Source: Health Products and Food Branch (CA) Revision Year: 2021
ZENHALE is contraindicated in:
ZENHALE should not be used to treat acute symptoms of asthma. Adequate education should be provided to the patient regarding the use of long-acting beta2-agonists and the acute treatment of asthma, with close-follow up to ensure compliance (see Respiratory).
Discontinuance: Treatment with inhaled corticosteroids should not be stopped abruptly in patients with asthma due to risk of exacerbation. In this case, therapy should be titrated down gradually, under physician supervision.
Particular care is needed for patients who are transferred from systemically active corticosteroids to ZENHALE, because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) axis function.
During periods of stress, including trauma, surgery, or infection, or a severe asthma attack, patients transferred from systemic corticosteroids will require supplementary treatment with a short course of systemic corticosteroids, which is gradually tapered as symptoms subside. It is recommended that such patients carry a supply of oral corticosteroids and a warning card indicating their need and recommended dosage of systemic corticosteroids during stressful periods. Periodic testing of adrenocortical function, particularly measurement of early morning plasma cortisol levels, is recommended.
Transfer of patients from systemic corticosteroid therapy to ZENHALE may unmask pre-existing allergic conditions previously suppressed by systemic corticosteroid therapy. If this occurs, symptomatic treatment is recommended.
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression (see Endocrine and Metabolism), growth retardation in children and adolescents, decrease in bone mineral density, cataracts and glaucoma (see Ophthalmologic). Therefore, it is important that the dose of ZENHALE is titrated to the lowest dose at which effective control of asthma is maintained.
Use of LABA as monotherapy (without ICS) for asthma has been associated with an increased risk of asthma-related death (see Salmeterol Multicenter Asthma Research Trial (SMART)). Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy.
When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations , intubations, death) compared with ICS alone (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting beta2-adrenergic Agonist Combination Products).
Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasone propionate/salmeterol with fluticasone propionate, and 1 trial compared mometasone furoate/formoterol with mometasone furoate (see CLINICAL TRIALS). The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol with fluticasone propionate. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A single, blinded, independent, joint adjudication committee determined whether events were asthma related.
The 3 adult and adolescent trials were designed to rule out a 2.0-fold increase in relative risk for ICS/LABA compared with ICS, and the pediatric trial was designed to rule out a 2.7-fold increase in this relative risk. Each individual trial met its pre-specified objective and demonstrated noninferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.
Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older:
| ICS/LABA (n=17,537)a | ICS (n=17,552)a | ICS/LABA vs. ICS Hazard Ratio (95% CI)b | |
|---|---|---|---|
| Serious asthma-related eventc | 116 | 105 | 1.10 (0.85, 1.44) |
| Asthma-related death | 2 | 0 | |
| Asthma-related intubation (endotracheal) | 1 | 2 | |
| Asthma-related hospitalization (≥24-hour stay) | 115 | 105 |
ICS/LA ICS = Inhaled Corticosteroid; LABA = Long-acting beta2-adrenergic Agonist.
a Randomized subjects who had taken at least 1 doseof study drug. Planned treatment used for analysis.
b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials.
c Number of subjects with an event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects may have had one or more events, but only the first event was counted for analysis. A single, blinded, independent, joint adjudication committee determined whether events were asthma related.
The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significant increase in risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27).
A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.
ZENHALE should not be used in conjunction with another long-acting beta2-agonist.
Do not exceed recommended dosage with ZENHALE.
The dose of ZENHALE should be individualized to the patient’s needs and should be at the lowest possible dose to fulfill the therapeutic objective. It should not be increased beyond the maximum recommended dose (see DOSAGE AND ADMINISTRATION). No evidence supports that the administration of ZENHALE in amounts greater than recommended doses increases efficacy.
A small increase in QTc interval has been reported with therapeutic doses of formoterol. It is not known if this becomes clinically significant when concomitant medications causing similar effects are prescribed and/or in the presence of heart diseases, hypokalemia, or hypoxia.
ZENHALE, like other beta2-agonist containing products, should be used with caution in patients with ischemic heart disease, cardiac arrhythmias (especially third-degree atrioventricular block), severe cardiac decompensation, idiopathic subvalvular aortic stenosis, hypertension, aneurysm, pheochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, known or suspected prolongation of the QT interval (QTc >0.44 sec).
During clinical trials with ZENHALE, oral candidiasis, which is associated with the use of inhaled glucocorticosteroids, occurred in some patients. This infection may require treatment with appropriate antifungal therapy and in some patients discontinuance of ZENHALE may be necessary. After dosing with ZENHALE, patients should be advised to rinse their mouths with water and spit out the contents without swallowing.
ZENHALE will usually permit control of asthma symptoms with less suppression of HPA axis function than therapeutically equivalent oral doses of prednisone.
When using inhaled corticosteroids, the possibility for clinically significant adrenal suppression may occur, especially after treatment with higher than recommended doses. This must be considered during periods of stress or elective surgery, when additional systemic corticosteroids may be needed.
Osteoporosis and fracture are the major complications of long-term asthma treatment with parenteral or oral steroids. Inhaled corticosteroid therapy is also associated with dose-dependent bone loss although the degree of risk is very much less than with oral steroid. This risk may be offset by estrogen replacement in post-menopausal women, and by titrating the daily dose of inhaled steroid to the minimum required to maintain optimal asthma control. It is not yet known whether the peak bone density achieved during youth is adversely affected if substantial amount of inhaled corticosteroid are administered prior to 30 years of age. Failure to achieve maximal bone density during youth could increase the risk of osteoporotic fracture when those individuals reach 60 years of age and older.
Orally inhaled corticosteroids, including Zenhale, may cause a reduction in growth velocity when administered to pediatric patients. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. Monitor the growth of pediatric patients receiving Zenhale routinely (e.g. via stadiometry) (see Monitoring and Laboratory Tests). To minimize the systemic effects of orally inhaled corticosteroids, including Zenhale, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms.
Potentially serious hypokalemia may occur as a result of beta2-agonist therapy. Hypokalemia may increase susceptibility to cardiac arrhythmias. Particular caution is advised in patients with severe asthma as hypokalemia may be potentiated by hypoxia and concomitant treatment (see DRUG INTERACTIONS / Drug-Drug Interactions). It is recommended that serum potassium levels be monitored in such situations.
Due to the hyperglycemic effect of beta2-stimulants, including formoterol, additional blood glucose monitoring is recommended in diabetic patients.
There is an enhanced effect of corticosteroids on patients with hypothyroidism.
In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy.
These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroid. Cases of serious eosinophilic conditions have been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between inhaled corticosteroid and these underlying conditions has not been established.
There is an enhanced effect of corticosteroids on patients with cirrhosis.
Immediate hypersensitivity reactions including angioedema, urticaria, flushing and bronchospasm may occur after administration of ZENHALE.
Use ZENHALE with caution, if at all, in patients with quiescent tuberculosis infections of the respiratory tract.
Patients who are receiving corticosteroids or other immunosuppressant medicines should be advised of the risk of exposure to certain infections (e.g. chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs. This is of particular importance in children. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intravenous immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.
ZENHALE should not be introduced in acutely deteriorating asthma, which is a potentially life threatening condition. Increasing use of rapid onset, short duration inhaled bronchodilators to control symptoms indicates deterioration of asthma control. Sudden and progressive deterioration in asthma control is potentially life-threatening and the treatment plan should be reevaluated. Also, where current dosage of ZENHALE has failed to give adequate control of reversible obstructive airways disease the patient should be reviewed by a physician (see DOSAGE AND ADMINISTRATION).
Before introducing ZENHALE, adequate education should be provided to the patient on how to use the drug and what to do if asthma flares up.
During long-term therapy, HPA axis function and haematological status should be assessed periodically. For patients at risk, monitoring of bone and ocular effects (cataract and glaucoma) should also be considered in patients receiving maintenance therapy with ZENHALE. It is recommended that the height of children and adolescents receiving prolonged treatment with inhaled corticosteroids is regularly monitored.
Cases of cataracts and glaucoma have been reported with use of mometasone furoate. For patients at risk, monitoring of ocular effects (cataract and glaucoma) should be considered in patients receiving maintenance therapy with ZENHALE.
Visual disturbance may be reported with systemic and topical (including, intranasal, inhaled and intraocular) 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 of visual disturbances; this may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
ZENHALE is not indicated for rapid relief of bronchospasm or other acute episodes of asthma. In the event of an acute attack, a short-acting 2-agonist should be used. A short-acting 2-agonist should be available to the patient at all times. Patients must be informed of the need to seek medical treatment immediately if their asthma deteriorates suddenly.
ZENHALE should not be initiated in patients during rapidly deteriorating or potentially-life threatening episodes of asthma. ZENHALE has not been studied in patients with acutely deteriorating asthma.
The prescriber should reassess asthma therapy if symptoms persist. If after dosing has been increased to maintain control, asthmatic episodes are not responsive to bronchodilators, or the patient exhibits decreased lung function (e.g. peak flow), the underlying condition may have deteriorated. In such cases, consideration should be given to the need for additional corticosteroid or alternative therapies.
As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, treatment with ZENHALE should be discontinued immediately and alternative therapy substituted.
There are no adequate and well-controlled studies of ZENHALE use in pregnant women. Studies in animals with mometasone furoate, like other glucocorticoids, have shown reproductive toxicity (see TOXICOLOGY); however the potential risk for humans is unknown. ZENHALE should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Infants born of mothers who received corticosteroids during pregnancy are to be observed carefully for hypoadrenalism.
Like other beta2-adrenergic stimulants, formoterol may inhibit labour due to a relaxant effect on uterine smooth muscle.
There are no data from well-controlled human studies on the use of ZENHALE in nursing mothers. Glucocorticoids are excreted in human milk. The excretion of mometasone furoate into human breast milk has not been investigated. Formoterol has been detected in the milk of rats. Based on data for the individual components, a decision on whether to continue/discontinue therapy with ZENHALE should be made taking into account the benefit of breast-feeding to the child and the benefit of ZENHALE therapy to the woman.
The safety and efficacy of ZENHALE have not been established in children less than 5 years of age.
No overall differences in safety and effectiveness were observed between these patients and younger patients, in clinical studies. There is no adjustment of dosage of ZENHALE in geriatric patients.
ZENHALE contains both mometasone furoate and formoterol, therefore the type and severity of adverse reactions associated with each individual component of ZENHALE may be expected. Use of LABA monotherapy increases the risk of serious asthma-related events (death, hospitalizations, and intubations) (see WARNINGS AND PRECAUTIONS, General). There is no evidence of additional adverse events following concurrent administration of the two components.
Tremor, palpitations, electrocardiogram QT prolongation, tachycardia, hypertension and headache have been reported and are associated with pharmacological side effects of beta2-agonist treatment (including ZENHALE). Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and ventricular extrasystoles) may occur in some patients.
Rarely, hypersensitivity reactions, including rash, urticaria, bronchospasm, arthralgia, angioedema, and anaphylactic reaction may occur in some patients.
Due to the mometasone furoate component for oral inhalation, oral candidiasis can occur in some patients. Incidence of oral candidiasis may be reduced by rinsing the mouth with water after using the product. Symptomatic candidiasis can be treated with topical antifungal therapy.
Systemic and local corticosteroid use may also result in the following:
As with other inhalation therapy, paradoxical bronchospasm may occur rarely.
See WARNINGS AND PRECAUTIONS for more detailed information.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Safety data is based on the 3 pivotal clinical trials (P04073, P04334, and P04431) and the longterm safety trial (P04139). The total number of patients (12 years of age and older with asthma) participating in these studies was 2659, of which 1131 were exposed to ZENHALE. Eight hundred and sixty (860) patients were exposed to ZENHALE in the 12 to 26 week studies and 271 patients were exposed to ZENHALE in the 1 year study.
Table 2 demonstrates the incidence of treatment related adverse reactions associated with ZENHALE based upon the pooled data of the three pivotal clinical trials.
Table 2. Treatment related adverse reactions in ZENHALE groups occurring at an incidence of ≥1% and more commonly than placebo:
| Adverse Reactions | ZENHALE* | Mometasone Furoate* | Formoterol* | Placebo* | ||||
|---|---|---|---|---|---|---|---|---|
| 50/5 n=182 n (%) | 100/5 n=424 n (%) | 200/5 n=255 n (%) | 50 mcg n=188 n (%) | 100 mcg n=192 n (%) | 200 mcg n=240 n (%) | 5 mcg n=390 n (%) | n=384 n (%) | |
| Oral Candidiasis | 3 (1.6) | 4 (0.9) | 4 (1.6) | 1 (0.5) | 1 (0.5) | 2 (0.8) | 3 (0.8) | 3 (0.8) |
| Nausea | 2 (1.1) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Headache | 2 (1.1) | 1 (0.2) | 1 (0.4) | 1 (0.5) | 1 (0.5) | 0 | 2 (0.5) | 2 (0.5) |
| Pharyngolaryngeal pain | 2 (1.1) | 0 | 0 | 1 (0.5) | 0 | 0 | 3 (0.8) | 0 |
| Average Duration of Exposure (days) | 162 | 116 | 81 | 159 | 165 | 79 | 139 | 137 |
These results are based on clinical trials P04073, P04334 & P04431.
* All treatments were administered as two inhalations twice daily.
In a comparator safety study of one year treatment duration, patients 12 years of age and older were treated with medium dose ZENHALE 100/5 (n=141), high dose ZENHALE 200/5 (n=130) or an active comparator (n=133, 68 medium dose and 65 high dose inhaled corticosteroid/LABA combination).
Safety outcomes were similar to those observed in the 12 to 26 week trials and no treatmentrelated deaths or clinically judged asthma deteriorations or reduction in lung function were observed.
