ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Kuvan 100 mg soluble tablets
2.
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.
3.
Soluble tablet.
Off-white to light yellow soluble tablet with “177” imprinted on one face.
4.
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.
2
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.
3
Paediatric patients
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.
4
Caution is advised when sapropterin is used in patients with predisposition to convulsions. In clinical
studies of patients with BH4 deficiency treated with a preparation of sapropterin, convulsions and
exacerbation of convulsions was observed. This was not observed in the clinical trials of Kuvan in
patients with PKU.
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, as
it may cause increased excitability and irritability.
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.
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.
5
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.
System Organ Class
Very Common
Common
Nervous system disorders
Headache
Respiratory, thoracic and
mediastinal disorders
Rhinorrhoea
Pharyngolaryngeal pain
Nasal congestion
Cough
Gastrointestinal disorders
Diarrhoea
Vomiting
Abdominal pain
Metabolism and nutrition
disorders
Hypophenylalaninemia
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.
5.
5.1 Pharmacodynamic properties
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.
6
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 842.7 ±
299.6 μmol/l and 888.3 ± 323.1 μmol/l, respectively. The mean ± SD decrease from baseline in blood
phenylalanine levels at the end of the 6 week study period was 235.9 ± 257.0 μmol/l for the
sapropterin treated group (n=41) as compared to an increase of 2.9 ± 239.5 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 148.5 ±134.2 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
17.513 ±13.268 mg/kg/day for the group treated with sapropterin dihydrochloride 20 mg/kg/day,
compared to 3.259 ± 5.291 mg/kg/day for the placebo group (p = 0.006). For the sapropterin treatment
group, the mean ± SD total dietary phenylalanine tolerance was 38.406 ± 21.606 mg/kg/day during
treatment with sapropterin dihydrochloride 20 mg/kg/day compared to 15.660 ± 7.159 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.
7
5.2 Pharmacokinetic properties
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.
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.
8
6.
6.1 List of excipients
Mannitol (E421)
Calcium hydrogen phosphate, anhydrous
Crospovidone type A
Ascorbic acid (E300)
Sodium stearyl fumarate
Riboflavin (E101)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store below 25°C.
Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
Disposal
No special requirements.
Handling
Patients should be advised not to swallow the desiccant capsule found in the bottle.
7.
Merck Serono Europe Limited
56, Marsh Wall
London E14 9TP
United Kingdom
9
8.
EU/1/08/481/001
EU/1/08/481/002
EU/1/08/481/003
9.
Date of the first authorisation: 2 December 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu.
10
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
11
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Merck KGaA
Frankfurter Str. 250
64293 Darmstadt
Germany
Merck KGaA & Co. Werk Spittal
Hösslgasse 20
9800 Spittal / Drau
Austria
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 9.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.3 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
• When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
• At the request of the EMEA
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
CARTON AND BOTTLE LABEL
1.
Kuvan 100 mg soluble tablets
Sapropterin dihydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each soluble tablet contains 100 mg of sapropterin dihydrochloride (equivalent to 77 mg of
sapropterin).
3.
LIST OF EXCIPIENTS
4.
30 soluble tablets
120 soluble tablets
240 soluble tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use, after dissolution.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Each bottle of Kuvan contains a small plastic tube of desiccant (silica gel). Do not swallow the tube or
the contents.
8.
EXPIRY DATE
EXP
15
9.
SPECIAL STORAGE CONDITIONS
Store below 25°C.
Keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Serono Europe Limited
56, Marsh Wall
London E14 9TP
United Kingdom
EU/1/08/481001
EU/1/08/481/002
EU/1/08/481/003
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
kuvan
16
B. PACKAGE LEAFLET
17
PACKAGE LEAFLET: INFORMATION FOR THE USER
Kuvan 100 mg soluble tablets
Sapropterin dihydrochloride
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Kuvan
is and what it is used for
3.
How to take Kuvan
4.
Possible side effects
5.
How to store Kuvan
6.
Further information
1.
WHAT KUVAN IS AND WHAT IT IS USED FOR
Kuvan is a synthetic copy of a body’s own substance called tetrahydrobiopterin (BH4). BH4 is
required by the body to use an amino acid called phenylalanine in order to build another amino acid
called tyrosine.
Kuvan is used for the treatment of hyperphenylalaninaemia (HPA) or phenylketonuria (PKU), due to
abnormally high levels of phenylalanine in the blood, which can be harmful. Kuvan reduces these
levels in some patients who respond to BH4 and can help increase the amount of phenylalanine that
can be included in the diet.
Kuvan is also used for the treatment of an inherited disease called BH4 deficiency, in which the body
cannot produce enough BH4. Because of very low BH4 levels phenylalanine is not used properly and
its levels rise, resulting in harmful effects. By replacing the BH4 that the body cannot produce, Kuvan
reduces the harmful excess of phenylalanine in the blood and increases the dietary tolerance to
phenylalanine.
2.
BEFORE YOU TAKE KUVAN
Do not take Kuvan
If you are allergic (hypersensitive) to sapropterin or any of the other ingredients of Kuvan.
Take special care with Kuvan
You should consult your doctor:
-
if your child that was prescribed Kuvan is under 4 years of age
-
if you are 65 years of age or older
-
if you have problems with your kidney or liver
-
if you are ill. Consultation with a physician is recommended during illness as blood
phenylalanine levels may increase
-
if you have predisposition to convulsions
-
if you are using any of the medicines listed below under “Taking other medicines”
18
-
If you have any further questions, ask your doctor or pharmacist.
2.
Before you take Kuvan
When you are treated with Kuvan, your doctor will test your blood to verify how much phenylalanine
and tyrosine it contains and may decide to adjust the dose of Kuvan or your diet if needed.
You must continue your diet treatment as recommended by your doctor. Do not change your diet
without contacting your doctor.
Taking other medicines
You should consult your doctor if you are taking:
-
levodopa (used to treat Parkinson’s disease)
-
agents that cause vasodilation, including those administered topically, by affecting nitric oxide
(NO) metabolism or action, including the classical NO donors (such as glyceryl trinitrate
(GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP) and molsidomin),
phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Taking Kuvan with food and drink
Kuvan should be taken with food at the same time each day preferably in the morning.
Pregnancy and breast-feeding
For Kuvan no information is available for human pregnancies. Animal studies do not indicate direct or
indirect harmful effects with respect to pregnancy
,
embryonal/foetal development, birth or postnatal
development.
If maternal phenylalanine levels are not strictly controlled before and during pregnancy, this could be
harmful to the mother and the foetus. In case of pregnancy your doctor will tell you how to control
phenylalanine levels adequately
.
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.
Be sure to tell your doctor if you are pregnant or breast-feeding, if you think you might be pregnant, or
if you are planning to become pregnant or are planning to begin breast-feeding.
You should not take Kuvan if you are breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. Kuvan is not
expected to affect the ability to drive and use machines.'
3.
HOW TO TAKE KUVAN
Always take Kuvan exactly as your doctor has told you. You should check with your doctor if you are
not sure.
Dosage
PKU
The usual starting dose of Kuvan in adult and paediatric patients with PKU is 10 mg for each kg of
body weight. Take the soluble tablets as a single daily dose with a meal to increase the absorption, and
at the same time each day, preferably in the morning. Your doctor may adjust your dose, usually
between 5 and 20 mg for each kg of body weight per day, depending on your condition.
19
-
inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim)
BH4 deficiency
The usual starting dose of Kuvan in adult and paediatric patients with BH4 deficiency is 2 to 5 mg for
each kg of body weight. Take the soluble tablets as a single daily dose, with a meal to increase the
absorption, and at the same time each day, preferably in the morning. Your doctor may adjust your
dose up to 20 mg for each kg of body weight per day, depending on your condition. It may be
necessary to divide the total daily dose into 2 or 3 doses, distributed over the day, to achieve the best
therapeutic effect.
The table below is an example of how an appropriate dose is calculated:
Body weight (kg)
Number of tablets
(Kuvan dose 10 mg/kg)
Number of tablets
(Kuvan dose 20 mg/kg)
10
1
2
20
2
4
30
3
6
40
4
8
50
5
10
Method of Administration
Adults
Place the tablets in a glass or cup (120 to 240 ml) of water and stir until dissolved.
Paediatric patients
The prescribed number of tablets should be placed in a glass or cup (up to 120 ml) of water and stir
until dissolved.
For doses below 100 mg, one tablet should be dissolved in 100 ml of water. Your doctor will tell you
to administer only a certain volume of the solution corresponding to the appropriate dose. An accurate
measuring device with suitable graduations should be used for this purpose.
It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster you can crush
them. Small particles may be visible in the solution, but they will not affect the effectiveness of the
medicine. Drink the dissolved preparation of Kuvan with a meal, at the same time each day, preferably
in the morning within 15 to 20 minutes of its preparation.
Make sure you do not swallow the desiccant capsule contained in the bottle.
If you take more Kuvan than you should
If you take more Kuvan than prescribed, you may experience side effects that could include headache
and dizziness. You should immediately contact your doctor or pharmacist if you take more Kuvan than
prescribed.
If you forget to take Kuvan
Do not take a double dose to make up for a forgotten dose.
If you stop taking Kuvan
Do not stop taking Kuvan without prior discussion with your doctor, as phenylalanine levels in the
blood may increase.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
20
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Kuvan can cause side effects, although not everybody gets them.
Frequencies of side effects are defined as:
-
very common: affects more than 1 user in 10
-
uncommon: affects 1 to 10 users in 1,000
-
rare: affects 1 to 10 users in 10,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data.
Very common side effects
: headache and runny nose.
Common side effects
: sore throat, nasal congestion or stuffy nose, cough, diarrhoea, vomiting,
stomach ache and too low levels of phenylalanine in blood tests.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE KUVAN
Keep out of the reach and sight of children.
Do not use Kuvan after the expiry date which is stated on the bottle and the carton after “EXP”. The
expiry date refers to the last day of that month.
Store below 25°C.
Keep the bottle tightly closed in order to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Kuvan contains
-
The active substance is sapropterin dihydrochloride. Each tablet contains 100 mg of sapropterin
dihydrochloride (equivalent to 77 mg of sapropterin).
-
The other ingredients are mannitol (E421), calcium hydrogen phosphate anhydrous,
crospovidone type
A, ascorbic acid (E300), sodium stearyl fumarate, and riboflavin (E101).
What Kuvan looks like and contents of the pack
Kuvan is supplied as soluble tablets. The soluble tablets are off-white to light yellow and have “177”
imprinted on one face.
It may be available in bottles with child-resistant closure of 30, 120 or 240 soluble tablets. Each bottle
contains a small plastic tube of desiccant (silica gel).
Not all pack sizes may be marketed.
21
-
common: affects 1 to 10 users in 100
Marketing Authorisation Holder
Merck Serono Europe Limited
56, Marsh Wall
London E14 9TP
United Kingdom
Manufacturer
Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany
or
Merck KGaA & Co. Werk Spittal, Hösslgasse 20, 9800 Spittal / Drau, Austria
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
MERCK NV/SA
Brusselsesteenweg 288
B-3090 Overijse
Tél/Tel: +32-2-686 07 11
Luxembourg/Luxemburg
MERCK NV/SA
Brusselsesteenweg 288
B-3090 Overijse, Belgique/Belgien
Tél/Tel: +32-2-686 07 11
България
Мерк България ЕАД
Бул. „Проф. Цветан Лазаров“ 83
София 1582
България
Teл: +359 28075 111
Magyarország
Merck Kft.
Bocskai út 134-146.
H-1113 Budapest
Tel: +36-1-463-8100
Česká republika
Merck spol. s r.o.
Na Hřebenech II. 1718/10
CZ-140 00 Praha 4
Tel. +420 272084211
Malta
Cherubino Ltd
Delf Building
Sliema Road
MT-GZR 06 Gzira Malta
Tel: +356-21-343270/1/2/3/4
Danmark
Merck A/S
Strandvejen 102 B, 4th
DK-2900 Hellerup
Tlf: +45 35253550
Nederland
Merck BV
Tupolevlaan 41-61
NL-1119 NW Schiphol-Rijk
Tel: +31-20-6582800
Deutschland
Merck Serono GmbH
Alsfelder Straße 17
D-64289 Darmstadt
Tel: +49-6151-6285-0
Norge
Merck Serono Norge
Luhrtoppen 2
N-1470 Lørenskog
Tlf: +47 67 90 35 90
Eesti
Merck Serono OÜ
Tornimäe 7 - 132
EE-10145, Tallinn
Tel: +372 682 5882
Österreich
Merck GesmbH.
Zimbagasse 5
A-1147 Wien
Tel: +43 1 57600-0
22
Ελλάδα
Merck A.E.
Κηφισίας 41-45, Κτίριο Β
GR-151 23 Μαρούσι
Αθήνα
Tηλ: +30-210-61 65 100
Polska
Merck Sp. z o.o.
Al. Jerozolimskie 178
PL-02-486 Warszawa
Tel.: +48 22 53 59 700
España
Merck S.L.
María de Molina, 40
E-28006 Madrid
Línea de Información: 900 200 400
Tel: +34-91-745 44 00
Portugal
Merck, s.a.
Rua Alfredo da Silva, 3-C
P-1300-040 Lisboa
Tel: +351-21-361 35 00
France
Merck Serono s.a.s.
37, rue Saint-Romain
F-69379 Lyon cedex 08
Tél.: +33-4-72 78 25 25
Numéro vert : 0 800 888 024
România
MERCK d.o.o.,
Dunajska cesta 119
SI-1000 Lubliana, Slovenia
Tel: +386 1 560 3 800
Ireland
Merck Serono Ltd
Bedfont Cross, Stanwell Road
Feltham, Middlesex TW14 8NX
United Kingdom
Tel: +44-20 8818 7200
Slovenija
MERCK d.o.o.
Dunajska cesta 119
SI-1000 Ljubljana
Tel: +386 1 560 3 800
Ísland
Icepharma hf
Lynghálsi 13
IS-110 Reykjavík
Tel: + 354 540 8000
Slovenská
republika
Merck spol. s r.o.
Tuhovská 3
SK-831 06 Bratislava
Tel: + 421 2 49 267 111
Italia
Merck Serono S.p.A.
Via Casilina 125
I-00176 Roma
Tel: +39-06-70 38 41
Suomi/Finland
Merck Oy
Pihatörmä 1 C
FIN-02240 Espoo
Puh/Tel: +358-9-8678 700
Κύπρος
Χρ. Γ. Παπαλοϊζου Λτδ
Λεωφόρος Κιλκίς 35,
CY-2234 Λατσιά, Λευκωσία
Τηλ.: +357 22490305
Sverige
Merck AB
S-195 87 Stockholm
Tel: +46-8-562 445 00
Latvija
Merck Serono SIA
Duntes iela 23A
LV-1005, Rīga
Tel: +371 67152500
United Kingdom
Merck Serono Ltd
Bedfont Cross, Stanwell Road
Feltham, Middlesex TW14 8NX- UK
Tel: +44-20 8818 7200
23
Lietuva
Merck Serono UAB
Savanoriu pr. 192,
LT-44151 Kaunas
Tel: +370 37320603
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu. There are also links to other websites about rare diseases and
treatments.
24
Source: European Medicines Agency
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