Kargluminsyra Waymade 200 mg Dispergerbar tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

04-10-2019

Produktens egenskaper Produktens egenskaper (SPC)

04-10-2019

Aktiva substanser:
kargluminsyra
Tillgänglig från:
Waymade BV
ATC-kod:
A16AA05
INN (International namn):
carglumic acid
Dos:
200 mg
Läkemedelsform:
Dispergerbar tablett
Sammansättning:
natriumlaurilsulfat Hjälpämne; kargluminsyra 200 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 5 tabletter; Burk, 15 tabletter; Burk, 60 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
53248
Tillstånd datum:
2017-12-29

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

14-01-2020

Produktens egenskaper Produktens egenskaper - engelska

14-01-2020

Läs hela dokumentet

Package leaflet: Information for the user

Kargluminsyra Waymade 200 mg Dispersible Tablets

Read all of this leaflet carefully before you start taking this medicine.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or your pharmacist.

- This medicine has been prescribed for you only. Do not pass it on to others. It may

harm them, even if their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor or pharmacist. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Carglumic Acid is and what it is used for

2. What you need to know before you take Carglumic Acid

3. How to take Carglumic Acid

4. Possible side effects

5. How to store Carglumic Acid

6. Contents of the pack and other information

1. What Carglumic Acid is and what it is used for

Your medicine is called Kargluminsyra Waymade 200 mg Dispersible Tablets. In this

leaflet it will be called Carglumic Acid.

Carglumic Acid can help to eliminate high ammonia levels in the blood. Ammonia is

especially toxic for the brain and can lead, in severe cases, to reduced levels of

consciousness and to coma.

High levels of ammonia in the blood may be due to:

the lack of a specific liver enzyme (N-acetylglutamate synthase). Patients with

this rare disorder is not able to eliminate nitrogen waste, which builds up after

eating protein. This disorder persists throughout the life of the affected patient,

requiring lifelong treatment.

2. What you need to know before you take Carglumic Acid

Do not take Carglumic Acid:

if you are hypersensitive (allergic) to carglumic acid or any of the other ingredients

of these tablets (see section 6 for a list of ingredients);

during breast-feeding.

Warnings and precautions

Carglumic Acid treatment should be initiated under the supervision of a doctor

experienced in treating metabolic disorders.

Your doctor will evaluate your individual response to carglumic acid before starting

any long-term treatment. The dose should be individually adjusted in order to

maintain normal ammonia plasma levels.

Your doctor may prescribe a supplement called arginine or restrict your protein

intake.

In order to follow up your condition and your treatment, your doctor may examine

your liver, kidneys, heart and blood on a regular basis.

Other medicines and Carglumic Acid

Please tell your doctor or pharmacist if you are taking, have recently taken or might

take, any other medicines.

Carglumic Acid with food and drink

Take carglumic acid before meals or feeds.

Disperse the tablets in at least 5 to 10 ml of water and take it immediately. The

suspension will have a slightly acidic taste.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to

have a baby, ask your doctor for advice before taking this medicine.

Pregnancy

The effects of Carglumic Acid on pregnancy and the unborn child are not known.

Please consult your doctor for advice if you are pregnant or planning to become

pregnant.

Breast-feeding

Do not breast-feed your baby if you are taking Carglumic Acid. The excretion of

carglumic acid into breast milk has not been studied in women. Nevertheless,

carglumic acid has been shown to be present in the milk of lactating rats with

potential toxic effects for their fed pups.

Driving and using machines

Effects on the ability to drive and use machines are not known.

Carglumic Acid contains sodium

This medicinal product contains up to 3 mg of sodium per tablet. This should be

taken into consideration by patients on a controlled sodium diet.

The maximum recommended daily dose of this medicinal product contains 396 mg

sodium (found in table salt). This is equivalent to 20% of the adult recommended

maximum daily dietary intake for sodium.

3. How to take Carglumic Acid

Always take Carglumic Acid exactly as your doctor has instructed you. You should

check with your doctor or pharmacist if you are not sure.

The usual dose:

The initial daily dose is usually 100 mg per kilogram of body weight, up to a

maximum of 250 mg per kilogram of body weight (for example, if you weigh 10 kg,

you should take 1 g per day, or 5 tablets).

For patients suffering from N-acetylglutamate synthase deficiency, in the long term,

the daily dose usually ranges from 10 mg to 100 mg per kilogram of body weight.

Your doctor will determine the dose suitable to you in order to maintain normal

ammonia levels in your blood.

