Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
History of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium.
Spiolto Respimat should not be used in asthma. The efficacy and safety of Spiolto Respimat in asthma have not been studied.
Spiolto Respimat is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy.
As with other inhaled medicines Spiolto Respimat may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs Spiolto Respimat should be discontinued immediately and alternative therapy substituted.
Consistent with the anticholinergic activity of tiotropium, Spiolto Respimat should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.
Patients should be cautioned to avoid getting the spray 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 Spiolto Respimat 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.
As plasma concentration of tiotropium increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance ≤50 ml/min) Spiolto Respimat 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 5.2).
The experience with Spiolto Respimat is limited in patients with a history of myocardial infarction during the previous year, unstable or life-threatening cardiac arrhythmia, hospitalized for heart failure during the previous year or with a diagnosis of paroxysmal tachycardia (>100 beats per minute) because these patients were excluded from the clinical trials. Spiolto Respimat should be used with caution in these patient groups.
Like other beta2-adrenergic agonists, olodaterol may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave and ST segment depression, although the clinical significance of these observations is unknown.
Long acting beta2-adrenergic agonists should be administered with caution in patients with cardiovascular disorders, especially ischaemic heart disease, severe cardiac decompensation, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, hypertension, and aneurysm, in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval (e.g. QT >0.44 s), and in patients who are unusually responsive to sympathomimetic amines.
Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see section 4.5), which may increase the susceptibility to cardiac arrhythmias.
Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.
Caution needs to be taken in case of a planned operation with halogenated hydrocarbon anaesthetics due to an increased susceptibility to the adverse cardiac effects of beta agonist bronchodilators.
Spiolto Respimat should not be used in conjunction with any other medications containing long-acting beta2-adrenergic agonists.
Patients who have been taking inhaled, short-acting beta2-adrenergic agonists on a regular basis (e.g. four times a day) should be instructed to use them only for symptomatic relief of acute respiratory symptoms.
Spiolto Respimat should not be used more frequently than once daily.
As with all medications, immediate hypersensitivity reactions may occur after administration of Spiolto Respimat.
Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at an increased risk for these adverse events.
Although no formal in vivo drug interaction studies have been performed between Spiolto Respimat and other drugs, inhaled Spiolto Respimat has been used concomitantly with other COPD medicinal products, including short acting sympathomimetic bronchodilators and inhaled corticosteroids without clinical evidence of drug interactions.
The co-administration of tiotropium bromide, one component of Spiolto Respimat, with other anticholinergic containing drugs has not been studied and therefore is not recommended.
Concomitant administration of other adrenergic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Spiolto Respimat.
Concomitant treatment with xanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate any hypokalemic effect of adrenergic agonists (see section 4.4).
Beta-adrenergic blockers may weaken or antagonise the effect of olodaterol. Cardioselective beta-blockers could be considered, although they should be administered with caution.
Monamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval may potentiate the action of Spiolto Respimat on the cardiovascular system.
No relevant effect on systemic exposure to olodaterol has been observed in drug-drug interaction studies with coadministration of fluconazole, used as model inhibitor of CYP2C9.
Co-administration of ketoconazole as potent P-gp and CYP3A4 inhibitor increased systemic exposure to olodaterol by approximately 70%. No dose adjustment of Spiolto Respimat is necessary.
In vitro investigations have shown that olodat
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).
For olodaterol no clinical data on exposed pregnancies are available. Preclinical data for olodaterol revealed effects typical for beta-adrenergic agonists at high multiples of the therapeutic doses (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Spiolto Respimat during pregnancy.
Like other beta2-adrenergic agonists, olodaterol a component of Spiolto Respimat may inhibit labour due to a relaxant effect on uterine smooth muscle.
Clinical data from nursing women exposed to tiotropium and/or olodaterol are not available.
In animal studies for both tiotropium and olodaterol the substances and/or their metabolites have been detected in the milk of lactating rats, but it is not known whether tiotropium and/or olodaterol passes into human breast milk.
A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Spiolto Respimat should be made taking into account the benefit of breast-feeding to the child and the benefit of Spiolto Respimat therapy to the woman.
