TREBON 600 MG POWDER FOR ORAL SOLUTION - summary of medicine characteristics

Trebon 600 mg powder for oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet with powder used for the preparation of oral solution contains 600 mg of acetylcysteine.

Excipients with known effect

Each sachet contains 2,167.9 mg sorbitol and 9.5 mg sucrose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral solution

White powder with lemon flavour.

4.1 Therapeutic indications

Trebon is indicated in adults as a mucolytic therapy in chronic bronchitis and other respiratory conditions associated with thick mucus hypersecretion.

4.2 Posology and method of administration

Posology

In general the usual recommended dosage is: 600mg once daily

The dosage may be increased according to the instructions of the treating doctor based on the assessment of treatment outcomes.

Duration of treatment

The duration of therapy is dependent on the nature and severity of the illness, and should be decided by the doctor.

Paediatric population

Children older than 2 years of age and adolescents

The safety and efficacy of Trebon is not established in children aged 2 years and older and adolescents (see section 4.4). Other products with lower strengths of acetylcysteine are more suitable for this age group.

Children under 2 years of age

Trebon is contraindicated in children aged under 2 years (see section 4.3).

Elderly

Limited data in patients over 65 years of age is available.

Renal and hepatic impairment

In patients with renal or hepatic impairment there is insufficient data on whether dosage adjustments are required. Renal and hepatic impairment can reduce clearance and increase acetylcysteine plasma levels which may result in an increase in adverse drug reactions due to drug accumulation (see section 5.2).

Method of administration

Dissolve the content of one sachet in half a glass of water. This produces a solution that

should be consumed immediately.

4.3 Contraindications

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

The product should not be used in children under 2 years of age.

4.4 Special warnings and precautions for use

Serious skin reactions have been reported whilst taking acetylcysteine, but these occur rarely. For this reason, medical advice should be sought immediately and the patient should stop taking acetylcysteine in the event of new-onset changes to the skin and mucous membranes. See also section 4.8.

This product should be used with caution by patients with a history of peptic ulcer disease.

Acetylcysteine can, especially at the start of treatment, cause thinning and increased volume of bronchial secretions. If the patient is not able to expectorate this adequately, appropriate supportive measures should be implemented (such as postural drainage and suction removal).

The medicine should be administered with caution to asthmatic patients, due to the risk of bronchospasm. In the event of bronchospasm the drug should be discontinued immediately.

This product should be used with caution by patients with histamine intolerance. They should avoid long-term therapy because Acetylcysteine affects the metabolism of histamine and can lead to symptoms of intolerance (e.g. headaches, rhinitis, itching).

Renal and hepatic impairment

In patients with renal or hepatic impairment there is insufficient data on whether dosage adjustments are required. Renal and hepatic impairment can reduce clearance and increase acetylcysteine plasma levels which may result in an increase in adverse drug reactions due to drug accumulation (see section 5.2).

There is no evidence of the efficacy of acetylcysteine in the management of cystic fibrosis.

Pediatric population

Mucolytic drugs may obstruct the airways of children under 2 years of age, due to the physiological characteristics of the airways in this age group. The ability to cough up mucus may be limited. Therefore, the product must not be used in children under 2 years of age.

The safety and efficacy of Trebon is not established in children aged 2 years and older and adolescents, due to the high content of acetylcysteine in this medicinal product. Other products with lower strengths of acetylcysteine are more suitable for this age group.

Sorbitol

This medicinal product contains 2,167.9 mg sorbitol in each sachet. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

Sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. May be harmful to the teeth.

Sodium

This medicinal product contains less than 1 mmol sodium per sachet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Antibiotics

In vitro experiments report an inactivation of certain antibiotics (tetracyclines, aminoglycosides, fluoroquinolones, carbapenem, cephalosporins, penicillins) due to acetylcysteine when the substances were directly mixed. Therefore, antibiotics should be administered separately and at an interval of at least 2 hours.

Antitussives

Combined use of antitussives (cough-relieving agents) with acetylcysteine may cause dangerous secretory congestion due to the reduced cough reflex. Nitroglycerin

Administration of Trebon may lead to an increase in the vasodilatory and antiplatelet effect of glyceryl trinitrate. If the drugs are administered together the patient should be monitored for a hypotensive response.

Activated charcoal

Co-administration with activated charcoal can reduce the effectiveness of acetylcysteine.

Laboratory tests

Acetylcysteine may affect the recovery of salicylates in the colourimetric assay and also may give false-positive ketone bodies results in urinalysis (a biochemical parameter of the general urine test that is determined along with glucose in diabetic patients). This should be taken into account in patients having any blood or urine test, while taking acetylcysteine.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of acetylcysteine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Trebon is not recommended during pregnancy.

Breast-feeding

It is unknown whether acetylcysteine /metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Trebon therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no human data from the use of acetylcysteine in fertility.

