For the prevention and treatment of dyspnoea in:

•           chronic obstructive pulmonary disease (COPD)

•           mild to moderate adult and childhood asthma, as an adjunct to ₂-agonists during acute asthma attacks.

For inhalation with a nebuliser.

Posology

The dosage should be adapted to the individual requirements of the patient.

The following dosages are recommended:

For acute treatment

Adults and adolescents > 12 years of age:

The single inhaled dose is 0.5 mg ipratropium bromide, equivalent to 1 vial. Repeated doses can be ad- ministered until the dyspnoea has improved; the time interval between the doses must be determined by the physician.

For maintenance treatment

Adults and adolescents > 12 years of age:

1 vial 3 - 4 times daily.

Note

Daily doses of more than 2 mg ipratropium bromide (4 vials) must be regularly reviewed by the phy- sician.

Important note

The patient should be medically monitored during treatment.

If the patient's condition fails to show a satisfactory improvement or deteriorates despite treatment, medical advice must be sought so that modifications to the treatment plan, including the addition of corticosteroids, ₂-agonists or theophylline if necessary, can be made. In the event of acute or rapidly worsening dyspnoea, the patient must be instructed to get medical help immediately.

Method of administration

The solution is ready to use and does not need to be diluted. It is intended only for inhalation with suit- able inhalation devices and must not be taken orally or administered parenterally.

The solution should ideally be administered with the patient in a sitting or standing position. For detai- led instructions on use, see section 6.6.

Hypersensitivity

Immediate hypersensitivity reactions may occur following the use of Atrovent UDVs 500 µg/2 ml, su- ch as rare cases of rash, urticaria, angioedema, oropharyngeal oedema, bronchospasm and anaphylaxis.

Paradoxical bronchospasm

As with other inhaled medications, Atrovent UDVs 500 µg/2 ml may cause paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, Atrovent UDVs 500 µg/2 ml must be discontinued immediately and replaced with an alternative therapy.

Special populations

Ocular complications

Care must be taken not to allow the solution or mist to enter into the eyes.

Atrovent UDVs 500 µg/2 ml should be used with caution in patients with a predisposition for narrow- angle glaucoma.

If the product accidentally comes into contact with the eyes during use, mild, reversible ocular comp- lications may occur. There is a risk of an acute glaucoma attack, particularly in patients with narrow- angle glaucoma; the characteristic symptoms are eye pain, blurred vision, visual halos or coloured images, red eyes and corneal oedema.

If mydriasis and mild accommodation disturbances occur, treatment with miotic drops may be given.

In the event of severe ocular complications, an ophthalmologist should also be consulted.

In these patients, a mouthpiece rather than a face mask should ideally be used for inhalation in order to prevent the product from getting into the eyes.

Effect on the kidneys and urinary tract

In patients with micturition disorders (such as in prostatic hypertrophy or bladder neck obstruction), the benefit of treatment with ipratropium bromide must be carefully weighed against the potential risk of aggravating urinary retention.

Gastrointestinal motility disorders

Patients with cystic fibrosis are more likely to develop gastrointestinal motility disorders.

Chronic use of inhaled Atrovent together with other anticholinergic drugs has not been studied and is therefore not recommended.

-Adrenergic agents and xanthine derivatives (such as theophylline) may enhance the therapeutic eff- ect.

Other anticholinergic medications, such as those containing pirenzepine, may increase both the thera- peutic and undesirable effects.

The risk of acute glaucoma in patients with a history of narrow-angle glaucoma may be increased when Atrovent UDVs 500 µg/2 ml and -mimetics are administered simultaneously.

Pregnancy and breast-feeding

There are no data from use in pregnant or breast-feeding women.

Although no teratogenic effects have been identified to date, Atrovent UDVs 500 µg/2 ml should not be used during pregnancy (especially the first trimester) or while breast-feeding unless considered ne- cessary by the treating physician after careful benefit/risk assessment.

