Kuvan 100 mg soluble tablets

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

For a 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 adult and paediatric patients of 4 years of age and over 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 adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment (see section 4.2).

Treatment with Kuvan must be initiated and supervised by a physician experienced in the treatment of PKU and BH4 deficiency. Kuvan should be administered with a meal as a single daily dose, at the same time each day, preferably in the morning.

Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine levels and nutritional balance.

As HPA due to either PKU or BH4 deficiency is a chronic condition, once responsiveness is demonstrated, Kuvan is intended for long-term use. However, there are limited data regarding the long-term use of Kuvan.

Posology

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

PKU

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

BH4 deficiency

The starting dose of Kuvan in adult and paediatric patients with BH4 deficiency is 2 to 5 mg/kg body weight once daily. Doses may be adjusted up to 20 mg/kg/day. It may be necessary to divide the total daily dose into 2 or 3 administrations, distributed over the day, to optimise the therapeutic effect.

Determination of Response

It is of primary importance to initiate Kuvan treatment as early as possible to avoid the appearance of non-reversible clinical manifestations of neurological disorders in paediatric patients and cognitive deficits and psychiatric disorders in adults due to sustained elevations of blood phenylalanine.

Response to treatment is determined by a decrease in blood phenylalanine following treatment with Kuvan. Blood phenylalanine levels should be checked before initiating treatment and after 1 week of treatment with Kuvan at the recommended starting dose. If an unsatisfactory reduction in blood phenylalanine levels is observed, then the dose of Kuvan can be increased weekly to a maximum of 20 mg/kg/day, with continued weekly monitoring of blood phenylalanine levels over a one month period. The dietary phenylalanine intake should be maintained at a constant level during this period.

A satisfactory response is defined as a 30 percent reduction in blood phenylalanine levels or attainment of the therapeutic blood phenylalanine goals defined for an individual patient by the treating physician. Patients who fail to achieve this level of response within the described one month test period should be considered non-responsive and should not receive treatment with Kuvan.

Once responsiveness to Kuvan has been established, the dose may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy.

It is recommended that blood phenylalanine and tyrosine levels be tested one or two weeks after each dose adjustment and monitored frequently thereafter. Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho-motor development).

Method of administration

The tablets should be administered as a single daily dose with a meal, to increase the absorption, and at the same time each day preferably in the morning.

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 drunk within 15 to 20 minutes.

For doses below 100 mg, one tablet should be dissolved in 100 ml of water and the volume of solution corresponding to the prescribed dose administered. An accurate measuring device with suitable graduations should be used to ensure administration of the appropriate volume of solution.

Adults

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

Paediatric population

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

Dose adjustment

Treatment with Kuvan may decrease blood phenylalanine levels below the desired therapeutic level. Adjustment of the sapropterin dose or modification of dietary phenylalanine intake may be required to achieve and maintain blood phenylalanine levels within the desired therapeutic range.

Blood phenylalanine and tyrosine levels should be tested, particularly in children, one to two weeks after each dose adjustment and monitored frequently thereafter, under the direction of the treating physician.

If inadequate control of blood phenylalanine levels is observed during treatment with Kuvan, the patient's adherence to the prescribed treatment, and diet, should be reviewed before considering an adjustment of the dose of Kuvan.

Discontinuation of Kuvan treatment should be done only under the supervision of a physician. More frequent monitoring may be required, as blood phenylalanine levels may increase. Dietary modification may be necessary to maintain blood phenylalanine levels within the desired therapeutic range.

Special populations

Kuvan has not been specifically studied in paediatric patients under 4 years of age (see section 5.1).

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

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.

Hypersensitivity to the active substance or to any of the excipients.

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

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 Kuvan is required to ensure adequate control of blood phenylalanine and tyrosine levels and nutritional balance.

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

There are limited data regarding the long-term use of Kuvan.

Caution is advised when sapropterin is used in patients with predisposition to convulsions. Events of convulsion and exacerbation of convulsion have been reported in such patients.

Sapropterin should be used with caution in patients who are receiving concomitant levodopa, as combined treatment with sapropterin may cause increased excitability and irritability.

Special populations

Kuvan has not been specifically studied in paediatric patients under 4 years of age (see section 5.1).

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

Safety and efficacy of Kuvan in patients with renal or hepatic insufficiency have not been established.

No interaction studies have been performed.

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 agents while taking Kuvan.

BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of Kuvan with all agents 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 Kuvan to patients receiving treatment with levodopa. Events of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co-administration of levodopa and sapropterin in BH4-deficient patients.

Pregnancy

For Kuvan, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Maternal blood phenylalanine levels must 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 Kuvan should be considered only if strict dietary management does not adequately reduce blood phenylalanine levels. Caution must be exercised when prescribing to pregnant women.

Breastfeeding

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

No studies on the effects on the ability to drive and use machines have been performed.

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

In the pivotal clinical trials for Kuvan, the following undesirable effects have been identified.

Frequencies are defined as: Very common (1/10) and Common (1/100 to <1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Additional information

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

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.

Pharmacotherapeutic group: 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 Kuvan 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 Kuvan 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 Kuvan included 2, randomised placebo-controlled studies in patients with PKU. The results of these studies demonstrate the efficacy of Kuvan 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 Kuvan-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 controlled on a stable phenylalanine-restricted diet (blood phenylalanine 480 μmol/l on enrolment) were randomized 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 standardized 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

Kuvan has not been specifically studied in children under 4 years of age, although the published literature indicates that more than 600 children of 0 to 4 years old with PKU, have been exposed to treatment with an un-registered preparation of BH4, including at least 35 who received therapy 2 months. The maximum daily dose used was 20 mg/kg body weight.

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 (C_max) 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 10mg/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.

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.

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 an aluminium seal. Each bottle of Kuvan 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.

Disposal

No special requirements.

Handling

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

Merck Serono Europe Limited

56, Marsh Wall

London E14 9TP

United Kingdom

EU/1/08/481/001

EU/1/08/481/002

EU/1/08/481/003

Date of the first authorisation: 2 December 2008

07/2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu.