dosing syringe for administering volumes ≤10 mL and a 20 mL oral dosing syringe for administering volumes >10 mL.
• If your child is too young to drink from a glass or cup, you may administer the solution using the oral dosing syringe. Withdraw the prescribed volume from the solution prepared in the graduated measuring cup and place the tip of the oral dosing syringe into your child’s mouth. Direct the tip of the syringe toward the cheek. Slowly push the plunger and administer the solution gradually until the entire content of the syringe has been delivered.
• Discard any remaining solution. Remove the plunger from the barrel of the oral dosing syringe. Wash both components of the oral dosing syringe and the graduated measuring cup with warm water, and allow them to air dry. When the oral dosing syringe is dry, reinsert the plunger into the barrel. Store the oral dosing syringe and the graduated measuring cup for future use.

If you take more Kuvan than you should
If you take more Kuvan than prescribed, you may experience adverse effects such as headache and dizziness. If you take more Kuvan than prescribed, contact your doctor or pharmacist immediately.

If you forget to take Kuvan
Do not take a double dose to make up for the missed dose. Take the next dose at the usual time.

If you stop taking Kuvan
Do not stop taking Kuvan without first consulting your doctor, as this may lead to an increase in blood phenylalanine levels.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
A few cases of allergic reactions (such as skin rashes and severe reactions) have been reported. Their frequency is unknown (the frequency cannot be estimated from the available data).
If you experience red, itchy, raised areas on the skin (urticaria), runny nose, rapid or irregular heartbeat, swelling of the tongue and throat, sneezing, wheezing, severe breathing difficulties or dizziness, this may indicate a serious allergic reaction to the medicine. If you notice these symptoms, seek medical advice immediately.
Very common side effects (may affect more than 1 in 10 people):
Headache and runny nose.
Common side effects (may affect up to 1 in 10 people):
Sore throat, nasal congestion or blocked nose, cough, diarrhoea, vomiting, stomach ache, low levels of phenylalanine in the blood, indigestion and nausea (see section 2: "Warnings and precautions").
Side effects with unknown frequency (the frequency cannot be estimated from the available data):
Gastritis (inflammation of the inner lining of the stomach), oesophagitis (inflammation of the inner lining of the oesophagus).
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system detailed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Kuvan

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the vial and carton after
"Exp.". The expiry date refers to the last day of that month.
Store below 25°C.
Keep the vial tightly closed to protect the medicine from moisture.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Kuvan contains

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

Description of the appearance of Kuvan and contents of the pack
Kuvan 100 mg soluble tablets are whitish-yellow in colour with "177" imprinted on one side.
It is available in bottles with child-resistant closures containing 30, 120 or 240 soluble tablets. Each bottle contains a small plastic tube of desiccant (silica gel).
Not all pack sizes may be marketed.

Marketing Authorisation Holder
BioMarin International Limited
Shanbally, Ringaskiddy
County Cork
Ireland

Manufacturer
BioMarin International Limited
Shanbally, Ringaskiddy
County Cork
Ireland

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. Links to other websites on rare diseases and their therapeutic treatments are also provided.

Package leaflet: information for the patient

Kuvan 100 mg powder for oral solution

Sapropterin dihydrochloride
(Sapropterini dihydrochloridum)
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What Kuvan is and what it is used for

Kuvan contains the active substance sapropterin, which is a synthetic copy of a substance naturally present in our body called tetrahydrobiopterin (BH4). The role of the BH4 molecule is to help the body process an amino acid called phenylalanine by converting it into another amino acid called tyrosine.
Kuvan is used to treat hyperphenylalaninaemia (HPA) or phenylketonuria (PKU) in patients of any age. HPA and PKU are caused by abnormally high levels of phenylalanine in the blood, which 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 medicine is also used to treat an inherited disease called BH4 deficiency, in patients of any age, in which the body does not produce enough BH4. Due to very low levels of BH4, phenylalanine is not properly metabolized, leading to its accumulation and harmful effects. By replacing the BH4 that the body does not produce, Kuvan reduces the harmful effects of excess phenylalanine in the blood and increases phenylalanine tolerance in the diet.

