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

Sapropterin  dihydrochloride  is  also indicated   for  the  treatment  of  hyperphenylalaninaemia  (HPA) in adults and paediatric patients of  al  ages  with  tetrahydrobiopterin  (BH4)  deficiency  who  have been shown to be responsive to such treatment (see section 4.2).

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

Active  management  of  dietary  phenylalanine  and  overal  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, Sapropterin dihydrochloride is intended for long-term use (see section 5.1).

Posology

PKU

The starting dose of Sapropterin dihydrochloride in adult and paediatric patients  with  PKU is  10 mg/kg body weight once daily. The dose is adjusted, usual y 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 Sapropterin  dihydrochloride 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.

Sapropterin dihydrochloride 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 Sapropterin dihydrochloride 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 Sapropterin dihydrochloride, 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  Sapropterin  dihydrochloride  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 Sapropterin dihydrochloride and administration of Sapropterin dihydrochloride 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  Sapropterin  dihydrochloride  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 Sapropterin dihydrochloride 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 Sapropterin dihydrochloride  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

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

For patients with PKU, Sapropterin dihydrochloride 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 swal ow 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. Smal particles may be visible in the solution and wil 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 Sapropterin dihydrochloride pack.

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  smal 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.

Dietary intake

Patients treated  with  Sapropterin  dihydrochloride  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 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 to low blood phenylalanine and tyrosine  levels  during  infancy  has  been associated  with  impaired  neurodevelopmental outcome.  Active  management  of  dietary phenylalanine and overal protein intake while  taking  Sapropterin  dihydrochloride  is  required to ensure adequate control of blood phenylalanine and tyrosine levels and nutritional balance.

Health disturbances

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

Convulsions disorders

Caution should be exercised when prescribing sapropterin dihydrochloride to patients receiving treatment with levodopa. Cases of convulsion, 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).

Discontinuation of treatment

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

Sodium content

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 is  recommended when using such  medicinal  products while taking Sapropterin dihydrochloride.

BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Sapropterin dihydrochloride with al medicinal products that cause vasodilation, including those administered  topical y,  by  affecting  nitric  oxide  (NO)  metabolism  or  action   including   classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate  (ISDN),  sodium  nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil.

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

Pregnancy

There are  limited  amount  of  data  from  the  use  of  sapropterin  dihydrochloride  in  pregnant women. Animal studies do  not  indicate  direct  or  indirect  harmful  effects  with  respect  to  pregnancy, embryonal/foetal development, parturition or postnatal development.

Available disease-associated maternal and/or embryofoetal risk data from the Maternal Phenylketonuria Col aborative Study on  a  moderate  amount  of  pregnancies  and  live  births (between 300-1,000) in PKU-affected  women demonstrated that  uncontrol ed  phenylalanine levels above 600 μmol/l are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies.

Maternal blood phenylalanine levels must therefore be strictly control ed before and during pregnancy.  If  maternal  phenylalanine  levels  are  not  strictly  control ed  before  and  during pregnancy, this could be harmful to the mother and the foetus. Physician-supervised restriction

of dietary  phenylalanine intake prior to and throughout pregnancy is the first choice of  treatment in this patient group.

The use of Sapropterin dihydrochloride should be considered only  if  strict  dietary  management does not adequately reduce  blood phenylalanine levels. Caution  must  be  exercised  when  prescribing to pregnant women.

Breast-feeding

It is not known whether sapropterin or its  metabolites  are  excreted  in  human  breast  milk. Sapropterin dihydrochloride should not be used during breast-feeding.

Fertility

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

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

Summary   of the  safety profile

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

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

Tabulated list of adverse reactions

In the pivotal clinical trials  and  in  the  post-marketing  experience  for  sapropterin  dihydrochloride,  the fol owing adverse reactions have been identified.

The fol owing 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.

Paediatric population

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

Reporting of suspected adverse reactions

Reporting  suspected  adverse  reactions after authorisation of the medicinal product is important. It al ows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below)

Reporting of suspected adverse reactions

•   Saudi Arabia:

o Other GCC States:

Please contact the relevant competent authority.

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).

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

Mechanism of action

Hyperphenylalaninaemia  (HPA)  is  diagnosed as  an  abnormal  elevation  in  blood  phenylalanine levels and is usual y caused by autosomal  recessive  mutations  in  the  genes  encoding  for phenylalanine hydroxylase enzyme (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  cases,  phenylalanine  cannot  be  effectively  transformed  into  the  amino  acid  tyrosine,  leading to increased phenylalanine levels in the blood.

Sapropterin is a synthetic version of the natural y occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan.

The rationale for administration of Sapropterin dihydrochloride 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 phenylalanine sufficient to reduce or maintain blood phenylalanine levels, prevent  or  decrease  further  phenylalanine  accumulation,   and   increase tolerance to phenylalanine intake in the diet. The rationale for administration of Sapropterin dihydrochloride  in  patients with  BH4 Deficiency  is  to  replace  the  deficient  levels  of   BH4, thereby restoring the activity of phenylalanine hydroxylase.

