KUVAN Soluble tablet Ref.[9245] Active ingredients: Sapropterin

Treatment with Kuvan must be initiated and supervised by a physician experienced in the treatment of PKU and BH4 deficiency.

Active management of dietary phenylalanine and overall protein intake while taking this medicinal product 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 (see section 5.1).

Posology

PKU

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

BH4 deficiency

The starting dose of Kuvan in adult and paediatric patients with BH4 deficiency is 2 to 5 mg/kg body weight total daily dose. Doses may be adjusted up to a total of 20 mg/kg per day.

Kuvan is provided as 100 mg tablets. 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. A calculated dose of 451 mg to 499 mg should be rounded up to 500 mg corresponding to 5 tablets.

Dose adjustment

Treatment with sapropterin 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 the paediatric population, 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 sapropterin.

Discontinuation of 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.

Determination of response

It is of primary importance to initiate treatment as early as possible to avoid the appearance of non-reversible clinical manifestations of neurological disorders in paediatric patients and cognitive deficits and psychiatric disorders in adults due to sustained elevations of blood phenylalanine.

Response to this medicinal product is determined by a decrease in blood phenylalanine.Blood phenylalanine levels should be checked before administering Kuvan and after 1 week of use at the recommended starting dose. If an unsatisfactory reduction in blood phenylalanine levels is observed, then the dose can be increased weekly to a maximum of 20 mg/kg/day, with continued weekly monitoring of blood phenylalanine levels over a one month period. The dietary phenylalanine intake should be maintained at a constant level during this period.

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. Patients who fail to achieve this level of response within the described one month test period should be considered non-responsive, these patients should not be treated with Kuvan and administration of Kuvan should be discontinued.

Once responsiveness to the medicinal product has been established, the dose may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy.

It is recommended that blood phenylalanine and tyrosine levels be tested one or two weeks after each dose adjustment and monitored frequently thereafter under the direction of the treating physician. 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).

Special population

Elderly

Safety and efficacy of Kuvan in patients above 65 years of age have not been established. Caution must be exercised when prescribing to elderly patients.

Renal or 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 such patients.

Paediatric population

The posology is the same in adults, children, and adolescents.

Method of administration

Kuvan tablets should be administered with a meal to increase the 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.

Patients should be advised not to swallow the desiccant capsule found in the bottle.

The prescribed number of tablets should be placed in a glass or cup of water 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 drank within 15 to 20 minutes.

Patients above 20 kg body weight

The prescribed number of tablets should be placed in a glass or cup with 120 to 240 ml of water and stirred until dissolved.

Children up to 20 kg body weight

The measuring devices required for dosing in children up to 20 kg body weight (i.e. cup with graduations at 20, 40, 60, 80 ml; 10 ml and 20 ml oral syringes with graduation at 1 ml divisions) are not included in the Kuvan pack. These devices are supplied to the specialized paediatric centers for inborn errors of metabolism to be provided to the caregivers of the patients.

Depending on the dose (in mg/kg/day) the appropriate number of tablets should be dissolved in a volume of water as depicted in Tables 1-4, whereby the volume of the solution to be administered is calculated according to the prescribed total daily dose. The prescribed number of tablets for a 2, 5, 10 and 20 mg/kg/day dose should be placed in a cup (that shows the appropriate graduation markings at 20, 40, 60 and 80 ml) with the amount of water as depicted in Tables 1-4 and stirred until dissolved.

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 then be transferred to another cup for administration of the medicinal product. For small infants an oral syringe can be used. 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.

Table 1. 2 mg/kg per day dosing table for children weighing up to 20 kg:

* Reflects volume for total daily dose.
Discard unused solution within 20 minutes for tablet solution.

Table 2. 5 mg/kg per day dosing table for children weighing up to 20 kg:

* Reflects volume for total daily dose.
Discard unused solution within 20 minutes for tablet solution.

Table 3. 10 mg/kg per day dosing table for children weighing up to 20 kg:

* Reflects volume for total daily dose.
Discard unused solution within 20 minutes for tablet solution.

Table 4. 20 mg/kg per day dosing table for children weighing up to 20 kg:

* Reflects volume for total daily dose.
Discard unused solution within 20 minutes for tablet solution.

For cleaning, the plunger should be removed from the barrel of the oral syringe. Both parts of the oral syringe and the cup should be washed with warm water and air dry. When the oral syringe is dry, the plunger should be put back into the barrel. The oral syringe and the cup should be stored for next use.

Headache and dizziness have been reported after the administration of sapropterin dihydrochloride above the recommended maximum dose of 20 mg/kg/day. Treatment of overdose should be directed to symptoms. A shortening of the QT interval (-8.32 msec) was observed in a study with a 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).

Shelf life: 3 years.

Store below 25°C.

Keep the bottle tightly closed in order to protect from moisture.

High-density polyethylene (HDPE) bottle with child-resistant closure. The bottles are sealed with an aluminium seal. Each bottle contains a small plastic tube of desiccant (silica gel).

Each bottle contains 30, 120 or 240 tablets.

1 bottle per carton.

Not all pack sizes may be marketed.

Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Handling: Patients should be advised not to swallow the desiccant capsule found in the bottle.

For instructions for use, see section 4.2.