The risks of inadequate treatment should be given due weight in this assessment

Fertility

Clinical data on fertility are not available for ipratropium bromide. Non-clinical studies performed with ipratropium bromide showed no adverse effect on fertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. However, pa- tients should be advised that undesirable effects such as dizziness, accommodation disturbances, my- driasis and blurred vision may occur during treatment with Atrovent UDVs 500 µg/2 ml. Caution is therefore required when driving or using machines.

Like all medicines, Atrovent UDVs 500 µg/2 ml can cause side effects.

a)                  Summary of the safety profile

Many of the undesirable effects listed can be attributed to the anticholinergic properties of Atrovent.

b)                  Tabulated summary of undesirable effects

The undesirable effects listed were identified from clinical trial data and postmarketing surveillance. Their frequency is defined using the following convention:

Immune system disorders

Uncommon:                                                           Anaphylactic reactions, hypersensitivity

Nervous system disorders

Common:                                                               Headache, dizziness

Eye disorders

Uncommon:                                                           Blurred vision, mydriasis, increased intraocular

pressure (sometimes with eye pain), halo or rain- bow vision, conjunctival hyperaemia and corneal

oedema, glaucoma

Rare:                                                                     Accommodation disturbances

Cardiac disorders

Uncommon:                                                           Palpitations, (supraventricular) tachycardia

Rare:                                                                     Atrial fibrillation

Respiratory, thoracic and mediastinal disorders

Common:                                                               Cough, throat irritation

Uncommon:                                                            (Paradoxical) bronchospasm, laryngospasm, phar-

yngeal oedema, dry throat

Gastrointestinal disorders

Common:                                                                Dry mouth, taste disturbance, gastrointestinal mo-

tility disorders, nausea

Uncommon:                                                         Constipation, diarrhoea, abdominal pain, vomiting, stomatitis, oral oedema

Skin and subcutaneous tissue disorders

Uncommon:                                                           Rash, pruritus, angioedema

Rare:                                                                      Urticaria

Renal and urinary disorders

Uncommon:                                                           Urinary retention

c)           Common undesirable effects

As with any other inhaled medication, Atrovent may also be associated with local irritation in the th- roat. The most common undesirable effects reported in clinical trials were headache, throat irritation, cough, dry mouth, gastrointestinal motility disorders (including constipation, diarrhoea and vomiting), nausea and dizziness.

Reporting of suspected adverse reactions

Reporting suspected adverse reaction after authorisation of the medicinal product is important. It all- ows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professi- onals are asked to report any suspected adverse reactions to the Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices), Abt. Pharmakovigilanz, Kurt- Georg-Kiesinger Allee 3, D-53175 Bonn (website: www.bfarm.de).

No specific signs of overdose have been encountered to date.

However, in view of the wide therapeutic window and the fact that the product is administered topical- ly, no serious anticholinergic symptoms are to be expected. Mild systemic anticholinergic side effects such as dry mouth, accommodation disturbances and increased heart rate may occur.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants / Anticholinergics ATC code: R03BB01

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In non-clinical studies, it inhibits vagally-mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of Ca⁺⁺ which is caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Ca⁺⁺ release is mediated by the second messenger system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).

The bronchodilation following inhalation of Atrovent (ipratropium) is primarily local and specific to the lung and is not systemic in nature.

Preclinical and clinical evidence suggests that Atrovent (ipratropium) has no adverse effect on airway mucus secretion, mucociliary clearance or gas exchange.

Clinical trials

In controlled 85 - 90-day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema), significant improvements in lung function occurred within 15 min. These improvements reached a peak in 1 - 2 hours and persisted for 4 - 6 hours.

The bronchodilator effect of Atrovent in the treatment of acute bronchospasm associated with asthma has been demonstrated in studies in adults. In most of these studies, Atrovent was administered in co- mbination with an inhaled ₂-agonist.

Absorption

The therapeutic effect of Atrovent is produced by a local action in the airways. Time courses of bron- chodilation and systemic pharmacokinetics do not run in parallel.

Following inhalation, 10 - 30% of a dose is generally deposited in the lungs, depending on the formu- lation and inhalation technique. The majority of the dose is swallowed and passes through the gastro- intestinal tract.

The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes).

Cumulative renal excretion (0 - 24 hours) of parent compound is approx. 46% of an intravenously ad- ministered dose, below 1% of an oral dose and approx. 3 - 13% of an inhaled dose. On the basis of th- ese data, the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estima- ted at 2% and 7 - 28% respectively.

Taking this into account, swallowed portions of ipratropium bromide doses do not contribute signific- antly to systemic exposure.

Distribution

Kinetic parameters describing the disposition of ipratropium were calculated from plasma concentra- tions after intravenous administration. A rapid biphasic decline in plasma concentrations was observ- ed. The apparent volume of distribution at steady state (Vd_ss) is approx. 176 l (equivalent to 2.4 l/kg). The drug is minimally (less than 20%) bound to plasma proteins. Non-clinical data indicate that the quaternary ammonium compound ipratropium does not cross the placenta or the blood-brain barrier.

Biotransformation

After intravenous administration, approx. 60% of the dose is metabolised, probably to a large extent by oxidation in the liver.

The known metabolites, which are formed by hydrolysis, dehydration or elimination of the hydroxymethyl group in the tropic acid moiety, bind poorly to the muscarinic receptor and must be regarded as ineffective.

Elimination

The terminal elimination half-life is approx. 1.6 hours.

Ipratropium has a total clearance of 2.3 l/min and a renal clearance of 0.9 l/min.

After inhalation of ipratropium bromide with HFA 134a as the propellant, cumulative renal excretion over 24 hours was approx. 12%.

In an excretion balance study, cumulative renal excretion (6 days) of drug-related radioactivity (incl- uding parent compound and all metabolites) was 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% af- ter intravenous administration, 88.5% after oral administration and 69.4% after inhalation. Drug-rela- ted radioactivity after intravenous administration is excreted mainly via the kidneys. The elimination half-life of drug-related radioactivity (parent compound and metabolites) is 3.6 hours.

Local and systemic tolerability of ipratropium bromide has been comprehensively investigated in sev- eral animal species using various administration routes.

Single-dose toxicity

Acute inhalational, oral and intravenous toxicity has been assessed in several rodent and non-rodent species.

When administered by inhalation, the minimum lethal dose in male guinea pigs was 199 mg/kg. In rats, no mortality was observed up to the highest technically feasible doses (0.05 mg/kg after 4 hours of administration or 160 puffs of ipratropium bromide at a dose of 0.02 mg/puff).

The oral LD₅₀ values for mice, rats and rabbits were 1585, 1925 and 1920 mg/kg respectively. The in- travenous LD₅₀ values for mice, rats and dogs were 13.6, 15.8 and approx. 18.2 mg/kg respectively. Clinical symptoms included mydriasis, dry oral mucosa, dyspnoea, tremor, spasms and/or tachycardia.

Repeated-dose toxicity

Repeated-dose toxicity studies have been performed in rats, rabbits, dogs and rhesus monkeys. In inhalation studies up to 6 months in rats, dogs and rhesus monkeys, the no observed adverse effect levels (NOAELs) were 0.38 mg/kg/day, 0.18 mg/kg/day and 0.8 mg/kg/day respectively. Dryness of the oral mucosa and tachycardia were noted in dogs. No histopathological lesions related to ipratro- pium bromide were observed in the bronchopulmonary system or in any other organs. In rats, the NOAEL after 18 months of oral administration was 0.5 mg/kg/day.

Repeated-dose inhalation toxicity studies in rats for up to 6 months and in dogs for up to 3 months wi- th other formulations (intranasal formulation, alternative propellant HFA 134a and lactose powder for- mulations) revealed no additional information on the general toxicity profile of ipratropium bromide.