2. What you should know before taking Kuvan

Do not take Kuvan

• if you are allergic to sapropterin or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Kuvan, especially:

• if you are over 65 years old
• if you have problems with your kidneys or liver
• if you are ill. You should consult your doctor, as phenylalanine levels may increase during illness
• if you are prone to seizures

During treatment with Kuvan, your doctor will carry out blood tests to monitor the levels of phenylalanine and tyrosine in your blood and may decide, if necessary, to adjust your Kuvan dosage or your diet.
You must continue your dietary treatment as recommended by your doctor. Do not change your diet without consulting your doctor. Even while taking Kuvan, serious neurological problems may occur if phenylalanine levels in the blood are not properly controlled. During treatment with Kuvan, your doctor must continue to monitor phenylalanine blood levels frequently, to ensure they are not too high or too low.
Other medicines and Kuvan
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. In particular, you must inform your doctor if you are using:

• levodopa (used to treat Parkinson’s disease)
• medicines used to treat cancer (e.g. methotrexate)
• medicines used to treat bacterial infections (e.g. trimethoprim)
• medicines that cause dilation of blood vessels (such as glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomine, minoxidil).

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
If you are pregnant, your doctor will advise you on how to properly control your phenylalanine levels. If phenylalanine levels are not well controlled before or during pregnancy, this may harm both you and your baby. Your doctor will monitor dietary phenylalanine restriction before and during pregnancy.
If a strict diet does not adequately reduce phenylalanine levels in the blood, your doctor will decide whether you should take this medicine.
You must not take this medicine during breastfeeding.
Driving and using machines
Kuvan is not expected to affect your ability to drive or operate machinery.
Kuvan contains potassium citrate (E332)
This medicine contains 0.3 mmol (12.6 mg) of potassium per sachet. This should be taken into account in patients with impaired kidney function or those on a low-potassium diet.

3. How to take Kuvan

Take this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor.
Dosage for PKU
The recommended starting dose of Kuvan in patients with PKU is 10 mg per kg of body weight. Take Kuvan once daily with meals to enhance absorption, always at the same time, preferably in the morning. Your doctor may adjust your dose, usually between 5 and 20 mg per kg of body weight per day, depending on your individual needs.
Dosage for BH4 deficiency
The recommended starting dose of Kuvan in patients with BH4 deficiency ranges from 2 to 5 mg per kg of body weight. Take Kuvan with meals to enhance absorption. Divide the total daily dose into 2 or 3 doses taken throughout the day. Your doctor may adjust your dose up to 20 mg per kg of body weight per day, depending on your individual needs.
The table below is an example of how an appropriate dose is calculated

Administration method
For patients with PKU, the total daily dose should be taken once daily, always at the same time, preferably in the morning.
For patients with BH4 deficiency, the total daily dose should be divided into 2 or 3 doses throughout the day.

Use in patients with body weight above 20 kg
Make sure you know the dose of Kuvan powder prescribed by your doctor. For higher doses, your doctor may also prescribe Kuvan 500 mg oral solution powder. Ensure you know whether to use Kuvan 100 mg oral solution powder, or both medications, to prepare the dose. Open the sachet(s) only when you are ready to use them.

Preparation of the sachet(s)

• Open the Kuvan oral solution powder sachet(s) by folding and tearing or cutting along the dotted line in the upper right corner of the sachet.
• Empty the content of the sachet(s) into 120–240 mL of water. After dissolving the Kuvan powder in water, the solution should appear clear, colourless to yellow.

Administration of the medicine

• Drink the solution within 30 minutes.

Use in children with body weight up to 20 kg
For the preparation of Kuvan in children with body weight up to 20 kg, use only 100 mg sachets.
The dose depends on body weight, which changes as your child grows. Your doctor will inform you:

• the number of Kuvan 100 mg sachets required for one dose
• the amount of water needed to prepare one dose of Kuvan
• the amount of solution to administer to your child for the prescribed dose.

