Consumer medicine information

Kuvan

Sapropterin dihydrochloride

BRAND INFORMATION

Brand name

Kuvan

Active ingredient

Sapropterin dihydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kuvan.

SUMMARY CMI

Kuvan®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Kuvan?

Kuvan contains the active ingredient sapropterin dihydrochloride which is a synthetic copy of the body's own substance called tetrahydrobiopterin. Kuvan is used to treat hyperphenylalaninemia (HPA) by reducing blood phenylalanine levels in patients with phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. For more information, see Section 1. Why am I using Kuvan? in the full CMI.

2. What should I know before I use Kuvan?

Do not use if you have ever had an allergic reaction to Kuvan or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Kuvan? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Kuvan and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Kuvan?

  • Take Kuvan with meals.
  • Place the number of tablet(s) or sachet(s) your doctor has told you to take in a glass or cup of water or apple juice and stir until dissolved. Your doctor will tell you how much water or juice to use to dissolve the tablet(s) or powder, and the amount of the medicine mixture to take. You must take Kuvan exactly as explained by your doctor.
  • You may mix the crushed tablets in a small amount of soft food such as yoghurt or mashed banana.

More instructions can be found in Section 4. How do I use Kuvan? in the full CMI.

5. What should I know while using Kuvan?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Kuvan
  • Keep all your doctor's appointments so your progress can be checked.
  • Call your doctor straight away if you become ill for any reason.
Things you should not do
  • Do not change your diet without contacting your doctor.
  • Do not stop using this medicine unless your doctor tells you to.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Kuvan affects you.
Looking after your medicine
  • Keep the tablets in the bottle and sachets in a cool dry place below 25°C.
  • Keep the bottle tightly closed to protect the tablets from moisture.
  • Do not use the tablets if more than 2 months has passed since first opening the bottle.

For more information, see Section 5. What should I know while using Kuvan? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If they do occur, they are usually minor and temporary. Do not be alarmed by this list. You may not experience any of them.

The common side effects include headache, runny nose, sore throat, blocked nose, throat infection, mouth and throat pain, cough, pain in the oesophagus, oesophagitis (inflammation of the lining of the food pipe), gastritis (inflammation of the lining of the stomach), gastrointestinal problems (e.g. vomiting, upset stomach, nausea, diarrhoea, stomach ache) and blood Phe levels that are too low. The serious side effects are symptoms of an allergic reaction (shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest, swelling of the face, lips, tongue, or other parts of the body, rash, itching, hives, or flushed red skin), and symptoms of severe gastritis (inflammation of the stomach lining) or oesophagitis (inflammation of the lining of the food pipe), e.g. severe upper stomach area discomfort or pain, nausea and vomiting, blood in your vomit or stool, black or tarry stools, swallowing that is difficult or painful.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Kuvan® (phonetic pronunciation – SAP-roe-PTER-in)

Active ingredient: sapropterin dihydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Kuvan. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Kuvan.

Where to find information in this leaflet:

1. Why am I using Kuvan?
2. What should I know before I use Kuvan?
3. What if I am taking other medicines?
4. How do I use Kuvan?
5. What should I know while using Kuvan?
6. Are there any side effects?
7. Product details

1. Why am I using Kuvan?

Kuvan contains the active ingredient sapropterin dihydrochloride which is a synthetic copy of the body's own substance called tetrahydrobiopterin (BH4). Kuvan is identical to the body's own natural BH4 except that it is made in a laboratory. BH4 is used by the body to process phenylalanine (Phe) in order to build another amino acid called tyrosine, which is a building block for several important brain chemicals.

Kuvan is used to treat hyperphenylalaninemia (high blood phenylalanine levels) in patients with phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. People with PKU or BH4 deficiency have abnormally high levels of Phe in the blood. Phe is a necessary amino acid but it is harmful in excessive amounts and people with PKU or BH4 deficiency cannot process Phe normally. A Phe restricted diet will reduce Phe levels in the body and some people also need treatment with Kuvan.

Kuvan is used together with dietary restrictions to reduce Phe in the blood. Not everyone with PKU or BH4 deficiency responds to Kuvan but if you do respond, you may be able to tolerate more Phe in your diet than you could without treatment.

2. What should I know before I use Kuvan?

Warnings

Do not use Kuvan if:

  • you are allergic to sapropterin dihydrochloride, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions, in particular you:
    - have or have had kidney or liver disease
    - have or have had convulsions ('fits')
    - have gastritis (inflammation of the stomach lining)
    - have oesophagitis (inflammation of the food pipe [gullet])
    - do not feel well before you start to take Kuvan. The levels of Phe in your blood may be higher if you are currently ill
  • are over 50 years old
  • your child is less than 1 month old. More frequent monitoring is recommended in children
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. It is very important to control blood Phe during pregnancy as high Phe can harm you or your baby. Dietary management is the first option. Your doctor will consider the use of Kuvan only if strict dietary management does not adequately reduce your blood Phe levels.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known whether Kuvan passes into breast milk. You should not take Kuvan if you are breastfeeding.

3. What if I am taking other medicines?

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

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

  • methotrexate (a medicine used to treat arthritis, psoriasis and some cancers)
  • trimethoprim (an antibiotic)
  • any heart medicine or angina treatment, e.g. glyceryl trinitrate, isosorbide dinitrate or sodium nitroprusside
  • any medicine for the treatment of impotence, such as sildenafil, vardenafil, or tadalafil
  • minoxidil (a medicine used to treat hair loss and high blood pressure)
  • levodopa (a medicine used to treat Parkinson's disease)

These medicines may be affected by Kuvan or may affect how well it works. You may need to use different amounts of your medicines, or take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Kuvan.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Kuvan.

4. How do I use Kuvan?

Follow carefully all directions given to you by your doctor, dietitian or pharmacist.

Kuvan is taken as tablet(s) or powder for oral solution in sachet(s) dissolved in water or apple juice.

It is not possible to know whether or not Kuvan will work for you until you start taking it. Your doctor will monitor your blood Phe levels when you start taking Kuvan to see if it is working.

How much to take

Your doctor will tell you how many tablets or sachets to take. You must take Kuvan exactly as explained by your doctor.

PKU

The usual starting dose of Kuvan in adults and children with PKU is 10 mg for each kg of body weight per day. Your doctor may adjust your dose depending on your condition, response to treatment, and as your child grows. The recommended daily dose is between 5 mg and 20 mg for each kg of body weight per day.