Intranasal administration for up to 6 months revealed a no effect level (NOEL) of > 0.20 mg/kg/day in dogs and confirmed the results of earlier studies with intranasal administration for up to 13 weeks. Re- peated-dose toxicity studies of ipratropium bromide have shown the toxicological profiles of the HFA formulation and the conventional CFC formulation to be similar.

Local tolerability

An aqueous solution of ipratropium bromide (0.05 mg/kg) was locally well tolerated when administer- ed to rats by inhalation (single administration over 4 hours). In the repeated-dose toxicity study, ipratr- opium bromide was locally well tolerated.

Immunogenicity

Neither active anaphylaxis nor passive cutaneous anaphylactic reactions occurred in guinea pigs.

Genotoxicity and carcinogenicity

There was no evidence of genotoxicity in vitro (Ames test) or in vivo (micronucleus test, dominant le- thal test in mice, cytogenetic assay in Chinese hamster bone marrow cells).

No tumorigenic or carcinogenic effects were demonstrated in long-term studies in mice and rats.

Reproductive and developmental toxicity

Studies to investigate the possible influence of ipratropium bromide on fertility, embryo-/foetotoxicity and peri-/postnatal development have been performed in mice, rats and rabbits.

High oral doses (1000 mg/kg/day in rats and 125 mg/kg/day in rabbits) were maternotoxic for both sp- ecies and embryo-/foetotoxic in rats and resulted in lower foetal weight. Malformations related to ipra- tropium bromide were not observed. The highest technically feasible doses for inhalation of the meter- ed-dose aerosol (1.5 mg/kg/day in rats and 1.8 mg/kg/day in rabbits) had no adverse effects on repro- duction.

Sodium chloride, hydrochloric acid 3.6% (for pH adjustment), purified wate

Atrovent UDVs 500 µg/2 ml and disodium cromoglicate solutions should not be administered simul- taneously in the same nebuliser.

Store below 30 ºC. Keep vials in the original carton.

Clear, colourless nebuliser solution in a colourless, transparent PE unit-dose vial. The unit-dose vials are packed in 10s in hermetically sealed white aluminium pouches.

Pack sizes:

Original pack containing 50 unit-dose vials each holding 2 ml

The solution is ready to use and does not need to be diluted. It is intended only for inhalation with suitable inhalation devices and must not be taken orally or administered parenterally.

The solution should ideally be administered with the patient in a sitting or standing position.

Instructions for use

1.    Get the inhalation device (nebuliser) ready in accordance with the instructions provided by the manufacturer and your doctor.

2.    Separate one unit-dose vial from the strip (Fig. 1).

Fig. 1

3.    Open the vial by twisting off the top (Fig. 2).

Fig. 2

4.    Squeeze all the contents of the vial into the nebuliser chamber (Fig. 3).

Fig. 3

5.    Assemble the nebuliser and use as directed.

6.    After use, dispose of any solution remaining in the nebuliser chamber and then clean the nebuliser, following the manufacturer's instructions.

Patients must be instructed in the correct use of Atrovent UDVs 500 µg/2 ml.

Care must be taken not to allow the solution or mist to enter the eyes. The nebulised solution should be administered via a mouthpiece. If a mouthpiece is not available and a nebuliser mask is used, care mu- st be taken to ensure that it fits properly. Patients who are predisposed to glaucoma should take partic- ular care to ensure their eyes are protected during inhalation.

As the solution contains no preservatives, the contents of the vial must be inhaled immediately after opening. Any solution left in the vial should be discarded.

A fresh vial should be used for each dose. Partly-used, damaged or accidentally opened vials must be discarded.

Atrovent UDVs 500 µg/2 ml can be administered using a range of commercially available nebulisers. Where wall oxygen is available, the solution is best administered at a flow rate of 6 - 8 l/min.

Atrovent UDVs 500 µg/2 ml are suitable for concurrent inhalation with ambroxol (e.g. as contained in Mucosolvan^® solution for inhalation).