Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: TEVA UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, UNITED KINGDOM
Hypersensitivity to the active substance tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium, or to any of the excipients listed in section 6.1, including lactose monohydrate which contains milk protein.
Tiotropium bromide, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy.
Immediate hypersensitivity reactions may occur after administration of tiotropium bromide inhalation powder.
Consistent with its anticholinergic activity, tiotropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. (see section 4.8).
As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Braltus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Tiotropium should be used with caution in patients with recent myocardial infarction <6 months; any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation for heart failure (NYHA Class III or IV) within the past year. These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.
As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance ≤50 ml/min), tiotropium bromide should be used only if the expected benefit outweighs the potential risk.There is no long term experience in patients with severe renal impairment (see section 5.2).
Patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these eye symptoms develop, patients should stop using tiotropium bromide and consult a specialist immediately.
Dry mouth, which has been observed with anti-cholinergic treatment, may in the long term be associated with dental caries.
Tiotropium bromide should not be used more frequently than once daily (see section 4.9).
Each capsule contains 18 mg lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. The excipient lactose may contain trace amounts of milk proteins which may cause reactions in those with severe hypersensitivity or allergy to milk protein.
Although no formal drug interaction studies have been performed, tiotropium bromide inhalation powder has been used concomitantly with other drugs without clinical evidence of drug interactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, commonly used in the treatment of COPD.
Use of long-acting β2 agonists (LABA) or inhaled corticosteroids (ICS) was not found to alter the exposure to tiotropium.
The co-administration of tiotropium bromide with other anticholinergic drugs has not been studied and is therefore not recommended.
Clinical data on fertility are not available for tiotropium. A non-clinical study performed with tiotropium showed no indication of any adverse effect on fertility (see section 5.3).
There is a very limited amount of data from the use of tiotropium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (see 5.3). As a precautionary measure, it is preferable to avoid the use of Braltus during pregnancy.
It is unknown whether tiotropium bromide is excreted in human breast milk. Despite studies in rodents which have demonstrated that excretion of tiotropium bromide in breast milk occurs only in small amounts, use of tiotropium bromide is not recommended during breast-feeding. Tiotropium bromide is a long-acting compound. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Braltus should be made taking into account the benefit of breast-feeding to the child and the benefit of Braltus therapy to the woman.
No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness, blurred vision, or headache may influence the ability to drive and use machinery.
Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide.
The frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (9,647 patients) from 28 pooled placebo-controlled clinical trials with treatment periods ranging from four weeks to four years.
Frequency 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), not known (cannot be estimated from the available data).
| System Organ Class/MedDRA Preferred Term | Frequency |
|---|---|
| Metabolism and nutrition disorders | |
| Dehydration | Not known |
| Nervous system disorders | |
| Dizziness Headache Taste disorders Insomnia | Uncommon Uncommon Uncommon Rare |
| Eye disorders | |
| Vision blurred Glaucoma Intraocular pressure increased | Uncommon Rare Rare |
| Cardiac disorders | |
| Atrial fibrillation Supraventricular tachycardia Tachycardia Palpitations | Uncommon Rare Rare Rare |
| Respiratory, thoracic and mediastinal disorders | |
| Pharyngitis Dysphonia Cough Bronchospasm Epistaxis Laryngitis Sinusitis | Uncommon Uncommon Uncommon Rare are Rare Rare |
| Gastrointestinal disorders | |
| Dry mouth Gastro-oesophageal reflux disease Constipation Oropharyngeal candidiasis Intestinal obstruction, including ileus paralytic Gingivitis Glossitis Dysphagia Stomatitis Nausea Dental caries | Common Uncommon Uncommon Uncommon Rare Rare Rare Rare Rare Rare Not known |
| Skin and subcutaneous tissue disorders, immune system disorders | |
| Rash Urticaria Pruritus Hypersensitivity (including immediate reactions) Angioedema Anaphylactic reaction Skin infection, skin ulcer Dry skin | Uncommon Rare Rare Rare Rare Not known Not known Not known |
| Musculoskeletal and connective tissue disorders | |
| Joint swelling | Not known |
| Renal and urinary disorders | |
| Dysuria Urinary retention Urinary tract infection | Uncommon Uncommon Rare |
The excipient lactose may contain trace amounts of milk proteins which may cause reactions in those with severe hypersensitivity or allergy to milk protein.
Tiotropium bromide should be discontinued immediately if a hypersensitivity or allergic reaction occurs and the patient should then be managed in the usual way.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Braltus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
In controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 4% of patients.
In 28 clinical trials, dry mouth led to discontinuation in 18 of 9,647 tiotropium treated patients (0.2%).
Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation and intestinal obstruction including ileus paralytic as well as urinary retention.
An increase in anticholinergic effects may occur with increasing age.
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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