Leaflet SAPROPTERINA DIPHARMA 100mg soluble tablets

Treatment with sapropterin dihydrochloride must be initiated and supervised by a physicianexperienced in the treatment of PKU and BH4 deficiency.

Active management of dietary phenylalanine and overall protein intake while taking this medicinalproduct 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 isdemonstrated, Sapropterin Dipharma is intended for long-term use (see section 5.1).

PKU

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

BH4 deficiency

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

Sapropterin Dipharma is provided as 100 mg tablets. The calculated daily dose based on body weightshould be rounded to the nearest multiple of 100. For instance, a calculated dose of 401 to 450 mgshould be rounded down to 400 mg corresponding to 4 tablets. A calculated dose of 451 mg to 499 mgshould be rounded up to 500 mg corresponding to 5 tablets.

Treatment with sapropterin may decrease blood phenylalanine levels below the desired therapeuticlevel. Adjustment of the sapropterin dihydrochloride dose or modification of dietary phenylalanineintake may be required to achieve and maintain blood phenylalanine levels within the desiredtherapeutic range.

Blood phenylalanine and tyrosine levels should be tested, particularly in the paediatric population, oneto two weeks after each dose adjustment and monitored frequently thereafter, under the direction ofthe treating physician.

If inadequate control of blood phenylalanine levels is observed during treatment with sapropterindihydrochloride, the patient’s adherence to the prescribed treatment, and diet, should be reviewedbefore considering an adjustment of the dose of sapropterin.

Discontinuation of treatment should be done only under the supervision of a physician. More frequentmonitoring may be required, as blood phenylalanine levels may increase. Dietary modification may benecessary 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 deficitsand psychiatric disorders in adults due to sustained elevations of blood phenylalanine.

Response to this medicinal product is determined by a decrease in blood phenylalanine. Bloodphenylalanine levels should be checked before administering sapropterin dihydrochloride and after 1week of use at the recommended starting dose. If an unsatisfactory reduction in blood phenylalaninelevels is observed, then the dose can be increased weekly to a maximum of 20 mg/kg/day, withcontinued weekly monitoring of blood phenylalanine levels over a one month period. The dietaryphenylalanine 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 orattainment of the therapeutic blood phenylalanine goals defined for an individual patient by thetreating physician. Patients who fail to achieve this level of response within the described one monthtest period should be considered non-responsive, these patients should not be treated with sapropterindihydrochloride and administration of sapropterin dihydrochloride should be discontinued.

Once responsiveness to the medicinal product has been established, the dose may be adjusted withinthe 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 eachdose adjustment and monitored frequently thereafter under the direction of the treating physician.

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

Safety and efficacy of sapropterin dihydrochloride in patients above 65 years of age have not beenestablished. Caution must be exercised when prescribing to elderly patients.

Safety and efficacy of sapropterin dihydrochloride in patients with renal or hepatic insufficiency havenot been established. Caution must be exercised when prescribing to such patients.

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

Oral use.

Sapropterin Dipharma tablets should be administered with a meal to increase the absorption.

For patients with PKU, Sapropterin Dipharma should be administered as a single daily dose, and at thesame time each day preferably in the morning.

For patients with BH4 deficiency, divide the total daily dose into 2 or 3 administrations, distributedover the day.

The prescribed number of tablets should be placed in a glass or cup of water or apple juice and stirreduntil dissolved. It may take a few minutes for the tablets to dissolve. To make the tablets dissolvefaster they can be crushed. Small particles may be visible in the solution and will not affect theeffectiveness of the medicinal product. The solution should be drunk within 15 to 20 minutes.

Sapropterin Dipharma soluble tablets may also be crushed and then mixed in a small amount of softfoods such as apple sauce or pudding.

The prescribed dose of Sapropterin Dipharma soluble tablets dissolved in water as described above,may be administered via an enteral feeding tube ≥4 Fr (French catheter scale). Follow themanufacturer’s instructions for the feeding tube to administer the medicinal product. To ensureadequate dosing, after administration of the oral solution, the enteral feeding tube must be flushed withwater. See section 6.6 for further details.

Patients above 20 kg body weight

The prescribed number of tablets should be placed in a glass or cup with 60 to 240 ml of water orapple juice 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 withgraduations at 20, 40, 60, 80 ml; 10 ml and 20 ml oral syringes with graduation at 1 ml divisions) arenot included in the Sapropterin Dipharma pack. These devices are supplied to the specialisedpaediatric centres 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 avolume of water or apple juice as depicted in Tables 1-4, whereby the volume of the solution to beadministered is calculated according to the prescribed total daily dose. The prescribed number oftablets for a 2, 5, 10 and 20 mg/kg/day dose should be placed in a cup (that shows the appropriategraduation markings at 20, 40, 60 and 80 ml) with the amount of water or apple juice as depicted in

Tables 1-4 and stirred until dissolved. For dosage equal to 100 mg and multiples of 100 mg, thesoluble tablets may also be mixed in a small amount of soft foods, such as apple sauce or pudding.

If only a portion of this solution needs to be administered, an oral syringe should be used to withdrawthe volume of solution to be administered. The solution may then be transferred to another cup foradministration of the medicinal product. For small infants an oral syringe can be used. A 10 ml oralsyringe should be used for administration of volumes of 10 ml and a 20 ml oral syringe foradministration of volumes of > 10 ml.

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

Weight (kg) Total dose Number of tablets to be Volume of Volume of solution(mg/day) dissolved dissolution to be administered(100 mg strength only) (ml) (ml)*2 4 1 80 33 6 1 80 54 8 1 80 65 10 1 80 86 12 1 80 107 14 1 80 118 16 1 80 139 18 1 80 1410 20 1 80 1611 22 1 80 1812 24 1 80 1913 26 1 80 2114 28 1 80 2215 30 1 80 2416 32 1 80 2617 34 1 80 2718 36 1 80 2919 38 1 80 3020 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 tablets to be Volume of Volume of solution(mg/day) dissolved dissolution to be administered(100 mg strength only) (ml) (ml)*2 10 1 40 43 15 1 40 64 20 1 40 85 25 1 40 106 30 1 40 127 35 1 40 148 40 1 40 169 45 1 40 1810 50 1 40 2011 55 1 40 2212 60 1 40 2413 65 1 40 2614 70 1 40 2815 75 1 40 3016 80 1 40 3217 85 1 40 3418 90 1 40 3619 95 1 40 3820 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 tablets to be Volume of Volume of solution(mg/day) dissolved dissolution to be administered(100 mg strength only) (ml) (ml)*2 20 1 20 43 30 1 20 64 40 1 20 85 50 1 20 106 60 1 20 127 70 1 20 148 80 1 20 169 90 1 20 1810 100 1 20 2011 110 2 40 2212 120 2 40 2413 130 2 40 2614 140 2 40 2815 150 2 40 3016 160 2 40 3217 170 2 40 3418 180 2 40 3619 190 2 40 3820 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 tablets to be Volume of Volume of solution(mg/day) dissolved dissolution to be administered(100 mg strength only) (ml) (ml)*2 40 1 20 83 60 1 20 124 80 1 20 165 100 1 20 206 120 2 40 247 140 2 40 288 160 2 40 329 180 2 40 3610 200 2 40 4011 220 3 60 4412 240 3 60 4813 260 3 60 5214 280 3 60 5615 300 3 60 6016 320 4 80 6417 340 4 80 6818 360 4 80 7219 380 4 80 7620 400 4 80 80

*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 oralsyringe and the cup should be washed with warm water and air dry. When the oral syringe is dry, theplunger should be put back into the barrel. The oral syringe and the cup should be stored for next use.