BH4 deficiency

The usual starting dose of Kuvan in adults and children with BH4 deficiency is 2 mg to 5 mg for each kg of body weight per day. Your doctor may adjust your dose depending on your condition and response to treatment. The recommended daily dose is between 2 mg and 20 mg for each kg of body weight per day.

When to take Kuvan

PKU

Take the tablet(s) or sachet(s) dissolved in water or apple juice as a single daily dose with a meal and at the same time each day, preferably in the morning.

BH4 deficiency

Take the tablet(s) or sachet(s) dissolved in water or apple juice with a meal. Divide the total daily dose into 2 or 3 doses, distributed over the day, to achieve the best treatment effect.

How to take Kuvan

Tablets

  • Place the number of tablet(s) your doctor has told you to take in a glass or cup of water or apple juice and stir until dissolved. Your doctor will tell you how much water or juice to use to dissolve the tablet(s). It may take a few minutes for the tablets to dissolve.
  • To make the tablets dissolve faster you can crush them.
  • Don't worry if there are small particles in the solution. This will not affect how well it works.
  • Only prepare the solution when you are ready to take it. Kuvan solution should be drunk within 15 to 20 minutes after preparing it. Discard any unused solution.
  • You may mix the crushed tablets in a small amount of soft food such as yoghurt or mashed banana. Make sure all the soft food is consumed so the full dose of the medicine is taken.

Sachets

  • Open the sachet(s) of Kuvan powder for oral solution by folding and tearing or cutting at the dotted line in the upper right corner of the sachet.
  • Empty the contents of the sachet(s) into a glass or cup of water or apple juice. Your doctor will tell you how much water or juice to use to dissolve the powder. After dissolving Kuvan powder in water or apple juice, the solution must be clear and colourless to yellow.
  • Open the sachet(s) only when you are ready to use them. Drink the solution within 30 minutes. Discard any unused solution.

Adults and Children above 20 kg body weight

Place the number of tablet(s) or sachet(s) your doctor has told you to take in a glass or cup (120 - 240 mL) of water or apple juice and stir until dissolved.

Be sure that you know what dose of Kuvan powder your doctor prescribed. For higher doses, your doctor may also prescribe Kuvan 500 mg powder for oral solution. Be sure you know whether to use Kuvan 100 mg powder for oral solution, or both medicines to prepare your dose.

Children up to 20 kg body weight

If you are using Kuvan sachet to prepare the dose, only use the 100 mg sachet to prepare Kuvan for children weighing up to 20 kg body weight.

The dose of Kuvan is based on body weight. This will change as your child grows. Your doctor will tell you:

  • the number of Kuvan tablets or 100 mg sachet(s) needed for one dose
  • the amount of water or apple juice needed to mix one dose of Kuvan, and
  • the amount of the mixture (tablet(s) or 100 mg sachet(s) and water or apple juice) to give your child for their prescribed dose.

You will need to use an accurate measuring device (e.g. medicine cup or oral syringe) with suitable graduations for this purpose. Ask your pharmacist for an accurate measuring device. For each dose, a fresh solution should be prepared.

Ask your doctor or pharmacist if you have any questions about how to prepare Kuvan or how much to take.

Do not swallow the desiccant capsule contained in the bottle of tablets.

If you forget to use Kuvan

Kuvan should be used regularly at the same time(s) each day. If you miss your dose at the usual time, take it as soon as you remember on the same day.

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

Do not take a double dose to make up for the dose you missed.

At your next appointment, tell your doctor if you forgot to take Kuvan.

If you use too much Kuvan

If you think that you have used too much Kuvan, you may need urgent medical attention.

Symptoms of an overdose with Kuvan may include headache and dizziness.

You should immediately:

  • phone the Poisons Information Centre (In Australia telephone 131 126. In New Zealand telephone 0800 POISON or 0800 764 766), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Kuvan?

Things you should do

  • Keep all your doctor's appointments so your progress can be checked.
    While you are taking Kuvan, your doctor will test your blood regularly to check your levels of Phe and tyrosine and may decide to adjust the dose of Kuvan or your diet if needed.

Call your doctor straight away if you:

  • become ill for any reason even if the illness is not related to the reason you are taking Kuvan.
    Your doctor may want to check your Phe levels as other illnesses may increase blood Phe.

Remind any doctor, dentist or pharmacist you visit that you are using Kuvan.

Things you should not do

  • Do not change your diet without contacting your doctor.
    Any change you make to your diet may affect your blood Phe level. You must continue your diet treatment as recommended by your doctor.
  • Do not stop taking Kuvan unless your doctor tells you to.
    The Phe levels in your blood may increase. Your doctor will need to carefully monitor your blood Phe levels if you stop taking Kuvan.
  • Do not give Kuvan to anyone else, even if they have the same condition as you.
  • Do not take Kuvan to treat any other complaints unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Kuvan affects you.

The effect of Kuvan on your ability to drive a car or operate machinery has not been studied.

Looking after your medicine

  • Keep the tablets in the bottle and sachets in a cool dry place where the temperature stays below 25°C.
  • Keep the bottle tightly closed to protect the tablets from moisture. Keep the desiccant tube in the bottle.
  • Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Do not use the tablets if more than 2 months has passed since first opening the bottle.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Ear, nose or throat related
  • runny nose
  • sore throat
  • blocked or stuffy nose
  • throat infection (pharyngitis)
  • cough
  • mouth and throat pain
Nervous system related
  • headache
Gastrointestinal related
  • vomiting
  • upset stomach
  • nausea
  • diarrhoea (loose stools)
  • stomach ache
  • oesophagitis (inflammation of the lining of the food pipe)
  • pain in the oesophagus
  • gastritis (inflammation of the lining of the stomach)
Blood-test related
  • levels of Phe in blood tests that are too low
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction related:
  • shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest
  • swelling of the face, lips, tongue, or other parts of the body
  • rash, itching, hives or flushed, red skin
Gastrointestinal related:
  • symptoms of severe gastritis or oesophagitis, e.g. severe upper stomach area (abdominal) discomfort or pain, nausea and vomiting, blood in your vomit or stool, black or tarry stools, swallowing that is difficult or painful.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Some side effects may be found only by having a blood test, e.g. levels of Phe in blood tests that are too low.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Kuvan contains

Active ingredient
(main ingredient)		sapropterin dihydrochloride
  • 100 mg in each soluble tablet
  • 100 mg or 500 mg in each sachet of powder
Other ingredients
(inactive ingredients)		Tablets:
  • mannitol
  • calcium hydrogen phosphate
  • crospovidone
  • ascorbic acid
  • sodium stearylfumarate
  • riboflavin

Sachets:

  • mannitol
  • potassium citrate
  • sucralose
  • ascorbic acid

Do not take this medicine if you are allergic to any of these ingredients.

What Kuvan looks like

Kuvan soluble tablets are off-white to light yellow with "177" printed on one face. The tablets are supplied in a bottle of 30 tablets with a child-resistant closure. Each bottle contains a small plastic tube of desiccant (silica gel). (AUST R 165738).

Kuvan powder for oral solution is off-white to light yellow. Each carton contains 30 sachets. (100 mg: AUST R 297728, 500 mg: AUST R 297734).

Who distributes Kuvan

BioMarin Pharmaceutical Australia Pty Ltd
119 Willoughby Road
Crows Nest NSW 2065

Kuvan tablets are supplied in New Zealand by:

Pharmacy Retailing (NZ) Limited t/a Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks 2022
Auckland

For enquiries about Kuvan, contact [email protected]

To report adverse events, contact [email protected]

Alternatively, call BioMarin:

Australia: 1800 387 876

New Zealand: 0800 882 012

This leaflet was prepared in August 2021.

® Registered trademark of BioMarin Pharmaceutical Inc., USA

Published by MIMS May 2022

BRAND INFORMATION

Brand name

Kuvan

Active ingredient

Sapropterin dihydrochloride

Schedule

S4

 

1 Name of Medicine

Sapropterin dihydrochloride.

2 Qualitative and Quantitative Composition

Each soluble tablet contains 100 mg of sapropterin dihydrochloride (equivalent to 77 mg of sapropterin).
Each 100 mg sachet contains 100 mg of sapropterin dihydrochloride (equivalent to 77 mg of sapropterin).
Each 500 mg sachet contains 500 mg of sapropterin dihydrochloride (equivalent to 384 mg of sapropterin).

Excipients with known effect.

Contains 171.18 mg mannitol per tablet, 169.06 mg mannitol per 100 mg sachet and 845.31 mg mannitol per 500 mg sachet. Products containing mannitol may have a laxative effect or may cause diarrhoea.
Contains 12 mg potassium per 100 mg sachet, 62 mg potassium per 500 mg sachet and sucralose (sachets only).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Soluble tablets.

Kuvan is supplied as immediate release soluble tablet, off-white to light yellow with "177" imprinted on one face.

Powder for oral solution.

The powder is off-white to light yellow.

4 Clinical Particulars

4.1 Therapeutic Indications

Kuvan is indicated for the treatment of hyperphenylalaninemia (HPA) in sapropterin-responsive adult and paediatric patients with phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency (see Section 4.2 Dose and Method of Administration for definition of sapropterin responsiveness).

4.2 Dose and Method of Administration

Treatment with Kuvan must be initiated and supervised by a physician experienced in the treatment of PKU and BH4 deficiency.
Kuvan should be administered with a meal to increase absorption.
For patients with PKU, Kuvan should be administered as a single daily dose, and at the same time each day, preferably in the morning.
For patients with BH4 deficiency, divide the total daily dose into 2 or 3 administrations, distributed over the day.
Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine levels and nutritional balance.
As HPA due to either PKU or BH4 deficiency is a chronic condition, once responsiveness is demonstrated, Kuvan is intended for long-term use.
Cessation of treatment must be conducted with close physician observation and monitoring due to the possibility of rebound in blood phenylalanine levels above pre-treatment levels (see Section 4.8 Adverse Effects (Undesirable Effects)).

Dosage.

PKU.

The starting dose of Kuvan in adult and paediatric patients with PKU is 10 mg/kg bodyweight once daily. The dose is adjusted to achieve and maintain adequate blood phenylalanine levels as defined by the physician. The recommended daily dose is between 5 and 20 mg/kg/day.

BH4 deficiency.

The starting dose of Kuvan in adult and paediatric patients with BH4 deficiency is 2 to 5 mg/kg bodyweight total daily dose. The dose is adjusted to achieve and maintain adequate blood phenylalanine levels as defined by the physician. The recommended total daily dose is between 2 and 20 mg/kg/day. Divide the total daily dose into 2 or 3 administrations, distributed over the day.

Determination of response.

Response to Kuvan cannot be accurately pre-determined by laboratory testing alone (e.g. molecular testing), and can only be determined by a therapeutic trial of Kuvan. Response to Kuvan is determined by a decrease in blood phenylalanine following treatment with Kuvan. A satisfactory response is defined as a ≥ 30 percent reduction in blood phenylalanine levels or attainment of the therapeutic blood phenylalanine goals defined for an individual patient by the treating physician.
Blood phenylalanine levels should be checked before initiating Kuvan and after 1 week of administration with Kuvan at the recommended starting dose. If an unsatisfactory reduction in blood phenylalanine levels is observed, then the dose of Kuvan can be increased weekly to a maximum of 20 mg/kg/day, with continued weekly monitoring of blood phenylalanine levels. Patients whose blood Phe does not decrease from baseline after 1 month of administration at 20 mg/kg per day are non-responders and these patients should not be treated with Kuvan and administration of Kuvan should be discontinued. The dietary phenylalanine intake should be maintained at a constant level during this period.
Once responsiveness to Kuvan has been established, the dose may be adjusted according to response to therapy, within the therapeutic ranges specified under 'Dosage' above.
It is recommended that blood phenylalanine levels be tested one or two weeks after each dose adjustment and monitored frequently thereafter. Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine, nutrient intake, and psycho-motor development).

Administration.

The prescribed number of tablet(s) or sachet(s) should be placed in a glass or cup of water or apple juice and stirred until dissolved.
It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster they can be crushed. Small particles may be visible in the solution and will not affect the effectiveness of the medicinal product. The solution should be drunk within 15 to 20 minutes.
The solution obtained from the sachets of powder for oral solution should be drunk within 30 minutes.
Kuvan tablets may also be crushed and then mixed in a small amount of soft foods such as yoghurt or mashed banana.

Patients above 20 kg body weight.

Kuvan is provided as tablets and powder. The calculated daily dose based on body weight should be rounded to the nearest multiple of 100. For instance, a calculated dose of 401 to 450 mg should be rounded down to 400 mg corresponding to 4 tablets or 4 sachets of 100 mg powder. A calculated dose of 451 mg to 499 mg should be rounded up to 500 mg corresponding to 5 tablets or 1 sachet of 500 mg powder. The prescribed number of tablets or sachets should be placed in a glass or cup with 120 to 240 mL of water or apple juice and stirred until dissolved.