Clinical data on fertility are not available for tiotropium and olodaterol or the combination of both components. Preclinical studies performed with the individual components tiotropium and olodaterol showed no indication of any adverse effect on fertility (see 5.3).
No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that dizziness and blurred vision have been reported with the use of Spiolto Respimat. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience such symptoms, they should avoid potentially hazardous tasks such as driving or operating machinery.
Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide or to the β2-adrenergic properties of olodaterol, the components of Spiolto Respimat.
The frequencies assigned to the undesirable effects listed below are based on the crude incidence rates of adverse drug reactions (i.e. events attributed to Spiolto Respimat) observed in the tiotropium 5 microgram/olodaterol 5 microgram dose group (5646 patients), pooled from 8 active or placebo-controlled, parallel group clinical trials in COPD patients with treatment periods ranging between 4 and 52 weeks.
Adverse reactions reported in all clinical trials with Spiolto Respimat are shown below according to system organ class.
These also include all adverse reactions previously reported with one of the individual components.
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 | Adverse reaction | Frequency |
|---|---|---|
| Infections and infestations | Nasopharyngitis | not known |
| Metabolism and nutrition disorders | Dehydration | not known |
| Nervous system disorders | Dizziness | uncommon |
| Insomnia | rare | |
| Headache | uncommon | |
| Eye disorders | Vision blurred | rare |
| Glaucoma | not known | |
| Intraocular pressure increased | not known | |
| Cardiac disorders | Atrial fibrillation | rare |
| Tachycardia | uncommon | |
| Palpitations | rare | |
| Supraventricular tachycardia | rare | |
| Vascular disorders | Hypertension | rare |
| Respiratory, thoracic and mediastinal disorders | Cough | uncommon |
| Dysphonia | uncommon | |
| Laryngitis | rare | |
| Pharyngitis | rare | |
| Epistaxis | rare | |
| Bronchospasm | rare | |
| Sinusitis | not known | |
| Gastrointestinal disorders | Dry mouth | uncommon |
| Constipation | rare | |
| Oropharyngeal candidiasis | rare | |
| Gingivitis | rare | |
| Nausea | rare | |
| Intestinal obstruction Ileus paralytic | not known | |
| Dysphagia | not known | |
| Gastrooesophageal reflux disease | not known | |
| Glossitis | not known | |
| Stomatitis | rare | |
| Dental caries | not known | |
| Skin and subcutaneous tissue disorders, Immune system disorders | Hypersensitivity | rare |
| Angioedema | rare | |
| Urticaria | rare | |
| Pruritus | rare | |
| Anaphylactic reaction | not known | |
| Rash | rare | |
| Skin infection and skin ulcer | not known | |
| Dry skin | not known | |
| Musculoskeletal and connective tissue disorders | Arthralgia | rare |
| Back pain1 | rare | |
| Joint swelling | rare | |
| Renal and urinary disorders | Urinary retention | rare |
| Urinary tract infection | rare | |
| Dysuria | rare |
1 undesirable effects reported with Spiolto Respimat, but not with the individual components
Spiolto Respimat combines anticholinergic and β2-adrenergic properties due to its components tiotropium and olodaterol.
In the long term 52-weeks clinical trials with Spiolto Respimat, the most frequently observed undesirable anticholinergic effect was dry mouth which occurred in approximately 1.3% of patients treated with Spiolto Respimat and in 1.7% and 1% in the tiotropium 5 microgram and olodaterol 5 microgram arms, respectively. Dry mouth led to discontinuation in 2 of 4,968 patients (0.04%) treated with Spiolto Respimat.
Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention.
Olodaterol, one component of Spiolto Respimat is a member of the therapeutic class of long-acting beta2-adrenergic agonists. Therefore the occurrence of other undesirable effects related to the beta-adrenergic agonist class, which are not listed above, should be taken into consideration, such as, arrhythmia, myocardial ischaemia, angina pectoris, hypotension, tremor, nervousness, muscle spasms, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis.
An increase in anticholinergic effect 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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