Your child must drink the solution together with a meal.
Give your child the prescribed amount of solution within 30 minutes after dissolving. If you are unable to administer the dose to your child within 30 minutes of dissolving the powder, you must prepare a new solution, as the unused solution must not be used after 30 minutes have elapsed.

Materials required to prepare and administer the Kuvan dose to your child

• The number of Kuvan 100 mg sachets required for one dose
• A graduated measuring cup with markings at 20, 40, 60 and 80 mL
• A glass or cup
• A clean teaspoon or mixing utensil
• An oral dosing syringe (with 1 mL graduations) (10 mL syringe for administering volumes ≤10 mL or 20 mL syringe for administering volumes >10 mL)

If you do not have the graduated measuring cup for dissolving the powder and the 10 mL or 20 mL oral dosing syringe, ask your doctor to provide them.

Steps for preparing and administering the dose:

• Transfer the prescribed number of Kuvan 100 mg sachets into the graduated measuring cup. Pour into the measuring cup the amount of water indicated by your doctor (for example, your doctor may have instructed you to use 20 mL to dissolve one Kuvan sachet). Ensure the liquid volume corresponds to the amount indicated by your doctor. Mix with a teaspoon or clean utensil until the powder is completely dissolved. After dissolving the powder in water, the solution should appear clear, colourless to yellow.
• If your doctor has instructed you to administer only part of the solution, immerse the tip of the oral dosing syringe into the measuring cup. Slowly pull back the plunger to withdraw the amount specified by your doctor.
• Transfer the solution by slowly pushing the plunger until all the solution contained in the oral dosing syringe is transferred into a glass or cup for administration (for example, if your doctor instructed you to dissolve two 100 mg Kuvan sachets in 40 mL of water and to give 30 mL to your child, you should use the 20 mL oral dosing syringe twice to withdraw 30 mL (e.g., 20 mL + 10 mL) of solution and transfer it into a glass or cup for administration). Use a 10 mL oral dosing syringe for administering volumes ≤10 mL and a 20 mL oral dosing syringe for administering volumes >10 mL.
• If your child is too young to drink from a glass or cup, you may administer the solution using the oral dosing syringe. Withdraw the prescribed volume from the solution prepared in the graduated measuring cup and place the tip of the oral dosing syringe into your child’s mouth. Direct the tip of the syringe towards the cheek. Slowly push the plunger and administer the solution gradually until the entire content of the syringe has been administered.
• Discard any remaining solution. Remove the plunger from the barrel of the oral dosing syringe. Wash both parts of the oral dosing syringe and the graduated measuring cup with warm water, and allow them to air dry. Once the oral dosing syringe is dry, reinsert the plunger into the barrel. Store the oral dosing syringe and the graduated measuring cup for future use.

If you take more Kuvan than you should
If you take more Kuvan than prescribed, you may experience adverse effects such as headache and dizziness. If you take more Kuvan than prescribed, contact your doctor or pharmacist immediately.

If you forget to take Kuvan
Do not take a double dose to make up for the missed dose. Take the next dose at the usual time.

If you stop taking Kuvan
Do not stop taking Kuvan without first consulting your doctor, as this may lead to an increase in blood phenylalanine levels.

If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

A few cases of allergic reactions (such as skin rashes and severe reactions) have been reported. Their frequency is unknown (the frequency cannot be estimated from the available data).
If you experience red, itchy, raised areas on the skin (urticaria), runny nose, rapid or irregular heartbeat, swelling of the tongue and throat, sneezing, wheezing, severe breathing difficulties, or dizziness, this may indicate a serious allergic reaction to the medicine. If you notice these symptoms, seek immediate medical advice.

Very common side effects (may affect more than 1 in 10 people):
Headache and runny nose.

Common side effects (may affect up to 1 in 10 people):
Sore throat, nasal congestion or blocked nose, cough, diarrhoea, vomiting, stomach ache, low levels of phenylalanine in the blood, indigestion and nausea (see section 2: "Warnings and precautions").