Children up to 20 kg body weight (if using Kuvan powder, use only 100 mg powder sachet(s)).

The appropriate number of tablet(s) or 100 mg sachet(s) should be dissolved in a volume of water or apple juice depicted in Tables 1-4 based on the prescribed daily dose.
An accurate measuring device (e.g. medicine cup or oral syringe) with suitable graduations should be used to ensure administration of the appropriate volume of solution. If only a portion of this solution needs to be administered, an oral syringe should be used to withdraw the volume of solution to be administered. The solution may be transferred to another cup for administration of the medicine. For small infants who cannot drink from a cup, the solution corresponding to the prescribed daily dose may be administered into the mouth via the oral syringe. A 10 mL oral syringe should be used for administration of volumes of ≤ 10 mL and a 20 mL oral syringe for administration of volumes of > 10 mL. Any unused portion should be discarded.
It is recommended that the prescriber, clinic nurse or pharmacist calculate and specify the volume of administration as well as the dose, in particular for young children, to reduce the risk of dosing errors.
Patients should be advised not to swallow the desiccant capsule found in the bottle of tablets.
Discard unused solution within 30 minutes for powder solution and 20 minutes for tablet solution.
Discard unused solution within 30 minutes for powder solution and 20 minutes for tablet solution.
Discard unused solution within 30 minutes for powder solution and 20 minutes for tablet solution.
Discard unused solution within 30 minutes for powder solution and 20 minutes for tablet solution.

Monitoring.

Treatment with Kuvan may decrease blood phenylalanine levels below the desired therapeutic level. Adjustment of the Kuvan dose or modification of dietary phenylalanine intake may be required to achieve and maintain blood phenylalanine levels within the desired therapeutic range.
Blood phenylalanine and tyrosine levels should be tested, particularly in children, one to two weeks after each dose adjustment and monitored frequently thereafter, under the direction of the treating physician.
If inadequate control of blood phenylalanine levels is observed during treatment with Kuvan, the patient's adherence to the prescribed treatment, and diet, should be reviewed before considering an adjustment of the dose of Kuvan.
Discontinuation of Kuvan treatment should be done only under the supervision of a physician. More frequent monitoring may be required, as blood phenylalanine levels may increase. Dietary modification may be necessary to maintain blood phenylalanine levels within the desired therapeutic range.

4.3 Contraindications

Kuvan is contraindicated in patients with hypersensitivity to sapropterin or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Specialist physician.

Treatment with Kuvan should be directed by specialist physicians knowledgeable in the management of PKU and BH4 deficiency.

Determination of response.

Kuvan does not work in all patients with PKU or BH4 deficiency but only in those who have shown a definite response. Response to treatment cannot be predetermined by laboratory testing (e.g. molecular testing) but can only be determined by a therapeutic trial of Kuvan (see Section 4.2 Dose and Method of Administration).

Dietary intake.

Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho-motor development).

Low blood phenylalanine levels.

Sustained or recurrent dysfunction in the phenylalanine-tyrosine-dihydroxy-L-phenylalanine (DOPA) metabolic pathway can result in deficient body protein and neurotransmitter synthesis. Prolonged elevations in blood phenylalanine levels in patients with PKU and BH4 deficiency can result in severe neurologic damage, including severe mental retardation, microcephaly, delayed speech, seizures and behavioural abnormalities. This may occur even if patients are taking Kuvan but not adequately controlling their blood phenylalanine levels within the recommended target range. Conversely, prolonged exposure to low blood phenylalanine and tyrosine levels during infancy has been associated with impaired neurodevelopmental outcome. Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine and tyrosine levels and nutritional balance.
It is of primary importance to initiate Kuvan treatment as early as possible to avoid the appearance of nonreversible clinical manifestations of neurological disorders in paediatric patients and cognitive deficits and psychiatric disorders in adults due to sustained elevations of blood phenylalanine.

Convulsion disorders.

Caution is advised when Kuvan is used in patients with predisposition to convulsions. Events of convulsion and exacerbation of convulsion have been reported in such patients.
Kuvan should be used with caution in patients who are receiving concomitant levodopa, as combined treatment may cause increased excitability and irritability. Events of convulsion and exacerbation of convulsion have been observed during coadministration of levodopa and sapropterin dihydrochloride in BH4-deficient patients.

Intercurrent illness.

Consultation with a physician is recommended during concomitant illness as blood phenylalanine levels may increase.

Gastritis and oesophagitis.

Gastritis and oesophagitis were reported as serious adverse reactions. Monitor patients for signs and symptoms of these conditions.

Use in renal and hepatic impairment.

Safety and efficacy of Kuvan in patients with renal or hepatic insufficiency have not been established. Caution must be exercised when prescribing to patients with renal or hepatic insufficiency.
An increased incidence of altered renal microscopic morphology (collecting tubule basophilia) was observed in rats following chronic oral administration of sapropterin dihydrochloride at doses higher than 80 mg/kg/day, i.e. at exposures (based on area under curve, AUC) about 3 times the exposure at the maximal recommended human dose. No kidney changes were seen in marmoset monkeys after chronic treatment at oral doses of up to 320 mg/kg/day, approximately 2.6 times the highest dose anticipated in humans, based on body surface area.

Use in the elderly.

The safety and efficacy of Kuvan in patients over 50 years of age, including adults who did not receive early dietary treatment, have not been established. Caution must be exercised when prescribing to elderly patients.

Paediatric use.