Clinical efficacy

The Phase III clinical development program  for sapropterin dihydrochloride included 2, randomised placebo-control ed studies in patients with PKU.  The  results  of  these  studies demonstrate the  efficacy  of  sapropterin  dihydrochloride  to  reduce  blood  phenylalanine  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 to placebo. The baseline blood phenylalanine levels for the sapropterin dihydrochloride-treated group and the  placebo  group were  similar,  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  week  study  period was 236 ± 257 μmol/l for the sapropterin treated group (n=41) as compared to an increase of 2.9

± 240 μmol/l for the placebo  group (n=47) (p<0.001). For patients with baseline blood phenylalanine levels ≥600 μmol/l, 41.9% (13/31) of those  treated  with  sapropterin  and  13.2% (5/38) of those treated with placebo  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 control ed on a stable phenylalanine-restricted diet (blood phenylalanine ≤480 μmol/l on enrolment) were randomised 3:1 to  treatment with  sapropterin  dihydrochloride  20  mg/kg/day (n=33) or placebo (n=12). After 3-weeks of treatment with sapropterin dihydrochloride 20 mg/kg/day, blood phenylalanine levels were significantly reduced; the mean ± SD decrease from baseline in blood phenylalanine level within this group was 149 ± 134 μmol/l (p<0.001). After  3  weeks, subjects in both the sapropterin and placebo treatment groups were continued on their phenylalanine-restricted diets and dietary phenylalanine intake was increased or decreased using standardised phenylalanine supplements with a goal to maintain blood phenylalanine levels at

<360  μmol/l.  There was a significant difference in dietary  phenylalanine tolerance in the sapropterin treatment group as compared to the placebo group. The mean ± SD increase in dietary phenylalanine tolerance 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,  the  mean  ±  SD  total  dietary  phenylalanine tolerance was 38.4 ± 21.6 mg/kg/day during treatment with sapropterin dihydrochloride 20 mg/kg/day compared to 15.7 ± 7.2 mg/kg/day before treatment

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  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 in conjunction with a phenylalanine-restricted diet (n=27),  or  just a  phenylalanine-restricted  diet  (n=29)   over  a  26- week Study Period.

It was intended that al 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 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 this study demonstrated that daily dosing with 10 or 20 mg/kg/day of sapropterin dihydrochloride in conjunction with a phenylalanine-restricted diet led to  statistical y significant improvements in dietary  phenylalanine tolerance compared with dietary phenylalanine restriction alone  while  maintaining  blood  phenylalanine  levels  within  the  target  range   (≥120   to   <360  μmol/l). The adjusted mean dietary phenylalanine tolerance in the sapropterin dihydrochloride in conjunction with a phenylalanine-restricted diet group was 80.6 mg/kg/day and was statistical y 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  phenylalanine   tolerance   while   on   sapropterin   dihydrochloride treatment in  conjunction  with  a  Phe-restricted  diet,  demonstrating  sustained  benefit  over   3.5 years.

The second study was a multicenter, uncontrol ed, open-label study designed to  evaluate the safety and effect on preservation of neurocognitive function of sapropterin dihydrochloride 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   sapropterin dihydrochloride; 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 sapropterin dihydrochloride. Patients with pre-existing neurocognitive impairment (IQ <80) were  excluded  from the study. Ninety-three patients were  enrol ed  into  Part 1, and 65 patients were enrolled  into  Part 2, of whom 49 (75%) patients  completed  the  study with 27 (42%) patients providing Ful Scale IQ (FSIQ) data at year 7.

Mean Indices of Dietary Control were maintained between 133 μmol/L and 375 μmol/L blood phenylalanine for al age groups at  al  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 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 clinical y expected variation of ±5 points. No additional adverse reactions were identified with long-term use of sapropterin dihydrochloride in children less than 7 years of age.

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

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. The absorption of sapropterin is higher after a high-fat, high-calorie meal as compared to  fasting,  resulting,  in  average,  in  40-85%  higher  maximum blood concentrations achieved 4 to 5 hours after administration.

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

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

Biotransformation

Sapropterin dihydrochloride is primarily metabolised in the  liver  to  dihydrobiopterin  and biopterin. Since sapropterin dihydrochloride is a synthetic version  of  the  natural y  occurring  6R- BH4, it can be reasonably anticipated to  undergo the same metabolism, including  6R-BH4 regeneration.

Elimination

Fol owing  intravenous  administration  in  rats,  sapropterin  dihydrochloride  is   mainly   excreted   in the urine. Following oral administration  it  is  mainly  eliminated  through  faeces  while  a  smal 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 substantial y affecting clearance or volume of distribution.

Drug interactions

In vitro studies

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 intestinal concentration of Sapropterin  dihydrochloride 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 vivo studies

In healthy subjects, administration  of  a  single  dose  of  Sapropterin   dihydrochloride  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. Based on the in vitro and in vivo results, co-administration of  Sapropterin  dihydrochloride  is  unlikely  to  increase systemic  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  (col ecting  tubule  basophilia)  was observed in rats following chronic oral administration of sapropterin dihydrochloride at exposures at or slightly above the maximal recommended human dose.

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

No tumorigenic activity was observed in an oral  carcinogenicity  study  in  mice  at  doses  of up  to 250 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 is considered 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 and 10 times the maximum  recommended  human  dose,  based  on  body  surface area

Sapropterin dihydrochloride 100 mg Tablets

Mannitol   (Pearlitol   160C),   Ascorbic acid,  Crospovidone                                                                                            (Kol idon CL), Riboflavin, Col oidal Silicon Dioxide (Aerosil 200), Sodium Stearyl Fumarate, Mannitol (Pearlitol SD 200).

Not applicable

Store below 30ºC.

30’s Count HDPE Container

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