Leaflet KUVAN 100mg soluble tablets

Kuvan 100 mg soluble tablets

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

For the full list of excipients, see section 6.1.

Soluble tablet

Off-white to light yellow soluble tablet with “177” imprinted on one face.

Kuvan is indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of allages with phenylketonuria (PKU) who have been shown to be responsive to such treatment (see section 4.2).

Kuvan is also indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patientsof all ages with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to suchtreatment (see section 4.2).

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

Active management of dietary phenylalanine and overall protein intake while taking this medicinal productis 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).

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 bloodphenylalanine 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 weighttotal 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 tothe nearest multiple of 100. For instance, a calculated dose of 401 to 450 mg should be rounded down to400 mg corresponding to 4 tablets. A calculated dose of 451 mg to 499 mg should be rounded up to 500 mgcorresponding to 5 tablets.

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 achieveand maintain blood phenylalanine levels within the desired therapeutic range.

Blood phenylalanine and tyrosine levels should be tested, particularly in the paediatric population, one to twoweeks after each dose adjustment and monitored frequently thereafter, under the direction of the treatingphysician.

If inadequate control of blood phenylalanine levels is observed during treatment with Kuvan, the patient’sadherence to the prescribed treatment, and diet, should be reviewed before considering an adjustment of thedose 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-reversibleclinical manifestations of neurological disorders in paediatric patients and cognitive deficits and psychiatricdisorders in adults due to sustained elevations of blood phenylalanine.

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

A satisfactory response is defined as a ≥30 percent reduction in blood phenylalanine levels or attainment ofthe therapeutic blood phenylalanine goals defined for an individual patient by the treating physician. Patientswho fail to achieve this level of response within the described one month test period should be considerednon-responsive, these patients should not be treated with Kuvan and administration of Kuvan should bediscontinued.

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

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

Special population

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

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.

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

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 daypreferably in the morning.

For patients with BH4 deficiency, divide the total daily dose into 2 or 3 administrations, distributed over theday.

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. Itmay 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 stirreduntil 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 at20, 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 metabolismto 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 ofwater as depicted in Tables 1-4, whereby the volume of the solution to be administered is calculatedaccording to the prescribed total daily dose. The prescribed number of tablets for a 2, 5, 10 and 20 mg/kg/daydose should be placed in a cup (that shows the appropriate graduation markings at 20, 40, 60 and 80 ml) withthe 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 thevolume 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 oral syringeshould be used for administration of volumes of ≤10 ml and a 20 ml oral syringe for administration ofvolumes 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, the plungershould be put back into the barrel. The oral syringe and the cup should be stored for next use.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Dietary intake

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

Low blood phenylalanine and tyrosine 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 exposure tolow blood phenylalanine and tyrosine levels during infancy has been associated with impairedneurodevelopmental outcome. Active management of dietary phenylalanine and overall protein intake whiletaking Kuvan is required to ensure adequate control of blood phenylalanine and tyrosine levels andnutritional balance.

Health disturbances

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

Convulsions disorders

Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases ofconvulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co-administration of levodopa and sapropterin in BH4-deficient patients (see section 4.5).

Rebound, as defined by an increase in blood phenylalanine levels above pre-treatment levels, may occurupon cessation of treatment.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

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 isrecommended when using such medicinal products while taking Kuvan.

BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Kuvanwith all medicinal products that cause vasodilation, including those administered topically, by affecting nitricoxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbidedinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitorsand minoxidil.

Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa. Cases ofconvulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co-administration of levodopa and sapropterin in BH4-deficient patients.

There are limited amount of data from the use of Kuvan in pregnant women. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition orpostnatal development.

Available disease-associated maternal and/or embryofoetal risk data from the Maternal Phenylketonuria

Collaborative Study on a moderate amount of pregnancies and live births (between 300-1,000) in

PKU-affected women demonstrated that uncontrolled phenylalanine levels above 600 μmol/l are associatedwith a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies.

Maternal blood phenylalanine levels must therefore be strictly controlled before and during pregnancy. Ifmaternal phenylalanine levels are not strictly controlled before and during pregnancy, this could be harmfulto the mother and the foetus. Physician-supervised restriction of dietary phenylalanine intake prior to andthroughout pregnancy is the first choice of treatment in this patient group.