The posology is the same in adults, children and adolescents.
Paediatric patients, aged 1 month and older, with HPA due to PKU and BH4 deficiency have been treated with Kuvan in clinical studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Children aged less than 1 month were not studied in clinical trials.
Published literature indicates that more than 2,700 children with PKU aged newborn to 4 years have been administered BH4, including at least 43 who received therapy for 2 months or longer. BH4 deficiency is an extremely rare condition but reports of published studies include at least 120 patients starting treatment when less than 4 years of age (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Based on an in vitro study, there is potential for Kuvan to inhibit P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the gut at the therapeutic doses.
In healthy subjects, administration of a single dose of Kuvan at the maximum therapeutic dose of 20 mg/kg had no effect on the pharmacokinetics of a single dose of digoxin (P-gp substrate) administered concomitantly.
Although concomitant administration of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim) has not been studied, such medicinal products may interfere with BH4 metabolism. Caution is recommended when using such agents during treatment with Kuvan.
BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Kuvan with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomine), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil.
Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa, as increased excitability and irritability has been reported during concomitant use. Events of convulsion and exacerbation of convulsion have been observed during co-administration of levodopa and sapropterin dihydrochloride in BH4-deficient patients.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Sapropterin dihydrochloride at oral doses up to 400 mg/kg/day (about 16 times the exposure in adults taking 20 mg/kg/day, based on AUC values) had no effect on the fertility of male or female rats.
(Category B1)
There are limited data from the use of Kuvan in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
Available data from the Maternal Phenylketonuria Collaborative Study on 576 pregnancies and 414 live births in PKU-affected women demonstrated that uncontrolled phenylalanine levels above 600 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies.
Maternal blood phenylalanine levels must be strictly controlled before and during pregnancy. If maternal phenylalanine levels are not strictly controlled before and during pregnancy, this could be harmful to the mother and the fetus. Physician-supervised restriction of dietary phenylalanine intake prior to and throughout pregnancy is the first choice of treatment in this patient group.
In rats, following intravenous administration of radiolabelled sapropterin, radioactivity was found to be distributed in fetuses. No increase in total biopterin concentrations in fetuses was observed in rats after oral administration of 10 mg/kg sapropterin dihydrochloride. However, in pregnant guinea pigs there was a marked increase in sapropterin and/or its metabolites in the fetus after oral administration of 20 mg/kg sapropterin dihydrochloride.
No clear evidence of teratogenic activity was found in rats or rabbits at doses of 400 and 600 mg/kg/day, corresponding to about 16 and 19 times, respectively, the exposure in adults at the maximum recommended human dose (based on AUC). Sapropterin dihydrochloride had no effect on parturition and postnatal development in rats at doses of 400 mg/kg/day.
The use of Kuvan during pregnancy should be considered only if strict dietary management does not adequately reduce blood phenylalanine levels. Caution must be exercised when prescribing to pregnant women.
 It is not known whether sapropterin or its metabolites are excreted in human breast milk. Kuvan should not be used during breastfeeding.
Excretion of total biopterin in milk occurred in rats when sapropterin dihydrochloride (10 mg/kg) was administered by the intravenous route. No increase in total biopterin concentrations in milk was observed in rats after oral administration of 10 mg/kg sapropterin dihydrochloride. There were no effects on the development of rat pups of dams given 400 mg/kg/day sapropterin dihydrochloride orally from gestation day 17 to postpartum day 20 (approximately 16 times the exposure in adults at the maximum recommended human dose, based on AUC).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

In clinical trials, Kuvan has been administered to 579 patients with PKU in doses ranging from 5 to 20 mg/kg/day for lengths of treatment ranging from 1 week to 3 years. Patients were aged 4 to 48 years old at study entry. The patient population was nearly evenly distributed in gender, and approximately 95% of patients were Caucasian.
Approximately 35% of the 579 patients with PKU who received treatment with Kuvan in the clinical trials experienced adverse events. The overall incidence of adverse events in patients receiving Kuvan was similar to that reported with patients receiving placebo. The most commonly reported adverse reactions for which a causal relationship is at least a reasonable possibility are headache and rhinorrhoea.
Rebound, as defined by an increase in blood phenylalanine levels above pretreatment levels, may occur upon cessation of treatment.
Table 5 shows by preferred term the number and percentage of 74 patients with PKU who had treatment emergent adverse events (regardless of relationship) that occurred in at least 4% of patients following exposure to Kuvan at doses of 10 to 20 mg/kg/day for 6 to 10 weeks in 2 double-blind, placebo-controlled clinical trials.
In addition, hypophenylalaninaemia occurred in 2% patients treated with Kuvan (n = 1) and in 12% patients treated with placebo (n = 9).
In open label, uncontrolled clinical trials in which all patients received Kuvan in doses of 5 to 20 mg/kg/day, adverse reactions were similar in type and frequency to those reported in the double blind, placebo controlled clinical trials.
In a clinical trial involving children who received treatment with sapropterin dihydrochloride, the most commonly reported adverse reactions are "amino acid level decreased" (hypophenylalaninaemia), vomiting and rhinitis.

Post-marketing experience.

Cases of hypersensitivity reactions (including serious adverse reactions and rash), dyspepsia, gastritis, nausea, oesophageal pain, oropharyngeal pain, pharyngitis and oesophagitis have been observed in the post-marketing setting.
A 10-year post-approval safety surveillance program of another formulation of the same active ingredient (sapropterin dihydrochloride granules) was conducted in Japan with 30 patients, 27 of these patients had BH4 deficiency and 3 had PKU. The most common adverse reactions identified during this program were convulsions and exacerbation of convulsions in 3 patients (see Section 4.4 Special Warnings and Precautions for Use) and increased gamma-glutamyltransferase (GGT) in 2 patients.

Reporting suspected adverse reactions.

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

Headache and dizziness have been reported after the administration of Kuvan above the recommended maximum dose of 20 mg/kg/day. Treatment of overdose should be directed to symptoms.
In a clinical study to evaluate the effects of Kuvan on cardiac repolarization, shortening of the QT interval was observed (maximum placebo-subtracted mean change from baseline of the QTc interval was -8.32 ms) with single supra-therapeutic dose of 100 mg/kg (5 times the maximum recommended dose); this should be taken into consideration in managing patients who have a pre-existing shortened QT interval (e.g. patients with familial short QT syndrome) (see Section 5.1 Pharmacodynamic Properties, Effects of Kuvan on the QTc interval).
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Hyperphenylalaninaemia (HPA) is diagnosed as an abnormal elevation in blood phenylalanine (Phe) levels and is usually caused by autosomal recessive mutations in the genes encoding for the liver enzyme phenylalanine hydroxylase (in the case of phenylketonuria, PKU) or for the enzymes involved in 6R-tetrahydrobiopterin (6R-BH4) biosynthesis or regeneration (in the case of BH4 deficiency). BH4 deficiency is a group of disorders arising from mutations or deletions in the genes encoding for one of the five enzymes involved in the biosynthesis or recycling of BH4.
In both PKU and BH4 deficiency, Phe cannot be effectively transformed into the amino acid tyrosine, leading to increased Phe levels in the blood. However, in patients with BH4 deficiency there are other enzymes in addition to phenylalanine hydroxylase that cannot function properly. These include tryptophan and tyrosine hydroxylase (located in the brain and other tissues) and nitric oxide synthase.
Sapropterin dihydrochloride is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan.
The rationale for administration of Kuvan in patients with BH4 responsive PKU is to enhance the activity of the defective phenylalanine hydroxylase and thereby increase or restore the oxidative metabolism of Phe sufficient to reduce or maintain blood Phe levels, prevent or decrease further Phe accumulation, and increase tolerance to Phe intake in the diet. The rationale for administration of Kuvan in patients with BH4 deficiency is to replace the deficient levels of BH4, thereby restoring the activity of phenylalanine hydroxylase.
In PKU patients who are responsive to BH4 treatment, blood Phe levels decrease within 24 hours after a single administration of Kuvan, although maximal effect on Phe level may take up to a month, depending on the patient. A single daily dose of Kuvan is adequate to maintain stable blood Phe levels over a 24-hour period. In a substudy of the clinical trial described as 'Study 3' under Section 5.1 Pharmacodynamic Properties, Clinical trials, blood Phe levels were measured multiple times over a 24-hour period in 12 patients taking 10 mg/kg/day. The blood Phe levels remained stable during the 24-hour observation period: mean (± Standard Deviation) was 661 (± 433) micromol/L at pre-dose and 631 (± 454) micromol/L at 24 hours post-dose; the lowest mean value during the 24-hour period was 477 (± 241) micromol/L at 16 hours post-dose. No consistent relationship between meals and blood Phe levels was observed during the 24-hour period.

