SAPROPTERIN DIHYDROCHLORIDE 100 MG SOLUBLE TABLETS - summary of medicine characteristics

Sapropterin dihydrochloride 100 mg Soluble Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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, round (of diameter about 9.5 mm) tablet, with “L71” imprinted on one side and “T” on the other side.

4.1 Therapeutic indications

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

4.2 Posology and method of administration

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 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, Sapropterin dihydrochloride is intended for longterm 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, 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 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 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 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 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

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.

4.3 Contraindications

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

4.4 Special warnings and precautions for 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 overall 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 illness 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’.

4.5 Interaction with other medicinal products and other forms of interaction

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 all medicinal products that cause vasodilation, including those administered topically, 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.

4.6 Fertility, pregnancy and lactation

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 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 jrmol/l are associated with 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. If maternal phenylalanine levels are not strictly controlled 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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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 following adverse reactions have 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.

Immune system disorders

Not known:            Hy­persensitivity reactions (including serious allergic

reactions) and rash

Metabolism and nutrition disorders

Common:            Hy­pophenylalani­naemia

Nervous system disorders

Very common: Headache

Respiratory, thoracic and mediastinal disorders

Very common: Rhinorrhoea

Common:             P­haryngolarynge­al pain, nasal congestion, cough

Gastrointestinal disorders

Common:

Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea

Not known:

Gastritis, oesophagitis

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 usually 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 naturally 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-controlled 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 jimol/l and 888 ± 323 jimol/l, respectively. The mean ± SD decrease from baseline in blood phenylalanine levels at the end of the 6 week study period was 236 ± 257 jimol/l for the sapropterin treated group (n=41) as compared to an increase of 2.9 ± 240 jimol/l for the placebo group (n=47) (p<0.001). For patients with baseline blood phenylalanine levels >600 jimol/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 jimol/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 controlled on a stable phenylalanine-restricted diet (blood phenylalanine <480 jimol/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 jimol/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 jimol/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 all patients maintained blood phenylalanine levels within a range of 120–360 jrmol/l (defined as >120 to <360 jrmol/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 statistically significant improvements in dietary phenylalanine tolerance compared with dietary phenylalanine restriction alone while maintaining blood phenylalanine levels within the target range (>120 to <360 jrmol/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 statistically 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, uncontrolled, 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 enrolled into Part 1, and 65 patients were enrolled into Part 2, of whom 49 (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 jrmol/L and 375 jrmol/L blood phenylalanine for 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 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 clinically 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.

5.2 Pharmacokinetic properties

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, following 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 naturally occurring 6R-BH4, it can be reasonably anticipated to undergo the same metabolism, including 6R-BH4 regeneration.

Elimination

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 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 substantially 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 pM) is lower than P-gp (IC50=158 pM).

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.

5.3 Preclinical safety data

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 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 cells and an increase in chromosome aberrations was detected in Chinese hamster lung and ovary cells.

However, sapropterin has not been shown to be genotoxic 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 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421)

Pregelatinised Starch

Crospovidone (E1202)

Riboflavin (E101)

Ascorbic Acid (E300)

Sodium Stearyl Fumarate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

18 months

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Keep the bottle tightly closed and store in the original package to protect from moisture and light.

6.5 Nature and contents of container

High-density polyethylene (HDPE) bottle with either white or green child-resistant closure. Each bottle contains 30 or 120 tablets. The bottles are sealed with an aluminium seal. Each bottle contains a small plastic tube of desiccant (silica gel).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited,

Ridings Point,

Whistler Drive,

Castleford,

WF10 5HX,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/2530

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/10/2021