4.7 Effects on ability to drive and use machines

Acetylcysteine has no influence on the ability to drive and use machines.

4.8 Undesirable effects

In the evaluation of side effects following frequencies are defined as:

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 the available data).

Immune system disorders

Uncommon: Hypersensitivity

Very rare: Anaphylactic shock, anaphylactic/a­naphylactoid reaction Nervous system disorders

Uncommon: Headache

Ear and labyrinth disorders

Uncommon: Tinnitus

Cardiac disorders

Uncommon: Tachycardia

Vascular disorders

Uncommon: Hypotension

Very rare: Haemorrhage

Respiratory, thoracic and mediastinal disorders

Rare: Bronchospasm, dyspnoea

Gastrointestinal disorders

Uncommon: Vomiting, diarrhoea, stomatitis, abdominal pain, nausea Rare: Dyspepsia

Skin and subcutaneous tissue disorders

Uncommon: Urticaria, rash, angioedema, pruritus

General disorders and administration site conditions

Uncommon: Fever

Not known: Oedema

Acetylcysteine may have an undesirable effect on the gastric mucosa in patients with a history of peptic ulcer.

Serious skin reactions have been reported whilst taking acetylcysteine, but these occur rarely. For this reason, in the event of new onset changes of the skin and mucous membranes medical advice should be sought immediately and the patient should stop taking acetylcysteine.

A reduction of blood platelet aggregation in the presence of acetylcysteine has been confirmed by various studies. The clinical relevance is not yet understood.

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 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

There have been no cases of toxic overdose observed with orally-dosed acetylcysteine. Oral doses of up to 500mg/kg of acetylcysteine were tolerated without toxic effects.

a) Symptoms of intoxication

The following symptoms have been reported after overdoses of intravenous acetylcysteine: anaphylactoid reaction, bronchospasm and gastro-intestinal symptoms such as nausea, vomiting and diarrhoea. Oral overdose may lead to gastrointestinal adverse effects, such as nausea, vomiting and diarrhoea.

b) Treatment for overdose

Treatment of overdose is to be symptomatic and supportive treatment as indicated by the patient's clinical condition.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Mucolytics ATC code: R05 CB01

Mechanism of action

The mechanisms of action of NAC in these respiratory indications include mucolytic effects.

The mucolytic action is mediated by a reduction in the viscosity of bronchial mucus. This is explained by the depolymerisation with the disulfide bridges between the macromolecules in the mucus being opened.

5.2 Pharmacokinetic properties

Absorption

After oral administration acetylcysteine is rapidly and almost completely absorbed.

The oral bioavailability of acetylcysteine is very low (between 6 and 10%) due to high first pass effect. In humans maximum plasma concentration is reached in 1 to 3 hours after an oral dose.

Distribution

Approximately 50% of acetylcysteine is protein bound after oral administration.

There is no information available on the behaviour of acetylcysteine at the blood-brain barrier in humans.

Biotransformation

Acetylcysteine is metabolized by rapid hepatic biotransformation. The metabolites occur in three different forms: in free form into cysteine the active metabolite, bound to protein via labile disulfide bonds and as integral amino acids into diacetylcystine and cystine.

Elimination

Excretion of inactive metabolites (inorganic sulfates, diacetylcystine) is via the kidneys. The elimination half-life after oral administration is 6.25 hours.

Hepatic and Renal impairment

There is evidence that clearance of acetylcysteine can be significantly reduced up to 90 % in the subjects with end-stage renal disease. This could result in a dramatically longer half-life and a marked increase in systemic exposure to acetylcysteine in patients with end-stage renal disease. It is not known to what extent the results can be extrapolated to the less severe forms of renal impairment that are more likely to be encountered during routine use of the proposed product.

Restricted liver function causes the plasma half-life to increase up to 8 hours, based in one study of patients with chronic liver disease. The total clearance of acetylcysteine was found to be significantly reduced following an intravenous dose of 600 mg over three minutes in nine subjects with hepatic cirrhosis. See also section 4.2.

Elderly

Limited data in patients over 65 years of age is available.

5.3 Preclinical safety data

Reproductive toxicology

No evidence of teratogenicity was identified in non-standard embryo toxicity studies in rabbits and rats.

Acetylcysteine crosses the placenta in rats and can be detected in amniotic fluid.

There are no non-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid (E330)

Lemon juice flavour in powder (contains: natural flavouring substances, maltodextrin (maize), modified starch (E1450) (waxy maize), sucrose) Saccharin sodium (E954)

Macrogol (E1521)

Sorbitol (E420)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

After preparation, the solution should be used immediately.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Sachets consisting of paper, aluminum foil, and polyethylene.

Pack size: 10, 20 or 30 sachets.

Not all pack sizes may be marketed.