Effects of Kuvan on the QTc interval.

A thorough QTc study was performed in 56 healthy adults. This randomised, placebo and active controlled crossover study was conducted to determine if a single supra-therapeutic (100 mg/kg) dose of Kuvan or a single therapeutic dose (20 mg/kg) of Kuvan had an effect on cardiac repolarisation. In this study, Kuvan was administered after dissolving tablets in water under fed conditions. This study demonstrated a dose-dependent shortening of the QT interval. The maximum placebo-subtracted mean change from baseline of the QTc interval was -3.69 and -8.32 ms (lower bound of 90% CI: -5.3 and -10.6 ms) at 20 and 100 mg/kg, respectively.

Clinical trials.

Phenylketonuria (PKU). The efficacy and safety of Kuvan were evaluated in clinical trials in patients with PKU ranging in age from 1 month to 49 years old. Patients with significant concurrent diseases with potential to interfere with efficacy and safety analyses were excluded from the trials. The results of these studies demonstrate the efficacy of Kuvan to reduce blood Phe levels and to increase dietary Phe tolerance.
Study 1 was a multicentre, open-label, uncontrolled clinical trial of 489 patients with PKU who had baseline blood Phe levels ≥ 450 micromol/L. Patients ranged in age from 8 to 48 years (38 patients were 8-11 years old and 451 were 12 years of age or older). Patients were to receive treatment with Kuvan 10 mg/kg/day for 8 days. For the purposes of this study, response to Kuvan treatment was defined as a ≥ 30% decrease in blood Phe from baseline. At Day 8, 96 patients (20%) were identified as responders.
Study 2 was a multicentre, double-blind, placebo-controlled trial of patients with PKU who responded to Kuvan in Study 1. After a washout period from Study 1, patients were randomised equally for 6 weeks of treatment with Kuvan 10 mg/kg/day or placebo. Four (10%) of the 41 Kuvan-treated patients and 8 (17%) of the 47 placebo patients were 8-11 years old; all other treated patients were 12 years of age or older. Efficacy was assessed by the mean change in blood Phe level from baseline to Week 6 in the Kuvan-treated group as compared to the mean change in the placebo group.
The results showed that Kuvan 10 mg/kg/day significantly reduced blood Phe levels as compared to placebo (see Figure 1). The baseline blood Phe levels for the Kuvan-treated group and the placebo group were similar, with mean (± SD) baseline blood Phe levels of 843 (± 300) micromol/L and 888 (± 323) micromol/L, respectively. The mean (± SD) decrease from baseline in blood Phe levels at the end of the 6 week study period was 236 (± 257) micromol/L for the Kuvan treated group as compared to an increase of 3 (± 240) micromol/L for the placebo group (p < 0.001). For patients with baseline blood Phe levels ≥ 600 micromol/L, 42% (13/31) of those treated with Kuvan and 13% (5/38) of those treated with placebo had blood Phe levels < 600 micromol/L at the end of the 6-week study period (p = 0.012).
Study 3 was a multicentre, open-label, 22-week extension study in which 80 patients who responded to treatment in Study 1 and completed Study 2 were treated. During the first 6 weeks of Study 3, patients underwent forced dose-titration with 3 different doses of Kuvan. Treatment during this dose titration period consisted of 3 consecutive 2-week courses of Kuvan at doses of 5, then 20, and then 10 mg/kg/day. At baseline, mean (± SD) blood Phe was 844 (± 398) micromol/L. At the end of treatment with 5, 10, and 20 mg/kg/day, mean (± SD) blood Phe levels were 744 (± 384) micromol/L, 640 (± 382) micromol/L, and 581 (± 399) micromol/L, respectively.
During the period from Week 6 to Week 10, patients were maintained on Kuvan 10 mg/kg/day pending analysis of their blood Phe results from the forced dose titration period. Starting at the Week 10 visit, each patient was assigned to receive a fixed dose of 5, 10 or 20 mg/kg/day based on their blood Phe results measured at the Week 2 and Week 6 visit, then continued using this optimal Kuvan dose until the Week 22 visit. Of the 80 patients, 6 (8%) received 5 mg/kg/day, 37 (46%) received 10 mg/kg/day and 37 (46%) received 20 mg/kg/day Kuvan from Week 10 to Week 22. Patients who received 10 or 20 mg/kg/day at all time points between Week 10 and Week 22 had mean blood Phe levels during this time comparable to those obtained on the same dose during the forced dose-titration period. Patients treated with 5 mg/kg/day from week 10 to week 22 had mean blood Phe levels higher than during the forced dose-titration period.
The mean (± SD) blood Phe levels at the Weeks 12-22 visits ranged between 620 (± 371) and 652 (± 383) micromol/L. On average, patients maintained a stable reduction in Phe levels. The 95% confidence interval for the mean change from baseline blood Phe level at the first visit after subjects started using their optimal dose was (-297 micromol/L, -152 micromol/L), and each of the 95% confidence intervals for the mean change from baseline blood Phe level at Weeks 16, 20 and 22 overlap with this interval indicating persistence of the effect of Kuvan treatment.
Study 4 was a two-part, phase III study in PKU patients who were following a strict Phe restricted diet and who had blood Phe levels of ≤ 480 micromol/L at screening. In the first part of the study, there were 90 patients ranging in age from 4 to 12 years old inclusive; 50 (56%) were 4-7 years old, 37 (41%) were 8-11 years old and the remaining 3 (3%) were 12 years old. All patients (n = 90) were treated with open-label Kuvan 20 mg/kg/day for 8 days. Response to Kuvan was defined as a ≥ 30% decrease in blood Phe from baseline and blood Phe ≤ 300 micromol/L at Day 8. At Day 8, 50 patients (56%) had a ≥ 30% decrease in blood Phe and blood Phe level ≤ 300 micromol/L on Day 8 and were therefore eligible to enrol in the second part of the study.
The second part of Study 4 was a randomised, double-blind, placebo-controlled trial in which subjects were randomised 3:1 to treatment with Kuvan 20 mg/kg/day (n = 34) or placebo (n = 12) for 10 weeks. Of the 33 patients who received at least one dose of Kuvan, 16 (48.5%) were 4-7 years old, 15 (45.5%) were 8-11 years old and the remaining 2 (6.0%) were 12 years old. After 3 weeks of treatment with Kuvan 20 mg/kg/day, blood Phe levels were significantly reduced; the mean (± SD) decrease from baseline in blood Phe level within this group was 149 (± 134) micromol/L (p < 0.001). After 3 weeks, subjects in both the Kuvan and placebo treatment groups were continued on their Phe-restricted diets and dietary Phe intake was increased or decreased using standardised Phe supplements with a goal to maintain blood Phe levels at < 360 micromol/L. The mean (± SD) increase in dietary Phe tolerance was 17.5 (± 13.3) mg/kg/day for the Kuvan group compared to 3.3 (± 5.3) mg/kg/day for the placebo group (p = 0.006). For the Kuvan treatment group, the mean (± SD) total dietary Phe tolerance was 38.4 (± 21.6) mg/kg/day during treatment with Kuvan compared to 15.7 (± 7.2) mg/kg/day before treatment.
The Week 10 mean (± SD) Phe supplement tolerated by subjects treated with Kuvan was 20.9 (± 15.4) mg/kg/day, a value that was significantly increased (p < 0.001) from the pre-treatment value of zero, versus 2.9 (± 4.0) mg/kg/day in the placebo group (p = 0.027, statistically significant increase from zero but not clinically meaningful) (see Figure 2).
Subjects from Study 3 and the second part of Study 4 were eligible to enter a phase IIIb multicentre, open-label extension study to evaluate the safety of long-term treatment up to 3 years. Although the study was not designed to evaluate efficacy, it was notable that overall blood Phe concentrations remained less than 600 micromol/L.