The use of Kuvan should be considered only if strict dietary management does not adequately reduce bloodphenylalanine 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 notbe used during breast-feeding.

In preclinical studies, no effects of sapropterin on male and female fertility were observed.

Kuvan has no or negligible influence on the ability to drive and use machines.

Approximately 35% of the 579 patients aged 4 years and over who received treatment with sapropterindihydrochloride (5 to 20 mg/kg/day) in the clinical trials for Kuvan experienced adverse reactions. The mostcommonly reported adverse reactions are headache and rhinorrhoea.

In a further clinical trial, approximately 30% of the 27 children aged below 4 years who received treatmentwith sapropterin dihydrochloride (10 or 20 mg/kg/day) experienced adverse reactions. The most commonlyreported adverse reactions are “amino acid level decreased” (hypophenylalaninaemia), vomiting and rhinitis.

In the pivotal clinical trials and in the post-marketing experience for Kuvan, the following adverse reactionshave been identified.

The following definitions apply to the frequency terminology used hereafter:

very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to<1/1,000), very rare (<1/10,000), not known (cannot be estimated from available data)

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Not known: Hypersensitivity reactions (including serious allergic reactions) and rash

Common: Hypophenylalaninaemia

Very common: Headache

Very common: Rhinorrhoea

Common: Pharyngolaryngeal pain, nasal congestion, cough

Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea

Not known: Gastritis, oesophagitis

Frequency, type and severity of adverse reactions in children were essentially similar to those in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

Headache and dizziness have been reported after the administration of sapropterin dihydrochloride above therecommended maximum dose of 20 mg/kg/day. Treatment of overdose should be directed to symptoms. Ashortening of the QT interval (-8.32 msec) was observed in a study with a single supra-therapeutic dose of100 mg/kg (5 times the maximum recommended dose); this should be taken into consideration in managingpatients who have a pre-existing shortened QT interval (e.g. patients with familial short QT syndrome).

Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract andmetabolism products, ATC code: A16AX07

Hyperphenylalaninaemia (HPA) is diagnosed as an abnormal elevation in blood phenylalanine levels and isusually caused by autosomal recessive mutations in the genes encoding for phenylalanine hydroxylaseenzyme (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 ofdisorders arising from mutations or deletions in the genes encoding for one of the five enzymes involved inthe biosynthesis or recycling of BH4. In both cases, phenylalanine cannot be effectively transformed into theamino acid tyrosine, leading to increased phenylalanine levels in the blood.

Sapropterin is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylasesfor phenylalanine, tyrosine and tryptophan.

The rationale for administration of Kuvan in patients with BH4-responsive PKU is to enhance the activity ofthe defective phenylalanine hydroxylase and thereby increase or restore the oxidative metabolism ofphenylalanine sufficient to reduce or maintain blood phenylalanine levels, prevent or decrease furtherphenylalanine accumulation, and increase tolerance to phenylalanine intake in the diet. The rationale foradministration of Kuvan in patients with BH4 Deficiency is to replace the deficient levels of BH4, therebyrestoring the activity of phenylalanine hydroxylase.

The Phase III clinical development program for Kuvan included 2, randomised placebo-controlled studies inpatients with PKU. The results of these studies demonstrate the efficacy of Kuvan to reduce bloodphenylalanine levels and to increase dietary phenylalanine tolerance.

In 88 subjects with poorly controlled PKU who had elevated blood phenylalanine levels at screening,sapropterin dihydrochloride 10 mg/kg/day significantly reduced blood phenylalanine levels as compared toplacebo. The baseline blood phenylalanine levels for the Kuvan-treated group and the placebo group weresimilar, with mean ± SD baseline blood phenylalanine levels of 843 ± 300 μmol/l and 888 ± 323 μmol/l,respectively. The mean ± SD decrease from baseline in blood phenylalanine levels at the end of the 6 weekstudy period was 236 ± 257 μmol/l for the sapropterin treated group (n=41) as compared to an increase of2.9 ± 240 μmol/l for the placebo group (n=47) (p<0.001). For patients with baseline blood phenylalaninelevels ≥600 µmol/l, 41.9% (13/31) of those treated with sapropterin and 13.2% (5/38) of those treated withplacebo had blood phenylalanine levels < 600 µmol/l at the end of the 6-week study period (p=0.012).