Side effects with unknown frequency (the frequency cannot be estimated from the available data):
Gastritis (inflammation of the inner lining of the stomach), oesophagitis (inflammation of the inner lining of the oesophagus).

Reporting of side effects
If you get any side effect, including ones not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system detailed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Kuvan

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the sachet and carton after "Exp.". The expiry date refers to the last day of that month.
Store below 25°C.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Kuvan contains

• The active substance is sapropterin dihydrochloride. Each sachet contains 100 mg of sapropterin dihydrochloride, equivalent to 77 mg of sapropterin.
• The other ingredients are: mannitol (E421), potassium citrate (E332), sucralose (E955), and ascorbic acid (E300).

Description of the appearance of Kuvan and contents of the pack
The oral solution powder is transparent, white to slightly yellowish in colour. The powder is contained in single-dose sachets containing 100 mg of sapropterin dihydrochloride.
Each box contains 30 sachets.
Marketing Authorisation Holder and Manufacturer
BioMarin International Limited
Shanbally, Ringaskiddy
County Cork
Ireland
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.

Package leaflet: Information for the patient

Kuvan 500 mg powder for oral solution

Sapropterin dihydrochloride
(Sapropterini dihydrochloridum)
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What Kuvan is and what it is used for

Kuvan contains the active substance sapropterin, which is a synthetic copy of a substance naturally present in our body called tetrahydrobiopterin (BH4). The role of the BH4 molecule is to help the body process an amino acid called phenylalanine by converting it into another amino acid called tyrosine.
Kuvan is used to treat hyperphenylalaninaemia (HPA) or phenylketonuria (PKU) in patients of any age. HPA and PKU are conditions caused by abnormally high levels of phenylalanine in the blood, which can be harmful. Kuvan reduces these levels in certain patients who respond to BH4, and may help increase the amount of phenylalanine that can be included in the diet.
This medicine is also used to treat an inherited disease called BH4 deficiency, in patients of any age, in which the body does not produce enough BH4. Due to very low levels of BH4, phenylalanine is not properly metabolized, leading to its accumulation and harmful effects. By replacing the BH4 that the body fails to produce, Kuvan reduces the harmful effects of excess phenylalanine in the blood and increases tolerance to phenylalanine in the diet.

2. What you need to know before taking Kuvan

Do not take Kuvan

• if you are allergic to sapropterin or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Kuvan, especially:

• if you are over 65 years old
• if you have problems with your kidneys or liver
• if you are ill. You should consult your doctor, as phenylalanine levels may increase during illness
• if you are prone to seizures

During treatment with Kuvan, your doctor will carry out blood tests to monitor the levels of phenylalanine and tyrosine in your blood and may decide, if necessary, to adjust your dose of Kuvan or your diet.
You must continue your dietary treatment as recommended by your doctor. Do not change your diet without contacting your doctor. Even if you are taking Kuvan, serious neurological problems may occur if phenylalanine levels in the blood are not properly controlled. During treatment with Kuvan, your doctor must continue to monitor your blood phenylalanine levels frequently, to ensure they are not too high or too low.
Other medicines and Kuvan
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. In particular, you must inform your doctor if you are taking:

• levodopa (used to treat Parkinson's disease)
• medicines used to treat cancer (e.g. methotrexate)
• medicines used to treat bacterial infections (e.g. trimethoprim)
• medicines that cause dilation of blood vessels (such as glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomine, minoxidil).

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning a pregnancy, or breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
If you are pregnant, your doctor will advise you on how to properly control your phenylalanine levels. If phenylalanine levels are not well controlled before or during pregnancy, this may harm you and your baby. Your doctor will monitor dietary phenylalanine restriction before and during pregnancy.
If a strict diet does not adequately reduce phenylalanine levels in the blood, your doctor will decide whether you should take this medicine.
You must not take this medicine while breastfeeding.
Driving and using machines
Kuvan is not expected to affect your ability to drive or use machines.
Kuvan contains potassium citrate (E332)
This medicine contains 1.6 mmol (62.7 mg) of potassium per sachet. This should be taken into consideration in patients with impaired kidney function or those on a low-potassium diet.