Paediatric population.

The safety, efficacy and population pharmacokinetics of sapropterin dihydrochloride in paediatric patients aged < 7 years were studied in two open-label studies.
The first study (Study 5) was a multicentre, open-label randomised, controlled study in children < 4 years old with a confirmed diagnosis of PKU.
56 paediatric PKU patients < 4 years of age were randomised 1:1 to receive either 10 mg/kg/day sapropterin dihydrochloride plus a phenylalanine-restricted diet (n = 27), or just a phenylalanine-restricted diet (n = 29) over a 26-week Study Period.
It was intended that all patients maintained blood phenylalanine levels within a range of 120-360 micromol/L (defined as ≥ 120 to < 360 micromol/L) through monitored dietary intake during the 26-week Study Period. If after approximately 4 weeks, a patient's phenylalanine tolerance had not increased by > 20% versus baseline, the sapropterin dihydrochloride dose was increased in a single step to 20 mg/kg/day.
The results of Study 5 demonstrated that daily dosing with 10 or 20 mg/kg/day of sapropterin dihydrochloride plus phenylalanine-restricted diet led to statistically significant improvements in dietary phenylalanine tolerance compared with dietary phenylalanine restriction alone while maintaining blood phenylalanine levels within the target range (≥ 120 to < 360 micromol/L). The adjusted mean dietary phenylalanine tolerance in the sapropterin dihydrochloride plus phenylalanine-restricted group was 80.6 mg/kg/day and was statistically significantly greater (p < 0.001) than the adjusted mean dietary phenylalanine tolerance in dietary phenylalanine therapy alone group (50.1 mg/kg/day). In the clinical trial extension period, patients maintained dietary tolerance while on Kuvan treatment in conjunction with a Phe-restricted diet, demonstrating sustained benefit over 3.5 years.
The second study (Study 6) was a multicentre, uncontrolled, open-label study designed to evaluate the safety and effect on preservation of neurocognitive function of Kuvan 20 mg/kg/day in combination with a phenylalanine-restricted diet in children with PKU less than 7 years of age at study entry. Part 1 of the study (4 weeks) assessed patients' response to Kuvan; Part 2 of the study (up to 7 years of follow-up) evaluated neurocognitive function with age-appropriate measures and monitored long-term safety in patients responsive to Kuvan. Patients with pre-existing neurocognitive impairment (IQ < 80) were excluded from the study. Ninety-five patients were enrolled into Part 1, and 65 patients were enrolled into Part 2, of whom 49 (75%) patients completed the study with 27 (42%) patients providing Full Scale IQ (FSIQ) data at year 7.
Mean Indices of Dietary Control were maintained between 133 micromol/L and 375 micromol/L blood phenylalanine for all age groups at all time points. At baseline, mean Bayley-III score (102, SD = 9.1, n = 26), WPPSI-III score (98.8-100.4, SD = 14.0-15.4, n = 59) and WISC-IV score (113, SD = 9.8, n = 4) were within the average range for the normative population.
Among 62 patients with a minimum of two FSIQ assessments, the 95% lower limit confidence interval of the mean change over an average 2-year period was -1.6 points, within the clinically expected variation of ± 5 points. No additional adverse reactions were identified with long-term use of Kuvan for a mean duration of 6.5 years in children less than 7 years of age at study entry.
BH4 deficiency. Evidence of the safety and effectiveness of Kuvan for the treatment of HPA due to BH4 deficiency is provided by the results of analysis of data from a study conducted with Kuvan, results from studies conducted with sapropterin dihydrochloride granules registered in Japan for this indication, and published studies of clinical experience with BH4 identified via a systematic literature review. Clinical experience reported in published literature includes prospective and retrospective open-label studies, using both Phe blood levels and clinical outcomes (e.g. IQ and development measures), to determine efficacy. Approximately 120 patients were less than 4 years old at start of treatment, including 104 who started treatment when less than 1 year old.
An open-label, multicentre clinical trial evaluating the efficacy and safety of Kuvan for the treatment of HPA due to BH4 deficiency enrolled 12 patients, 9 with defects in enzymes of BH4 biosynthesis and 3 with defects in enzymes involved in BH4 recycling. Patients ranged in age from 3 to 35 years, 1 (8%) less than 4 years, 3 (25%) between 4-7 years, 2 (17%) between 8-11 years, and the remaining 6 patients (50%) were 12 years of age or older. Patients receiving an unregistered formulation of BH4 prior to study entry started treatment with Kuvan at approximately the same daily dose as the prior BH4 dose; other patients commenced treatment at 5 mg/kg/day. Dose adjustment up or down to a maximum of 20 mg/kg/day was permitted at study Week 6. Mean (± SD) blood Phe remained at levels similar to baseline (133 ± 135 micromol/L) at all study visits during treatment with Kuvan. Most subjects remained below the blood Phe target of < 360 micromol/L at all study visits including all patients with defects in enzymes of BH4 biosynthesis.
A study with sapropterin dihydrochloride 2.5% granules was conducted in 16 patients with BH4 deficiency treated with 2-5 mg/kg/day for a mean of 15.5 months. Blood Phe levels were reduced by sapropterin dihydrochloride, and were maintained within normal range for the duration of treatment. Based on a rating of global improvement, there was moderate or marked improvement in all 16 subjects. Subjects from this study together with another 14 subjects were subsequently entered into a post-marketing surveillance study. Although patients were meant to have BH4 deficiency, 3 were subsequently found to have HPA due to PKU. All 30 patients were treated for at least one year, with 19 patients treated for 10-20 years. For the study population with BH4 deficiency, 25/27 (93%) achieved a global improvement rating of 'markedly improved', 'improved' or 'slightly improved'.