In a separate 10-week, placebo-controlled study, 45 PKU patients with blood phenylalanine levels controlledon a stable phenylalanine-restricted diet (blood phenylalanine ≤480 μmol/l on enrolment) were randomised3:1 to treatment with sapropterin dihydrochloride 20 mg/kg/day (n=33) or placebo (n=12). After 3-weeks oftreatment with sapropterin dihydrochloride 20 mg/kg/day, blood phenylalanine levels were significantlyreduced; the mean ± SD decrease from baseline in blood phenylalanine level within this group was149 ± 134 μmol/l (p<0.001). After 3 weeks, subjects in both the sapropterin and placebo treatment groupswere continued on their phenylalanine-restricted diets and dietary phenylalanine intake was increased ordecreased using standardised phenylalanine supplements with a goal to maintain blood phenylalanine levelsat <360 μmol/l. There was a significant difference in dietary phenylalanine tolerance in the sapropterintreatment group as compared to the placebo group. The mean ± SD increase in dietary phenylalaninetolerance was 17.5 ± 13.3 mg/kg/day for the group treated with sapropterin dihydrochloride 20 mg/kg/day,compared to 3.3 ± 5.3 mg/kg/day for the placebo group (p=0.006). For the sapropterin treatment group, themean ± SD total dietary phenylalanine tolerance was 38.4 ± 21.6 mg/kg/day during treatment withsapropterin dihydrochloride 20 mg/kg/day compared to 15.7 ± 7.2 mg/kg/day before treatment.

The safety, efficacy and population pharmacokinetics of Kuvan in paediatric patients aged <7 years werestudied in two open-label studies.

The first study was a multicentre, open-label, randomised, controlled study in children <4 years old with aconfirmed diagnosis of PKU.

56 paediatric PKU patients <4 years of age were randomised 1:1 to receive either 10 mg/kg/day Kuvan inconjunction with a phenylalanine-restricted diet (n=27), or just a phenylalanine-restricted diet (n=29) over a26-week Study Period.

It was intended that all patients maintained blood phenylalanine levels within a range of 120-360 µmol/l(defined as ≥120 to <360 µmol/l) through monitored dietary intake during the 26-week Study Period. If afterapproximately 4 weeks, a patient’s phenylalanine tolerance had not increased by >20% versus baseline, the

Kuvan dose was increased in a single step to 20 mg/kg/day.

The results of this study demonstrated that daily dosing with 10 or 20 mg/kg/day of Kuvan in conjunctionwith a phenylalanine-restricted diet led to statistically significant improvements in dietary phenylalaninetolerance compared with dietary phenylalanine restriction alone while maintaining blood phenylalaninelevels within the target range (≥120 to <360 µmol/l). The adjusted mean dietary phenylalanine tolerance inthe Kuvan in conjunction with a phenylalanine-restricted diet group was 80.6 mg/kg/day and was statisticallysignificantly greater (p<0.001) than the adjusted mean dietary phenylalanine tolerance in dietaryphenylalanine therapy alone group (50.1 mg/kg/day). In the clinical trial extension period, patientsmaintained dietary phenylalanine tolerance while on Kuvan treatment in conjunction with a Phe-restricteddiet, demonstrating sustained benefit over 3.5 years.

The second study was a multicenter, uncontrolled, open-label study designed to evaluate the safety and effecton 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) evaluatedneurocognitive function with age-appropriate measures, and monitored long-term safety in patientsresponsive to Kuvan. Patients with pre-existing neurocognitive impairment (IQ <80) were excluded from thestudy. Ninety-three patients were enrolled into Part 1, and 65 patients were enrolled into Part 2, of whom49 (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 μmol/L and 375 μmol/L blood phenylalaninefor all age groups at all time points. At baseline, mean Bayley-III score (102, SD=9.1, n=27), WPPSI-

III score (101, SD=11, n=34) and WISC-IV score (113, SD=9.8, n=4) were within the average range for thenormative population.

