This information is intended for use by health professionals

1. Name of the medicinal product

Respontin® Nebules®

2. Qualitative and quantitative composition

1ml or 2ml plastic ampoules containing 0.25mg/ml of Ipratropium Bromide Ph.Eur.

3. Pharmaceutical form

Oral inhalation solution via a nebuliser.

4. Clinical particulars
4.1 Therapeutic indications

Respontin Nebules are indicated for the treatment of reversible airways obstruction.

4.2 Posology and method of administration

The dosage should be adapted to the individual needs of the patient. In children aged 12 years and under, only 1ml ampoules should be used.

For inhalation use.

Adults (including the elderly) and children over 12 years of age

The recommended dose is 250-500 micrograms (i.e. one vial of 250 micrograms in 1 ml or 1 vial of 500 micrograms in 2 ml) 3 to 4 times daily.

For treatment of acute bronchospasm, 500mcg. Repeated doses can be administered until the patient is stable. The time interval between the doses may be determined by the physician.

It is advisable not to exceed the recommended daily dose during either acute or maintenance treatment. Daily doses exceeding 2 mg in adults and children over 12 years of age should only be given under medical supervision.

Paediatric population

Children 6-12 years of age

The recommended dose is 250 micrograms (i.e. one vial of 250 micrograms in 1 ml) up to a total daily dose of 1mg (4 vials).

The time interval between doses may be determined by the physician.

Children 0–5 years of age (for treatment of acute asthma only)

The recommended dose is 125-250 micrograms (i.e. half to one vial of 250 micrograms in 1 ml) up to a total daily dose of 1 mg (4 vials).

Ipratropium bromide should be administered no more frequently than 6 hourly in children under 5 years of age.

For acute bronchospasm, repeated doses may be administered until the patient is stable.

Respontin may be combined with a short-acting beta2-agonist in the same nebuliser chamber, for simultaneous administration where co-administration is required. The solution should be used as soon as possible after mixing and any unused solution should be discarded.

Respontin can be administered using a range of commercially available nebulising devices. The dose of nebuliser solution may need to be diluted in order to obtain a final volume suitable for the particular nebuliser being used (usually 2 – 4 ml); if dilution is necessary use only sterile sodium chloride 0.9% solution.

Respontin and disodium cromoglycate inhalation solutions that contain the preservative benzalkonium chloride should not be administered simultaneously in the same nebuliser as precipitation may occur.

Please refer to the patient information leaflet for instructions on use with a nebuliser.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Initial dosing

Use of the nebuliser solution should be subject to close medical supervision during initial dosing.

Immediate hypersensitivity reactions

Immediate hypersensitivity reactions following the use of ipratropium bromide have been demonstrated by cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

Use of anticholinergic agents

Caution is advocated in the use of anticholinergic agents in patients predisposed to or with narrow-angle glaucoma, or with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-outflow obstruction).

Patients with cystic fibrosis

As patients with cystic fibrosis may be prone to gastro-intestinal motility disturbances, ipratropium bromide, as with other anticholinergics, should be used with caution in these patients.

Ocular complications

There have been isolated reports of ocular complications (i.e. mydriasis, increased intra-ocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide, either alone or in combination with an adrenergic beta2-agonist, has come into contact with the eyes during nebuliser therapy.

Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.

Correct administration

Patients must be instructed in the correct administration of Respontin Nebules and warned not to allow the solution or mist to enter the eyes. It is recommended that the nebulised solution is administered via a mouthpiece. If this is not available and a nebuliser mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.

Bronchoconstriction

As with other inhalation therapy, inhalation induced bronchoconstriction may occur with an immediate increase in wheezing after dosing. This should be treated straight away with a fast acting inhaled bronchodilator. Ipratropium bromide should be discontinued immediately, the patient assessed and, if necessary, alternative treatment instituted (see section 4.8 – paradoxical bronchospasm).

Lack of efficacy

If therapy does not produce a significant improvement or if the patient's condition gets worse, medical advice must be sought. In the case of acute or rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.

4.5 Interaction with other medicinal products and other forms of interaction

Beta-adrenergic drugs and xanthine preparations

There is evidence that the administration of ipratropium bromide with beta-adrenergic drugs and xanthine preparations may produce an additive bronchodilatory effect.

Beta 2-agonists

The risk of acute glaucoma in patients with a history of narrow-angle glaucoma (see section 4.4) may be increased when nebulised ipratropium bromide and beta 2-agonists are administered simultaneously.

4.6 Fertility, pregnancy and lactation

Fertility

Clinical data on fertility are not available for ipratropium bromide. Preclinical studies performed with ipratropium bromide showed no adverse effect on fertility.

Pregnancy

The safety of ipratropium bromide during human pregnancy has not been established. The benefits of using ipratropium bromide during a confirmed or suspected pregnancy must be weighed against the possible hazards to the unborn child. Preclinical studies have shown no embryotoxic or teratogenic effects following inhalation or intranasal application at doses considerably higher than those recommended in man.

Breast-feeding

It is not known whether ipratropium bromide is excreted into breast milk. It is unlikely that ipratropium bromide would reach the infant to an important extent, however caution should be exercised when ipratopium bromide is administered to nursing mothers.

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. However, patients should be advised that they may experience undesirable effects such as dizziness, accommodation disorder, mydriasis and blurred vision during treatment with ipratropium bromide. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable effects

Many of the listed undesirable effects can be assigned to the anticholinergic properties of ipratropium bromide. As with all inhalation therapy ipratropium bromide may show symptoms of local irritation. Adverse drug reactions were identified from data obtained in clinical trials and pharmacovigilance during post approval use of the drug.

The most frequent side effects reported in clinical trials were headache, throat irritation, cough, dry mouth, gastro-intestinal motility disorders (including constipation, diarrhoea and vomiting), nausea, and dizziness.

The frequency of adverse reactions is defined using the following convention: 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) and not known (cannot be estimated from available data).

System Organ Class

Adverse Reaction

Frequency

Immune system disorders

hypersensitivity, anaphylactic reaction, angioedema of tongue, lips and face

uncommon

Nervous system disorders

headache, dizziness

common

Eye disorders

(see section 4.4)

blurred vision, mydriasis, intraocular pressure increased, glaucoma, eye pain, halo vision, conjunctival hyperaemia, corneal oedema

uncommon

accommodation disorder

rare

Cardiac disorders

palpitations, supraventricular tachycardia

uncommon

atrial fibrillation, heart rate increased

rare

Respiratory, thoracic and mediastinal disorders

throat irritation, cough

common

bronchospasm, paradoxical bronchospasm (see section 4.4), laryngospasm, pharyngeal oedema, dry throat

uncommon

Gastrointestinal disorders

dry mouth, nausea, gastro-intestinal motility disorder

common

diarrhoea, constipation, vomiting, stomatitis

uncommon

Skin and subcutaneous tissue disorders

rash, pruritus

uncommon

urticaria

rare

Renal and urinary disorders

urinary retention (the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction)

uncommon

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No symptoms specific to overdosage have been encountered. In view of the wide therapeutic window and topical administration of ipratropium bromide, no serious anticholinergic symptoms are to be expected.

Symptoms

As with other anticholinergics, dry mouth, visual accommodation disturbances and tachycardia would be the expected symptoms and signs of overdose.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anticholinergic drug

ATC code: R03BB01

Ipratropium bromide is an anticholinergic bronchodilator which affects airways function primarily through its neural effects on the parasympathetic nervous system. Ipratropium bromide blocks the acetylcholine receptors on smooth muscle in the lung. Stimulation of these receptors normally produces contraction and depending on the degree of activation, bronchoconstriction. Thus ipratropium bromide will cause bronchodilatation.

In clinical trials using metered dose inhalers in patients with reversible bronchospasm associated with chronic obstructive pulmonary disease significant improvements in pulmonary function (FEV1 increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for approximately 4 hours.

Preclinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.

The bronchodilator effect of ipratropium bromide in the treatment of acute bronchospasm associated with asthma has been shown in studies in adults and children over 6 years of age. In most of these studies ipratropium bromide was administered in combination with an inhaled beta2-agonist.

5.2 Pharmacokinetic properties

Absorption

Ipratoprium bromide is a quaternary ammonium compound which is poorly absorbed from the gastro-intestinal tract, and is slow to cross mucous membranes and the blood/brain barrier.

Distribution

Following, inhalation, uptake into the plasma is minimal, a peak blood concentration is obtained 1½ to 3 hours after inhalation.

Elimination

Excretion is chiefly via the kidneys.

5.3 Preclinical safety data

The toxicity of ipratropium bromide has been investigated extensively in the following types of studies: acute, subchronic and chronic toxicity, carcinogenicity, reproductive toxicity and mutagenicity via oral, intravenous, subcutaneous, intranasal and/or inhalation routes. Based on these toxicity studies, the probability of systemic anticholinergic side effects decreases in the following order:

intravenous > subcutaneous > oral > inhalation > intranasal.

Pre-clinically, ipratropium bromide was found to be well-tolerated. Two-year carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to approximately 1,200 times the maximum recommended human daily dose for intranasal ipratropium. Results of various mutagenicity tests were negative.

Studies to investigate the possible influence of ipratropium bromide on fertility, embryo fetotoxicity, and peri-/postnatal development have been performed on mice, rats and rabbits. High oral levels, i.e. 1000 mg/kg/day in the rat and 125 mg/kg/day in the rabbit were maternotoxic for both species and embryo-/fetotoxic in the rat, where the foetal weight was reduced. Treatment related malformations were not observed. The highest, technically feasible doses for inhalation of the metered dose aerosol, 1.5 mg/kg/day (human equivalent dose of 0.24 mg/kg/day) in rats and 1.8 mg/kg/day (human equivalent dose of 0.576 mg/kg/day) in rabbits, showed no adverse effects on reproduction.

These doses are 6- and 14-fold the maximum recommended human daily dose (MRHDD) of 2 mg or 0.04 mg/kg (based on a body weight of 50 kg).

6. Pharmaceutical particulars
6.1 List of excipients

Sodium Chloride

Diluted Phosphoric Acid

Purified Water

6.2 Incompatibilities

None stated.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store below 25°C. Protect from light.

This product contains no preservative. A new Nebule should be used for each dose. A Nebule should be opened immediately before administration and any remaining solution should be discarded. Any unused Nebules should be discarded four weeks after opening the foil pack.

6.5 Nature and contents of container

1 or 2 ml low density polyethylene ampoules in boxes of 20 in strips of 5 or 10.

6.6 Special precautions for disposal and other handling

The nebulised solution may be inhaled through a face mask, T-piece or via an endotracheal tube. Intermittent positive pressure ventilation (IPPV) may be used but is rarely necessary. When there is a risk of anoxia through hypoventilation, oxygen should be added to the inspired air.

As many nebulisers operate on a continuous flow basis, it is likely that some nebulised drug will be released into the local environment. Ipratropium bromide should therefore be administered in a well-ventilated room, particularly in hospitals where several patients may be using nebulisers at the same time. Do not allow the solution or mist to enter the eyes.

7. Marketing authorisation holder

Glaxo Wellcome UK Limited

Stockley Park West,

Uxbridge,

Middlesex,

UB11 1BT.

8. Marketing authorisation number(s)

PL10949/0275

9. Date of first authorisation/renewal of the authorisation

15th April 2003

10. Date of revision of the text

17th November 2015

11. Legal status

POM.