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Swedish Orphan Biovitrum Ltd

1 Fordham House Court, Fordham House Estate, Newmarket Road, Cambridgeshire, CB7 5LL
Telephone: +44 (0)1638 722 380
Fax: +44 (0) 1638 723 167
WWW: http://www.sobi.com
Medical Information Direct Line: + 44 (0) 1638 722 380
Medical Information e-mail: sobi@professionalinformation.co.uk
Customer Care direct line: +44 (0) 1638 722 380
Medical Information Facsimile: + 44 (0) 1638 723 167


Summary of Product Characteristics last updated on medicines.ie: 17/08/2010
SPC Zaditen Elixir 1mg/5ml Oral Solution



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1. NAME OF THE MEDICINAL PRODUCT

Zaditen 1mg/5ml Oral Solution


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of oral solution contains 1 mg ketotifen (as the hydrogen fumarate).

Excipients

Each 5 ml of oral solution contains 4,000 mg of maltitol liquid (hydrogenated glucose syrup), 1.665 mg of methyl parahydroxybenzoate (E218), 833 micrograms of propyl parahydroxybenzoate (E216) and 100 mg of ethanol (see section 4.4 Special warnings and precautions for use).

For the full list of excipients, see section 6.1 List of excipients.


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3. PHARMACEUTICAL FORM

Oral Solution.

Clear, colourless syrup with a strawberry odour.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Preventative treatment of bronchial asthma, especially when associated with atopic symptoms.

Symptomatic treatment of allergic conditions including rhinitis and conjunctivitis.


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4.2 Posology and method of administration

Oral administration.

Adults:

1 mg twice daily with food. If necessary the dose may be increased to 2 mg twice daily. Patients known to be easily sedated should begin treatment with 0.5 to 1 mg at night for the first few days.

Children:

2 to 3 years:

0.05 mg (=0.25 ml Zaditen Oral Solution 1mg/5ml) per kilogram body weight twice daily (morning and evening).

3 years and above:

1 mg twice daily with food.

Use in the elderly:

No evidence exists that elderly patients require different dosages or show different side effects from younger patients.


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4.3 Contraindications

Known hypersensitivity to ketotifen or any of the excipients (see section 6.1 List of excipients).


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4.4 Special warnings and precautions for use

Post-marketing surveillance has shown exacerbation of asthma in approximately 2 per 1,000 patients. Since some of these asthmatic attacks might have been related to stopping existing treatment, it is important to continue such treatment for a minimum of two weeks after starting Zaditen. This applies especially to systemic corticosteroids and ACTH because of the possible existence of adrenocortical insufficiency in steroid-dependent patients; in such cases recovery of a normal pituitary-adrenal response to stress may take up to one year.

If it is necessary to withdraw Zaditen this should be done progressively over a period of 2 to 4 weeks. Symptoms of asthma may recur.

If intercurrent infection occurs Zaditen treatment must be supplemented by specific antimicrobial therapy.

The oral solution contains maltitol liquid. Some patients with rare hereditary problems of fructose intolerance should not take this medicine.

As Zaditen may lower the seizure threshold it should be used with caution in patients with a history of epilepsy.

A reversible fall in the thrombocyte count in patients receiving Zaditen concomitantly with oral anti-diabetic agents has been observed in a few cases. This combination of drugs should therefore be avoided until this phenomenon has been satisfactorily explained.

This medicinal product contains 2 vol% ethanol (alcohol), i.e. up to 100mg per dose, equivalent to 2ml beer and 0.83 ml wine per dose. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

This medicinal product contains parahydroxybenzoates. It may cause allergic reactions (possibly delayed).


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4.5 Interaction with other medicinal products and other forms of interaction

Zaditen may potentiate the effects of sedatives, hypnotics, antihistamines and alcohol.


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4.6 Pregnancy and lactation

Pregnancy

Although there is no evidence of any teratogenic effect, recommendations for Zaditen in pregnancy cannot be given.

Lactation

Ketotifen is excreted in breast milk; therefore mothers receiving Zaditen should not breast-feed.


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4.7 Effects on ability to drive and use machines

During the first days of treatment with Zaditen reactions may be impaired. Patients should be warned not to take charge of vehicles or machinery until the effect of Zaditen treatment on the individual is known. Patients should be advised to avoid alcoholic drinks.


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4.8 Undesirable effects

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1

Infections and infestation

 

Uncommon:

cystitis

Immune system disorders

 

Very rare:

erythema multiforme, Stevens-Johnson syndrome, severe skin reaction

Metabolism and nutrition disorders

 

Rare:

weight increased

Psychiatric disorders

 

Common:

excitation, irritability, insomnia, nervousness

Nervous system disorders

 

Uncommon:

dizziness

 

Rare:

sedation

Gastrointestinal disorders

 

Uncommon:

Dry mouth

Hepatobiliary disorders

 

Very rare:

Hepatitis, increase in liver enzymes

Sedation, dry mouth and dizziness may occur at the beginning of treatment, but usually disappear spontaneously with continued medication. Symptoms of CNS stimulation have been observed. Weight gain has also been reported.


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4.9 Overdose

The reported features of overdosage include confusion, drowsiness, nystagmus, headache, disorientation, tachycardia, hypotension, reversible coma; especially in children, hyperexcitability or convulsions. Bradycardia and respiratory depression should be watched for. Elimination of the drug with gastric- lavage or emesis is recommended. Otherwise general supportive treatment is all that is required.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antihistamines for systemic use, ATC code: R06AX17

Zaditen is a non-bronchodilator, anti-asthmatic drug which inhibits the effect of certain endogenous substances known to be inflammatory mediators, and thereby exerts anti-allergic activity.

Laboratory experiments indicate that this anti-anaphylactic activity may be due to the inhibition of release of allergic mediators such as histamine and leukotrienes and the inhibition of the development of airway hyperactivity associated with activation of platelets by PAF (platelet activating factor) or caused by neural activation following the use of sympathomimetic drugs or the exposure to allergen. In addition, Zaditen exerts a non-competitive blocking effect on histamine (H1) receptors.

Experimental investigations in asthmatic subjects have shown that Zaditen is as effective orally as a selective mast cell stabiliser administered by inhalation: antihistamines are ineffective in these tests.

The effectiveness of Zaditen in the prevention of bronchial asthma has been studied in long-term clinical trials. Asthma attacks were reduced in number, severity and duration and in some cases the patients were completely freed from attacks. Progressive reduction of corticosteroids and/or bronchodilators was also possible.

The prophylactic activity of Zaditen may take several weeks to become fully established.

Zaditen will not abort established attacks of asthma.


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5.2 Pharmacokinetic properties

Absorption

After oral administration, the absorption of Zaditen is almost complete. Bioavailability amounts to approximately 50% owing to a first-pass effect of about 50% in the liver. Maximal plasma concentrations are reached within 2 to 4 hours.

Distribution

Protein binding is 75%.

Biotransformation

The main metabolite is ketotifen-N-glucuronide. This is practically inactive.

Elimination

Ketotifen is eliminated biphasically, with a short half-life of 3 of 5 hours and a longer one of 21 hours. About 1% of the substance is excreted unchanged in the urine within 48 hours and 60 to 70% is excreted as metabolites.

Effect of food

The bioavailability of Zaditen is not influenced by the intake of food.


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5.3 Preclinical safety data

Acute toxicity

Acute toxicity studies of ketotifen in mice, rats and rabbits revealed oral LD50 values above 300mg/kg bodyweight and between 5 and 20mg/kg by the i.v. route. Adverse effects induced by overdose were dyspnea and motor excitation followed by spasms and drowsiness. Toxic signs appeared rapidly and disappeared within hours; there was no evidence of cumulative or delayed effects. Other studies yielded an oral LD50 value of ketotifen in rats of 161mg/kg and demonstrated that the toxicity of Zaditen syrup (LD50 31.1mg/kg) was attributable to the sorbitol excipient alone. A total daily dose of 10 ml administered to a child of 30kg would be equivalent to 0.33ml/kg Zaditen syrup and 0.07mg/kg ketotifen base, indicating a sufficiently wide safety margin.

No evidence of skin sensitizing potential of ketotifen was obtained in guinea pigs by intracutaneous injection.

Mutagenicity

Ketotifen and/or its metabolites were devoid of genotoxic potential, when investigated in vitro for induction of gene mutation in Salmonella typhimurium, for chromosome aberrations in V79 Chinese hamster cells, or for primary DNA-damage in rat hepatocyte cultures. No clastogenic activity was observed in vivo (cytogenic analysis of bone marrow cells in the Chinese hamster, bone marrow micronucleus assay in mice). Likewise, no mutagenic effects were evident on the germ cells of male mice in the dominant lethal test.

Carcinogenicity

In rats treated continuously in the diet for 24 months, maximum tolerated doses of 71mg/kg ketotifen per day revealed no carcinogenic potential. No evidence of tumorigenic effects was obtained in mice treated with up to 88mg/kg body weight in the diet for 74 weeks.

Reproductive Toxicity

No embryotoxic or teratogenic potential of ketotifen was revealed in rats or rabbits. In male rats treated for 10 weeks (i.e. more than a complete spermatogenic cycle) before mating, fertility was unaffected at a tolerated dose of 10mg/kg per day.

The fertility of female rats as well as prenatal development, pregnancy and weaning of the offspring were not adversely affected by ketotifen treatment at oral dose levels of up to 50mg/kg per day, although non-specific toxicity to the pregnant females was observed at and above 10mg/kg. Likewise, no adverse effect of treatment was found in the peri-natal phase. Due to the maternal toxicity, some decrease in pup survival and weight gain was recorded during the first days of post-natal development at the high dose level of 50mg/kg per day.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Propyl parahydroxybenzoate (E216)

Methyl parahydroxybenzoate (E218)

Strawberry flavour liquid

Citric acid anhydrous (E330)

Disodium hydrogen phosphate (E450)

Ethanol

Liquid maltitol (hydrogenated glucose syrup)

Purified water


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

3 years.


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6.4 Special precautions for storage

Do not store above 25oC.


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6.5 Nature and contents of container

Brown glass bottles with a polyethylene closure (polyethylene wad faced with PP, PVDC or PET lining) containing 300ml.

Amber glass bottle with a child resistant, tamper evident closure composed of a polypropylene or polyethylene outer, a polypropylene or polyethylene inner with a wad faced with PP, PVDC or PET lining, containing 300ml.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

Defiante Farmacêutica, S.A.Rua dos Ferreiros, 2609000-082 Funchal, Portugal


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8. MARKETING AUTHORISATION NUMBER(S)

PA 1581/3/1


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30th November 1979/ 31st May 2009


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10. DATE OF REVISION OF THE TEXT

2009-11-27



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Active Ingredients

 
   Ketotifen hydrogen fumarate