5.2 Pharmacokinetic Properties

Absorption.

Sapropterin is absorbed after oral administration of the dissolved tablet and the maximum blood concentration (Cmax) is achieved 3 to 4 hours after dosing in the fasted state. The rate and extent of absorption of sapropterin is influenced by food. Compared to fasting, absorption is higher after a high-fat, high-calorie meal, resulting, on average, in 40-85% higher maximum blood concentrations achieved 4 to 5 hours after administration. Neither the absolute bioavailability nor the bioavailability after oral administration in humans is known.

Distribution.

In nonclinical studies, sapropterin was primarily distributed to the kidneys, liver, adrenal glands and spleen as assessed by levels of total and reduced biopterin concentrations (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation; Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Very small amounts of sapropterin were distributed to the brain in adult rats but in juvenile rats total brain biopterin levels were significantly increased following sapropterin administration.

Metabolism.

6R-BH4 is primarily metabolised in the liver with dihydrobiopterin and dihydroxanthopterin as the main human metabolites. Since sapropterin is a synthetic version of the naturally occurring 6R-BH4, it can be reasonably anticipated to undergo the same metabolism, including 6R-BH4 regeneration. Folic acid and vitamin B12 may increase BH4 levels.

Excretion.

The mean elimination half-life of Kuvan in PKU patients was approximately 6-7 hours. Following intravenous administration in rats, sapropterin is mainly excreted in the urine. Following oral administration it is mainly excreted in the faeces while a small proportion is excreted in urine.

Population pharmacokinetics.

Population pharmacokinetic analysis of sapropterin including patients from birth to 49 years of age showed that body weight is the only covariate substantially affecting clearance or volume of distribution.

5.3 Preclinical Safety Data

Genotoxicity.

Sapropterin had variable mutagenic effects in bacterial cells and elicited an increase in chromosome aberrations in Chinese hamster lung and ovary cells. The results of the in vitro genotoxicity test in human lymphocytes were equivocal. Sapropterin has been shown to produce hydrogen peroxide in at least one in vitro cell culture system, which may explain the positive results in these assays. Sapropterin was not genotoxic in in vivo mouse micronucleus tests.

Carcinogenicity.

In a 2-year rat oral carcinogenicity study there was a statistically significant increase in the incidence of benign adrenal phaeochromocytoma in male rats treated with 250 mg/kg/day sapropterin dihydrochloride (about 10 times human exposure based on AUC). No evidence of a carcinogenic effect was evident in an abbreviated 78-week oral carcinogenicity study in mice at sapropterin dihydrochloride doses up to 250 mg/kg/day (18 times human exposure based on AUC).

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablets contain: mannitol, calcium hydrogen phosphate, crospovidone, ascorbic acid, sodium stearylfumarate and riboflavin.
Sachets contain: mannitol, potassium citrate, sucralose and ascorbic acid.

6.2 Incompatibilities

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

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Tablets.

Store below 25°C. Keep the bottle tightly closed in order to protect from moisture. Product should be used within two months after first opening the bottle.

Sachets.

Store below 25°C.

6.5 Nature and Contents of Container

Tablets.

Tablets are supplied in high-density polyethylene (HDPE) bottles with child-resistant closure. The bottles are sealed with an aluminium seal. Each bottle of Kuvan contains a small plastic tube of desiccant (silica gel). Each bottle is packaged in an individual carton and contains 30, 120 or 240# tablets.
1 bottle per carton.
# Not all pack sizes are being distributed in Australia.

Sachets.

The powder is contained in individual sachets of polyethylene terephthalate, aluminum, and polyethylene laminate heat sealed on four sides. An internal tear notch is located in the corner of the sachet to facilitate opening of the sachet.
Each carton contains 30 sachets.

6.6 Special Precautions for Disposal

In Australia, any unused medicines or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Sapropterin dihydrochloride is an off-white to light yellow crystalline powder. It melts with decomposition at 239-241°C. The stereochemical configuration of sapropterin dihydrochloride has been demonstrated by single-crystal X-ray analysis.
Sapropterin dihydrochloride is hygroscopic. At room temperature, sapropterin dihydrochloride is very soluble in water (> 1 g/mL). It is sparingly soluble in methanol (10 mg/mL) and ethanol (0.9 mg/mL), and practically insoluble (< 0.1 mg/mL) in aprotic solvents such as diethyl ether. The water/ octanol partition coefficient greatly favours dissolution in water indicating that the compound is hydrophilic. The most basic pKa value of sapropterin is 9.20 and consequently it will be fully ionised at gastrointestinal pH.

Chemical structure.


Molecular formula: C9H15N5O3.2HCl.

CAS number.

69056-38-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes