Posology : מינונים

4.2   Posology and method of administration

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 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. However, there are limited data regarding the long-term use of Kuvan.


Posology
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.

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 20 mg/kg per day.

Paediatric population

The posology is the same in adults and children.
Elderly patients

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.

Patients with 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.

Determination of Response

It is of primary importance to initiate Kuvan 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 Kuvan is determined by a decrease in blood phenylalanine following treatment with Kuvan. Blood phenylalanine levels should be checked before initiating Kuvan and after 1 week of treatment 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 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 of administration of Kuvan 20 mg/kg/day should be considered non- responsive and should not receive treatment with Kuvan.

Once responsiveness to Kuvan 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).

Dose adjustment

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.

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.

Adults

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

Paediatric population

Children above 20 kg body weight
The prescribed number of tablets should be placed in a glass or cup with up to 120 ml of water and stirred until dissolved.

Children up to 20 kg body weight
The devices required for dosing in children up to 20 kg body weight (i.e. medicine cup with graduations at 20, 40, 60, 80 ml; 10 ml and 20 ml oral dosing 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 daily dose. The prescribed number of tablets for a 2, 5, 10 and 20 mg/kg/day dose should be placed in a medicine 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 according to the prescribed daily dose a portion of this solution needs to be administered, an oral dosing syringe should be used to withdraw the volume of solution to be administered from the medicine cup and transferred to a glass or a cup for administration of the medicine.
For small infants who cannot drink from a glass or a cup the solution corresponding to the prescribed daily dose may be administered into the mouth via the oral dosing syringe. A 10 ml oral dosing syringe should be used for administration of volumes of ≤ 10 ml and a 20 ml oral dosing syringe for administration of volumes of > 10 ml.

Table 1 provides dosing information for children up to 20 kg at a dose of 2 mg/kg per day, Table 2 for dosing information at 5 mg/kg per day, Table 3 for dosing information at 10 mg/kg per day and Table 4 for dosing information at 20 mg/kg per day.

Table 1: 2 mg/kg per day Dosing Table for Children Weighing up to 20 kg 
Weight (kg)          Total dose            Number of         Volume of     Volume of solution (mg/day)            tablets to be      dissolution   to be administered dissolved           (ml)              (ml)*

2                    4                    1               80                3
3                    6                    1               80                5            4                    8                    1               80                6
5                   10                    1               80                8 6                   12                    1               80               10 7                   14                    1               80               11 8                   16                    1               80               13 9                   18                    1               80               14 10                   20                    1               80               16 11                   22                    1               80               18 12                   24                    1               80               19 13                   26                    1               80               21 14                   28                    1               80               22 15                   30                    1               80               24 16                   32                    1               80               26 17                   34                    1               80               27 18                   36                    1               80               29 19                   38                    1               80               30           20                   40                    1               80               32
*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 
Weight (kg)          Total dose           Number of             Volume of     Volume of solution (mg/day)           tablets to be          dissolution   to be administered dissolved               (ml)              (ml)*
2                   10                  1                    40                 4
3                   15                  1                    40                 6            4                   20                  1                    40                 8
5                   25                  1                    40                10 6                   30                  1                    40                12 7                   35                  1                    40                14 8                   40                  1                    40                16 9                   45                  1                    40                18 10                   50                  1                    40                20 11                   55                  1                    40                22 12                   60                  1                    40                24 13                   65                  1                    40                26 14                   70                  1                    40                28 15                   75                  1                    40                30 16                   80                  1                    40                32 17                   85                  1                    40                34 18                   90                  1                    40                36 19                   95                  1                    40                38           20                  100                  1                    40                40
*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 
Weight (kg)          Total dose           Number of             Volume of     Volume of solution (mg/day)           tablets to be          dissolution   to be administered dissolved               (ml)              (ml)*
2                   20                  1                    20                 4
3                   30                  1                    20                 6            4                   40                  1                    20                 8
5                   50                  1                    20                10 6                   60                  1                    20                12 7                   70                  1                    20                14 8                   80                  1                    20                16 9                   90                  1                    20                18 10                  100                  1                    20                20 11                  110                  2                    40                22 12                  120                  2                    40                24 13                  130                  2                    40                26 14                  140                  2                    40                28 15                  150                  2                    40                30 16                  160                  2                    40                32 17                  170                  2                    40                34 18                  180                  2                    40                36 19                  190                  2                    40                38           20                  200                  2                    40                40
*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 
Weight (kg)          Total dose           Number of             Volume of     Volume of solution (mg/day)           tablets to be          dissolution   to be administered dissolved               (ml)              (ml)*
2                   40                  1                    20                 8
3                   60                  1                    20                12            4                   80                  1                    20                16
5                  100                  1                    20                20 6                  120                  2                    40                24 7                  140                  2                    40                28 8                  160                  2                    40                32 9                  180                  2                    40                36 10                  200                  2                    40                40 11                  220                  3                    60                44 12                  240                  3                    60                48 13                  260                  3                    60                52 14                  280                  3                    60                56 15                  300                  3                    60                60 16                  320                  4                    80                64 17                  340                  4                    80                68 18                  360                  4                    80                72 19                  380                  4                    80                76           20                  400                  4                    80                80
*Reflects volume for total daily dose.
Discard unused solution within 20 minutes for tablet solution

After administration: Throw away any remaining solution as it should not be used beyond 20 minutes.

For cleaning, remove the plunger from the barrel of the oral dosing syringe. Wash both parts of the oral dosing syringe and the medicine cup with warm water and air dry. When the oral dosing syringe is dry, put the plunger back into the barrel. Store the oral dosing syringe and the medicine cup for next use.