3. How to take Kuvan

Kuvan 500 mg must be used only in patients with a body weight above 25 kg.
Always take this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor.

Dosage for PKU
The recommended initial dose of Kuvan in patients with PKU is 10 mg per kg of body weight. Take Kuvan once daily, with food to enhance its absorption, always at the same time, preferably in the morning. Your doctor may adjust your dose, usually between 5 and 20 mg per kg of body weight per day, depending on your individual needs.

Dosage for BH4 deficiency
The recommended initial dose of Kuvan in patients with BH4 deficiency ranges between 2 and 5 mg per kg of body weight. Take Kuvan with food to enhance its absorption. Divide the total daily dose into 2 or 3 doses taken throughout the day. Your doctor may adjust your dose up to 20 mg per kg of body weight per day, depending on your individual needs.

Method of administration
For patients with PKU, the total daily dose should be taken once daily, always at the same time and preferably in the morning.
For patients with BH4 deficiency, the total daily dose should be divided into 2 or 3 doses taken throughout the day.

Make sure you know the prescribed dose of Kuvan powder. For precise dosing, your doctor may also prescribe Kuvan 100 mg oral solution powder. Ensure you know whether you should use only Kuvan 500 mg oral solution powder or both medicines to prepare your dose. Open the sachet(s) only when you are ready to use them.

Preparing the sachet(s):

• Open the sachet(s) of Kuvan oral solution powder by folding, tearing, or cutting along the dotted line in the upper right corner of the sachet.
• Empty the contents of the sachet(s) into 120–240 mL of water. After dissolving the powder in water, the solution should appear clear, ranging from colourless to yellow.

Taking the medicine

• Drink the solution within 30 minutes.

If you take more Kuvan than you should
If you take more Kuvan than prescribed, you may experience adverse effects such as headache and dizziness. If you take an overdose of Kuvan, contact your doctor or pharmacist immediately.

If you forget to take Kuvan
Do not take a double dose to make up for the missed dose. Take the next dose at your usual time.

If you stop taking Kuvan
Do not stop taking Kuvan without first consulting your doctor, as this may lead to an increase in blood phenylalanine levels.

If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
A few cases of allergic reactions (such as skin rashes and severe reactions) have been reported. Their frequency is unknown (the frequency cannot be determined from the available data).
If you experience red, itchy, raised areas on the skin (urticaria), runny nose, rapid or irregular heartbeat, swelling of the tongue and throat, sneezing, wheezing, severe breathing difficulties, or dizziness, this may indicate a serious allergic reaction to the medicine. If you notice these symptoms, contact your doctor immediately.

Very common side effects (may affect more than 1 in 10 people):
Headache and runny nose.

Common side effects (may affect up to 1 in 10 people):
Sore throat, nasal congestion or stuffy nose, cough, diarrhoea, vomiting, stomach ache, low levels of phenylalanine in the blood, indigestion, and nausea (see section 2: "Warnings and precautions").

Side effects with unknown frequency (the frequency cannot be determined from the available data):
Gastritis (inflammation of the inner lining of the stomach), oesophagitis (inflammation of the inner lining of the oesophagus).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Kuvan

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the sachet and carton after "Exp.". The expiry date refers to the last day of that month.
Store below 25°C.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Kuvan contains

• The active substance is sapropterin dihydrochloride. Each sachet contains 500 mg of sapropterin dihydrochloride (equivalent to 384 mg of sapropterin).
• The other components are: mannitol (E421), potassium citrate (E332), sucralose (E955) and ascorbic acid (E300).

Description of the appearance of Kuvan and contents of the pack
The oral solution powder is transparent, white to yellowish in colour. The powder is contained in single-dose sachets containing 500 mg of sapropterin dihydrochloride.
Each carton contains 30 sachets.
Marketing Authorisation Holder and manufacturer
BioMarin International Limited
Shanbally, Ringaskiddy
County Cork
Ireland
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.