Among 62 patients with a minimum of two FSIQ assessments, the 95% lower limit confidence interval of themean 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 durationof 6.5 years in children less than 7 years of age at study entry.

Limited studies have been conducted in patients under 4 years of age with BH4 deficiency using anotherformulation of the same active substance (sapropterin) or an un-registered preparation of BH4.

Sapropterin is absorbed after oral administration of the dissolved tablet, and the maximum bloodconcentration (Cmax) is achieved 3 to 4 hours after dosing in the fasted state. The rate and extent of absorptionof sapropterin is influenced by food. The absorption of sapropterin is higher after a high-fat, high-caloriemeal as compared to fasting, resulting, in average, in 40-85% higher maximum blood concentrationsachieved 4 to 5 hours after administration.

Absolute bioavailability or bioavailability for humans after oral administration is not known.

In non-clinical studies, sapropterin was primarily distributed to the kidneys, adrenal glands, and liver asassessed by levels of total and reduced biopterin concentrations. In rats, following intravenous radiolabeledsapropterin administration, radioactivity was found to distribute in foetuses. Excretion of total biopterin inmilk was demonstrated in rats by intravenous route. No increase in total biopterin concentrations in eitherfoetuses or milk was observed in rats after oral administration of 10 mg/kg sapropterin dihydrochloride.

Sapropterin dihydrochloride is primarily metabolised in the liver to dihydrobiopterin and biopterin. Sincesapropterin dihydrochloride is a synthetic version of the naturally occurring 6R-BH4, it can be reasonablyanticipated to undergo the same metabolism, including 6R-BH4 regeneration.

Following intravenous administration in rats, sapropterin dihydrochloride is mainly excreted in the urine.

Following oral administration it is mainly eliminated through faeces while a small proportion is excreted inurine.

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

In vitro, sapropterin did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or

CYP3A4/5, nor induce CYP1A2, 2B6, or 3A4/5.

Based on an in vitro study, there is potential for sapropterin dihydrochloride to inhibit p-glycoprotein (P-gp)and breast cancer resistance protein (BCRP) in the gut at the therapeutic doses. A higher intestinalconcentration of Kuvan is needed to inhibit BCRP than P-gp, as inhibitory potency in intestine for BCRP(IC50=267 µM) is lower than P-gp (IC50=158 µM).

In healthy subjects, administration of a single dose of Kuvan at the maximum therapeutic dose of 20 mg/kghad no effect on the pharmacokinetics of a single dose of digoxin (P-gp substrate) administeredconcomitantly. Based on the in vitro and in vivo results, co-administration of Kuvan is unlikely to increasesystemic exposure to drugs that are substrates for BCRP.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology(CNS, respiratory, cardiovascular, genitourinary), and toxicity to reproduction.

An increased incidence of altered renal microscopic morphology (collecting tubule basophilia) was observedin rats following chronic oral administration of sapropterin dihydrochloride at exposures at or slightly abovethe maximal recommended human dose.

Sapropterin was found to be weakly mutagenic in bacterial cells and an increase in chromosome aberrationswas detected in Chinese hamster lung and ovary cells. However, sapropterin has not been shown to begenotoxic in the in vitro test with human lymphocytes as well as in in vivo micronucleus mouse tests.

No tumorigenic activity was observed in an oral carcinogenicity study in mice at doses of up to250 mg/kg/day (12.5 to 50 times the human therapeutic dose range).

Emesis has been observed in both the safety pharmacology and the repeated-dose toxicity studies. Emesis isconsidered to be related to the pH of the solution containing sapropterin.

No clear evidence of teratogenic activity was found in rats and in rabbits at doses of approximately 3 and10 times the maximum recommended human dose, based on body surface area.

Mannitol (E421)

Calcium hydrogen phosphate, anhydrous

Crospovidone type A

Ascorbic acid (E300)

Sodium stearyl fumarate

Riboflavin (E101)

Not applicable.

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 analuminium 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.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Handling

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

For instructions for use, see section 4.2.

BioMarin International Limited

Shanbally, Ringaskiddy

County Cork

Ireland

EU/1/08/481/001

EU/1/08/481/002

EU/1/08/481/003

Date of the first authorisation: 02 December 2008

Date of latest renewal: 02 December 2013

Date of revision of the text: MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.