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.
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.
As a precautionary measure, it is preferable to avoid the use of tiotropium/olodaterol during pregnancy.
Like other beta2-adrenergic agonists, olodaterol a component of tiotropium/olodaterol 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 tiotropium/olodaterol should be made taking into account the benefit of breast-feeding to the child and the benefit of tiotropium/olodaterol 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.
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 tiotropium/olodaterol. 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 frequencies assigned to the undesirable effects listed below are based on the crude incidence rates of adverse drug reactions 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 tiotropium/olodaterol 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 tiotropium/olodaterol, but not with the individual components
Tiotropium/olodaterol combines anticholinergic and β2-adrenergic properties due to its components tiotropium and olodaterol.
In the long term 52-weeks clinical trials with tiotropium/olodaterol combination, the most frequently observed undesirable anticholinergic effect was dry mouth which occurred in approximately 1.3% of patients treated with tiotropium/olodaterol 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 tiotropium/olodaterol.
Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention.
Olodaterol 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.
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