Carglumic Acid should ONLY be given by mouth, or through a feeding tube into the

stomach (using a syringe, if necessary).

When the patient is in hyperammonaemic coma, Carglumic Acid is administered by

fast push through a syringe via the tube set up to feed them.

If you take more Carglumic Acid than you should:

If you accidentally take too much of your medicine, tell your doctor at once or contact

your nearest hospital casualty department immediately. Take your medicine and this

leaflet with you.

If you forget to take Carglumic Acid

If you forget to take a dose take the next dose at the usual time. DO NOT take a

double dose to make up for a forgotten dose.

If you stop taking Carglumic Acid

Do not stop taking Carglumic Acid without informing your doctor.

If you have any further questions on the use of this product, ask your doctor or

pharmacist.

4. Possible side effects

Like all medicines, Carglumic Acid can have side effects, although not everybody

gets them.

The following side effects were reported as follows:

Common (may affect up to 1 in 10 people): increased sweating.

Uncommon (may affect up to 1 in 100 people):

reduced heartbeat, diarrhoea, fever, vomiting, increased transaminases (enzymes

that may indicate liver damage).

Frequency not known rash.

If any of these side effects becomes serious, or if you notice any side effects not

listed in this leaflet, please tell your doctor or pharmacist.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any

possible side effects not listed in this leaflet. You can also report side effects directly

[To be completed nationally]

By reporting side effects you can help provide more information on the safety of this

medicine.

5. How to store Carglumic Acid

Keep this medicine out of the sight and reach of children.

Do not use after the expiry date stated on the tablet container.

This medicinal product does not require any special storage conditions.

After first opening of the tablet container: do not refrigerate, do not freeze.

Discard 1 month after first opening.

Keep the container tightly closed in order to protect from moisture.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the

environment.

6. Contents of the pack and other information

What Carglumic Acid contains

The active substance is carglumic acid. Each tablet contains 200 mg of carglumic

acid. The other ingredients are microcrystalline cellulose, croscarmellose sodium,

sodium laurilsulfate, colloidal anhydrous silica, sodium stearyl fumarate.

What Carglumic Acid looks like and contents of the pack

Carglumic Acid Waymade 200 mg Dispersible Tablets are white to off-white

elongated tablets, 18 mm x 6 mm, with three score marks on each side and

embossed with 'N's on one side.

The tablet can be divided into equal halves.

Carglumic Acid is presented in containers of 5, 15 and 60 tablets. Not all pack sizes

may be marketed.

Marketing Authorisation Holder

Waymade B.V., Strawinskylaan 3127, 1077 ZX, Amsterdam, Netherlands.

Manufacturer

Waymade Plc., Sovereign House

Miles Gray Road, Basildon, Essex

SS14 3FR. United Kingdom

Waymade Plc., Josselin Road, Burnt Mills Industrial Estate, Basildon, Essex,

SS13 1QF. United Kingdom

Drehm Pharma GmbH, Hietzinger Hauptstraβe 37/2, 1130, Wein, Austria

For any information about this medicine, please contact the local representative of

the Marketing Authorisation Holder:

Waymade Plc

Sovereign House, Miles Gray Road Basildon, Essex SS14 3FR. United Kingdom

This leaflet was last revised in November 2019.

Carglumic Acid Waymade 200 mg Dispersible Tablets

To request a copy of this leaflet in Braille, large print or audio format, contact the

licence holder at the above address or telephone: 01268 535200 (select option

Medical Information) / e-mail: info@waymade.co.uk

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Kargluminsyra Waymade 200 mg Dispersible Tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1

General description

Each tablet contains 200 mg of carglumic acid.

2.2

Qualitative and quantitative composition

Each tablet contains up to 3 mg of sodium (see section 4.4).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Dispersible tablet.

The tablets are white to off-white, elongated dispersible tablets, 18 mm x 6 mm, with three score marks on

both sides and engraved ‘N’s on one side.

The tablet can be divided into equal halves.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Kargluminsyra Waymade 200 mg Dispersible Tablets are indicated in the treatment of:

hyperammonaemia due to N-acetylglutamate synthase primary deficiency.

4.2

Posology and method of administration

Kargluminsyra Waymade 200 mg Dispersible Tablet treatment should be initiated under the supervision of a

physician experienced in the treatment of metabolic disorders.

Posology

For N-acetylglutamate synthase deficiency:

Based on clinical experience, the treatment may be started as early as the first day of life.

The initial daily dose should be 100 mg/kg, up to 250 mg/kg if necessary.

It should then be adjusted individually in order to maintain normal ammonia plasma levels (see section 4.4).

In the long term, it may not be necessary to increase the dose according to body weight as long as adequate

metabolic control is achieved; daily doses range from 10 mg/kg to 100 mg/kg.

Carglumic acid responsiveness test

It is recommended to test individual responsiveness to carglumic acid before initiating any long term

treatment. As examples:

In a comatose child, start with a dose of 100 to 250 mg/kg/day and measure ammonia plasma

concentration at least before each administration; it should normalise within a few hours after starting

Kargluminsyra Waymade 200 mg dispersible tablets.

In a patient with moderate hyperammonaemia, administer a test dose of 100 to 200 mg/kg/day for 3

days with a constant protein intake and perform repeated determinations of ammonia plasma

concentration (before and 1 hour after a meal); adjust the dose in order to maintain normal ammonia

plasma levels.

Method of administration:

This medicine is for oral use ONLY (ingestion or via a nasogastric tube using a syringe, if necessary).

Based on pharmacokinetic data and clinical experience, it is recommended to divide the total daily dose into

two to four doses to be given before meals or feedings. The breaking of the tablets in halves allows most of

the required posology adjustments. Occasionally, the use of quarter tablets may also be useful to adjust the

posology prescribed by the physician.

The tablets must be dispersed in a minimum of 5-10 ml of water and ingested immediately or administered

by fast push through a syringe via a nasogastric tube.

The suspension has a slightly acidic taste.

4.3

Contraindications

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

Breast-feeding during the use of carglumic acid is contraindicated (see sections 4.6 and 5.3).

4.4

Special warnings and precautions for use

Therapeutic monitoring

Plasma levels of ammonia and amino acids should be maintained within normal limits.

As very few data on the safety of carglumic acid are available, systematic surveillance of liver, renal, cardiac

functions and haematological parameters is recommended.

Nutritional management

Protein restriction and arginine supplementation may be indicated in case of low protein tolerance.

This medicinal product contains up to 3 mg of sodium per tablet. This should be taken into consideration for

patients on a controlled sodium diet.

4.5

Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed.

4.6

Fertility, pregnancy and lactation

Pregnancy

For carglumic acid no clinical data on exposed pregnancies are available.

Animal studies have revealed minimal developmental toxicity (see section 5.3). Caution should be exercised

when prescribing to pregnant women.

Breast-feeding

Although it is not known whether carglumic acid is secreted into human milk, it has been shown to be

present in the milk of lactating rats (see section 5.3). Therefore, breast-feeding during the use of carglumic

acid is contraindicated. (see section 4.3).

Fertility

No human data on the effect of carglumic acid on fertility are available. In rats, no adverse effects have been

observed on male or female fertility with carglumic acid treatment (see section 5.3).

4.7

Effects on ability to drive and use machines

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

4.8

Undesirable effects

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are

defined as: very common (≥ 1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

- Undesirable effects in N-acetylglutamate synthase deficiency

Investigations

Uncommon

: increased transaminases

Skin and subcutaneous tissue disorders

Common

: increased sweating

Not known

: rash

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 <national reporting procedures, to be completed nationally>.

4.9

Overdose

In one patient treated with carglumic acid, where the dose was increased up to 750 mg/kg/day, symptoms of

intoxication occurred which can be characterised as a sympathomimetic reaction: tachycardia, profuse

sweating, increased bronchial secretion, increased body temperature and restlessness. These symptoms

resolved once the dose was reduced.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Amino acids and derivatives; ATC code: A16AA05

Mechanism of action

Carglumic acid is a structural analogue of N-acetylglutamate, which is the naturally occurring activator of

carbamoyl phosphate synthetase, the first enzyme of the urea cycle.

Carglumic acid has been shown in vitro to activate liver carbamoyl phosphate synthetase. Despite a lower

affinity of carbamoyl phosphate synthetase for carglumic acid than for N-acetylglutamate, carglumic acid

has been shown in vivo to stimulate carbamoyl phosphate synthetase and to be much more effective than N-

acetylglutamate in protecting against ammonia intoxication in rats. This could be explained by the following

observations:

i) The mitochondrial membrane is more readily permeable for carglumic acid than for N-acetylglutamate

ii) Carglumic acid is more resistant than N-acetylglutamate to hydrolysis by aminoacylase present in the

cytosol.

Pharmacodynamic effects

Other studies have been conducted in rats under different experimental conditions leading to increased

ammonia availability (starvation, protein-free or high-protein diet). Carglumic acid was shown to decrease

blood ammonia levels and increase urea levels in blood and urine, whereas the liver content of carbamoyl

phosphate synthetase activators was significantly increased.

Clinical efficacy and safety

In patients with N-acetylglutamate synthase deficiency, carglumic acid was shown to induce a rapid

normalisation of plasma ammonia levels, usually within 24 hours. When the treatment was instituted before

any permanent brain damage, patients exhibited normal growth and psychomotor development.

5.2

Pharmacokinetic properties

The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both radiolabelled

and unlabelled product.

Absorption

After a single oral dose of 100 mg/kg body weight, approximately 30% of carglumic acid is estimated to be

absorbed. At that dose-level, in 12 volunteers given carglumic acid 200 mg dispersible tablets, plasma

concentration peaked at 2.6 µg/ml (median; range 1.8-4.8) after 3 hours (median; range 2-4).

Distribution

The plasma elimination curve of carglumic acid is biphasic with a rapid phase over the first 12 hours after

administration followed by a slow phase (terminal half-life up to 28 hours).

Diffusion into erythrocytes is non-existent. Protein binding has not been determined.

Metabolism

A proportion of carglumic acid is metabolised. It is suggested that depending on its activity, the intestinal

bacterial flora may contribute to the initiation of the degradation process, thus leading to a variable extent of

metabolism of the molecule. One metabolite that has been identified in the faeces is glutamic acid.

Metabolites are detectable in plasma with a peak at 36-48 hours and a very slow decline (half-life around 100

hours).

The end product of carglumic acid metabolism is carbon dioxide, which is eliminated through the lungs.

Elimination

After a single oral dose of 100 mg/kg body weight, 9% of the dose is excreted unchanged in the urine and up

to 60% in the faeces.

Plasma levels of carglumic acid were measured in patients of all age categories, from newborn infants to

adolescents, treated with various daily doses (7 – 122 mg/kg/day). Their range was consistent with those

measured in healthy adults, even in newborn infants. Whatever the daily dose, they were slowly declining

over 15 hours to levels around 100 ng/ml.

5.3

Preclinical safety data

Safety pharmacology studies have shown that carglumic acid administered orally at doses of 250, 500, 1000

mg/kg had no statistically significant effect on respiration, central nervous system and cardiovascular system.

Carglumic acid showed no significant mutagenic activity in a battery of genotoxicity tests performed

in vitro

(Ames test, human lymphocyte metaphase analysis) and

in vivo

(micronucleus test in rat).

Single doses of carglumic acid up to 2800 mg/kg orally and 239 mg/kg intravenously did not induce any

mortality or abnormal clinical signs in adult rats. In newborn rats receiving daily carglumic acid by oral

gavage for 18 days as well as in young rats receiving daily carglumic acid for 26 weeks, the No Observed

Effect Level (NOEL) was established at 500 mg/kg/day and the No Observed Adverse Effect Level

(NOAEL) was established at 1000 mg/kg/day.

No adverse effects have been observed on male or female fertility. In rats and rabbits no evidence has been

seen of embryotoxicity, foetotoxicity or teratogenicity up to maternotoxic doses leading to fifty times

exposure as compared to humans in rats and seven times in rabbits. Carglumic acid is secreted in the milk of

lactating rats and although developmental parameters were unaffected, there were some effects on body

weight / body weight gain of pups breast-fed by dams treated with 500 mg/kg/day and a higher mortality of

pups from dams treated with 2000 mg/kg/day, a dose that caused maternotoxicity. The maternal systemic

exposures after 500 and 2000 mg/kg/day were twenty five times and seventy times the expected human

exposure.

No carcinogenicity study has been conducted with carglumic acid.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Microcrystalline cellulose

Croscarmellose sodium

Sodium laurilsulfate

Silica colloidal anhydrous

Sodium stearyl fumarate

6.2

Incompatibilities

Not applicable

6.3

Shelf life

2 years

After first opening of the tablet container: 1 month

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

After first opening of the tablet container: do not refrigerate or freeze.

Keep the container tightly closed in order to protect from moisture.

6.5

Nature and contents of container

5, 15 or 60 tablets in a high density polyethylene container with a child resistant polypropylene cap with a

liner and a desiccant unit.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements

7.

MARKETING AUTHORISATION HOLDER

Waymade B.V.,

Strawinskylaan 3127,

1077 ZX, Amsterdam,

Netherlands.

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2019-02-12

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