Trimbow 100/6/12.5

/ Kamada

Adults:
The recommended dose is two inhalations twice daily.
The maximum dose is two inhalations twice daily.
Patients should be advised to take this medicinal product every day even when asymptomatic.
If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be used for immediate relief.
Asthma: When choosing the starting dose strength of 100/6/12.5 micrograms, the patients’ disease severity, their previous asthma therapy including the inhaled corticosteroid (ICS) dose as well as the patients’ current control of asthma symptoms and risk of future exacerbation should be considered.
Stepping-down treatment: Patients should be regularly reassessed by a doctor, so that their doses of beclometasone/formoterol/glycopyrronium remain optimal and are only changed on medical advice. The doses should be titrated to the lowest doses at which effective control of asthma symptoms is maintained.
Special populations
Elderly:
No dose adjustment is required in elderly patients (65 years of age and older).
Renal impairment:
This medicinal product can be used at the recommended dose in patients with mild to moderate renal impairment. Use in patients with severe renal impairment or end-stage renal disease requiring dialysis, especially if associated with significant body weight reduction, should be considered only if the expected benefit outweighs the potential risk.
Hepatic impairment:
There are no relevant data on the use in patients with severe hepatic impairment and the medicinal product should be used with caution in these patients.
Paediatric population:
COPD
There is no relevant use of Trimbow 100/6/12.5 in the paediatric population (under 18 years of age) for the indication of COPD.
Asthma
This medicinal product is not indicated for children and adolescents under 18 years of age.

Chronic Obstructive Pulmonary Disease (COPD):
Maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting beta2-agonist or a combination of a long-acting beta2-agonist and a long-acting muscarinic antagonist.
Asthma:
Maintenance treatment of asthma, in adults not adequately controlled with a maintenance combination of a long-acting beta2-agonist and medium dose of inhaled corticosteroid, and who experienced one or more asthma exacerbations in the previous year.

Hypersensitivity to the active substances or to any of the excipients.

Not for acute use:
This medicinal product is not indicated for the treatment of acute episodes of bronchospasm, or to treat an acute disease exacerbation (i.e. as a rescue therapy).
Hypersensitivity:
Immediate hypersensitivity reactions have been reported after administration. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips and face), urticaria or skin rash, treatment should be discontinued immediately and alternative therapy instituted.
Paradoxical bronchospasm:
Paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator (reliever). Treatment should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Deterioration of disease:
It is recommended that treatment should not be stopped abruptly. If patients find the treatment ineffective, they should continue treatment but medical attention must be sought. Increasing use of reliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. Sudden or progressive deterioration in symptoms is potentially life-threatening and the patient should undergo urgent medical assessment.
Cardiovascular effects:
Due to the presence of a long-acting beta2-agonist and a long-acting muscarinic antagonist, this medicinal product should be used with caution in patients with cardiac arrhythmias, especially third degree atrioventricular block and tachyarrhythmias (accelerated and/or irregular heartbeat, including atrial fibrillation), idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, severe heart disease (particularly acute myocardial infarction, ischaemic heart disease, congestive heart failure), occlusive vascular diseases (particularly arteriosclerosis), arterial hypertension and aneurysm. Caution should also be exercised when treating patients with known or suspected prolongation of the QTc interval (QTc > 450 milliseconds for males, or > 470 milliseconds for females), either congenital or induced by medicinal products. Patients diagnosed with the described cardiovascular conditions were excluded from clinical studies with Trimbow. Limited data in asthmatic patients with cardiovascular co-morbidities or risk-factors suggest that these patients are also at higher risk of adverse reactions like local fungal infections or dysphonia.
If anaesthesia with halogenated anaesthetics is planned, it should be ensured that this medicinal product is not administered for at least 12 hours before the start of anaesthesia as there is a risk of cardiac arrhythmias.
Caution is also required when treating patients with thyrotoxicosis, diabetes mellitus, pheochromocytoma and untreated hypokalaemia.
See prescribing information for full details.
Pneumonia in patients with COPD:
An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.
See prescribing information for full details.
Systemic corticosteroid effects:
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. The daily dose of this medicinal product corresponds to a medium dose of inhaled corticosteroid; furthermore, these effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include: Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation, decrease in bone mineral density and, more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Therefore, it is important that the patient is reviewed regularly, and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.
This medicinal product should be administered with caution in patients with active or quiescent pulmonary tuberculosis and in patients with fungal and viral infections in the airways.
Hypokalaemia:
Potentially serious hypokalaemia may result from beta2-agonist therapy. This has the potential to produce adverse cardiovascular effects. Particular caution is advised in patients with severe disease as this effect may be potentiated by hypoxia. Hypokalaemia may also be potentiated by concomitant treatment with other medicinal products which can induce hypokalaemia, such as xanthine derivatives, steroids and diuretics.
Caution is also recommended when a number of reliever bronchodilators are used. It is recommended that serum potassium levels be monitored in such situations.
Hyperglycaemia:
The inhalation of formoterol may cause a rise in blood glucose levels. Therefore, blood glucose should be monitored during treatment following established guidelines in patients with diabetes.
Anticholinergic effect:
Glycopyrronium should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or urinary retention. Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop treatment and to contact their doctor immediately should any of these signs or symptoms develop.
Additionally, due to the anticholinergic effect of glycopyrronium, the long-term co-administration with other anticholinergic-containing medicinal products is not recommended.
Patients with severe renal impairment:
This medicinal product should only be used when the expected benefit outweighs the potential risk in patients with severe renal impairment, including those with end-stage renal disease requiring dialysis, especially if associated with a significant body weight reduction. These patients should be monitored for potential adverse reactions.
Patients with severe hepatic impairment:
This medicinal product should be used only if the expected benefit outweighs the potential risk. These patients should be monitored for potential adverse reactions.
Prevention of oropharyngeal infections:
In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse their mouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribed dose.
Visual disturbance:
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Stepping-down treatment:
Patients should be regularly reassessed by a doctor, so that their doses of beclometasone/formoterol/glycopyrronium remain optimal and are only changed on medical advice. The doses should be titrated to the lowest doses at which effective control of asthma symptoms is maintained.
Ethanol contents:
This medicinal product contains 8.856 mg of ethanol per actuation, which is equivalent to 17.712 mg per dose of two actuations. There is a theoretical potential for interaction in particularly sensitive patients taking disulfiram or metronidazole.

Common: Pneumonia (in COPD patients), pharyngitis, oral candidiasis, urinary tract infection, nasopharyngitis, headache , dysphonia.
See prescribing information for full details.

Pharmacokinetic interactions:
Since glycopyrronium is eliminated mainly by the renal route, interaction could potentially occur with medicinal products affecting renal excretion mechanisms. The effect of organic cation transport inhibition (using cimetidine as a probe inhibitor of OCT2 and MATE1 transporters) in the kidneys on inhaled glycopyrronium disposition showed a limited increase in its total systemic exposure (AUC_0-t) by 16% and a slight decrease in renal clearance by 20% due to co administration of cimetidine.
Beclometasone is less dependent on CYP3A metabolism than some other corticosteroids, and in general interactions are unlikely; however, the possibility of systemic effects with concomitant use of strong CYP3A inhibitors (e.g. ritonavir, cobicistat) cannot be excluded, and therefore caution and appropriate monitoring is advised with the use of such medicinal products.
Pharmacodynamic interactions:
Related to formoterol: Non-cardioselective beta-blockers (including eye drops) should be avoided in patients taking inhaled formoterol. If they are administered for compelling reasons, the effect of formoterol will be reduced or abolished.
Concomitant use of other beta-adrenergic medicinal products can have potentially additive effects; therefore, caution is required when other beta-adrenergic medicinal products are prescribed concomitantly with formoterol.
Concomitant treatment with quinidine, disopyramide, procainamide, antihistamines, monoamine oxidase inhibitors, tricyclic antidepressants and phenothiazines can prolong the QT interval and increase the risk of ventricular arrhythmias. In addition, L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2-sympathomimetics.
Concomitant treatment with monoamine oxidase inhibitors, including medicinal products with similar properties such as furazolidone and procarbazine, may precipitate hypertensive reactions.
There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.
Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate a possible hypokalaemic effect of beta2-agonists. Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.
Related to glycopyrronium: The long-term co-administration of this medicinal product with other anticholinergic-containing medicinal products has not been studied and is therefore not recommended.

There is no experience with or evidence of safety issues on the use of the propellant norflurane (HFA134a) during human pregnancy or lactation. However, studies on the effect of HFA134a on the reproductive function and embryofoetal development in animals revealed no clinically relevant adverse effects.
Pregnancy:
There are no or limited amount of data from the use in pregnant women.
Studies in animals have shown reproductive toxicity. Glucocorticoids are known to cause effects in the early gestation phase, while beta2-sympathomimetics like formoterol have tocolytic effects. Therefore, as a precautionary measure, it is preferable to avoid the use during pregnancy and during labour.
This medicinal product should only be used during pregnancy if the expected benefit to the patient outweighs the potential risk to the foetus. Infants and neonates born to mothers receiving substantial doses should be observed for adrenal suppression.
Breast-feeding:
There are no relevant clinical data on the use during breast-feeding in humans.
Glucocorticoids are excreted in human milk. It is reasonable to assume that beclometasone dipropionate and its metabolites are also excreted in human milk.
It is unknown whether formoterol or glycopyrronium (including their metabolites) are excreted in human milk but they have been detected in the milk of lactating animals. Anticholinergics like glycopyrronium could suppress lactation.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Trimbow therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility:
No specific studies have been performed with regard to the safety in human fertility. Animal studies have shown impairment of fertility.

An overdose may produce signs and symptoms due to the individual component’s pharmacological actions, including those seen with overdose of other beta2-agonists or anticholinergics and consistent with the known inhaled corticosteroid class effects. If overdose occurs, the patient’s symptoms should be treated supportively with appropriate monitoring as necessary.

Special precautions for storage
* Do not freeze.
* Do not expose to temperatures higher than 50°C.
* Do not pierce the pressurised container.
Prior to dispensing:
Store in a refrigerator (2°C-8°C).
After the dispensing:
Store at a temperature of up to 25°C for a maximum of 4 months.