Dysphonia was observed at a higher frequency in the longer term treatment trial at a reported incidence of 7/141 (5%) patients receiving ZENHALE 100/5 and 4/130 (3.1%) patients receiving ZENHALE 200/5. Overall, through 52 weeks of observation, 15 patients demonstrated a ≥1.0 point change in LOCS III score (measured at the Week 26 and Week 52 timepoints using the Lens Opacities Classification System, Version III) from Baseline. At Week 26, in the medium dose group, 2 (1.4%) patients receiving ZENHALE 100/5 and 4 (5.9%) patients receiving an active comparator demonstrated ocular changes. In the high dose group, 3 (2.3%) patients receiving ZENHALE 200/5 demonstrated ocular changes (no patients in the active comparator group). At Week 52, in the medium dose group, 4 (2.8%) patients receiving ZENHALE 100/5 and 1 (1.5%) patient receiving an active comparator demonstrated ocular changes. In the high dose group 3 (2.3%) patients receiving ZENHALE 200/5 and 1 (1.5%) patient receiving an active comparator demonstrated ocular changes. No incidences of appearance of posterior subcapsular cataracts typically associated with chronic use of high dose inhaled corticosteroid were reported in this clinical study. No clinically significant changes in blood chemistry, hematology, or ECG were observed.
The following additional treatment related adverse reactions occurred in these clinical trials (P04073, P04334, P04431, P04139) in patients using ZENHALE with an incidence of <1% and occurred at a greater incidence than placebo:
Cardiac Disorders: tachycardia, palpitations
Gastrointestinal Disorders: dry mouth
Immune System Disorders: hypersensitivity reactions with the following manifestations – bronchospasm, dermatitis allergic, urticaria
Infections and Infestations: pharyngitis
Musculoskeletal and Connective Tissue Disorders: muscle spasms*
Nervous System Disorders: tremor, dizziness*
Psychiatric Disorders: insomnia, nervousness*
Respiratory, Thoracic and Mediastinal Disorders: throat irritation
Vascular disorders: hypertension
* Reported in the 52 week safety study (P04139)
Electrocardiogram QT prolongation occurred at the same incidence as placebo (<1%).
The safety data for pediatric patients 5 years to less than 12 years of age are primarily based on a clinical trial of 24 weeks treatment duration with a 2-week safety follow-up. A total of 181 patients with asthma (92 male and 89 female) who were receiving any ICS/LABA therapy at trial entry were randomized to either ZENHALE 50/5 mcg (n=91) or mometasone furoate MDI 50 mcg (n=90), each administered as 2 inhalations twice daily. The mean age was 9.1 years, 22.1% were between the ages of 5 to 7 years, and more than half (53.6%) of the population was nonCaucasian, with 38.7% of the total population reporting at least two races (i.e., multiracial). Common treatment-emergent adverse events that occurred in patients treated with ZENHALE with an incidence of ≥3% and more frequently than patients treated with mometasone furoate alone included influenza, upper respiratory tract infection and headache. Overall, the safety profile for pediatric patients is similar to that observed in patients aged 12 years and older.
The following additional adverse reactions have been reported in post-marketing use with ZENHALE or post-marketing use with inhaled mometasone furoate or inhaled formoterol fumarate:
Cardiac Disorders: angina pectoris, cardiac arrhythmias, e.g. atrial fibrillation, ventricular extrasystoles, tachyarrhythmia
Eye disorders: vision blurred
Immune System Disorders: hypersensitivity reactions including severe hypotension, pruritus, rash, angioedema and anaphylactic reaction
Investigations: blood pressure increased (including hypertension)
Metabolism and nutrition disorders: hypokalaemia, hyperglycaemia
Nervous system disorders: syncope
Respiratory, Thoracic and Mediastinal Disorders: asthma aggravation which may include cough, dyspnea, wheezing and bronchospasm.
In clinical studies, concurrent administration of ZENHALE and other drugs, such as short-acting beta2-agonist and intranasal corticosteroids have not resulted in an increased frequency of adverse drug reactions. No formal drug interaction studies have been performed with ZENHALE. The drug interactions of the combination are expected to reflect those of the individual components.
Table 3. Established or potential Drug-Drug Interactions:
| Drug | Ref. | Effect | Clinical Comment |
|---|---|---|---|
| Ketoconazole and other strong CYP3A4 inhibitors | CT, T | Co-administration of inhaled mometasone furoate with the strong CYP3A4 enzyme inhibitor ketoconazole causes an increase in plasma concentration of mometasone furoate, whereas plasma cortisol levels appeared to decrease. Co-treatment with CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nelfinavir, saquinavir, ritonavir, cobicistatcontaining products), is expected to increase the risk of systemic side-effects. | The combination of mometasone furoate with strong CYP3A4 inhibitors, including cobicistat containing products should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects. |
| Acetylsalicylic acid | T | Use with caution in conjunction with corticosteroids in hypoprothrombinemia. | |
| Adrenergic agents | T | Concomitant administration of other sympathomimetic agents may potentiate the undesirable effects of formoterol. | Apart from the recommended use of shortacting beta2-agonist rescue medication, caution should be exercised when considering the coadministration of ZENHALE with other adrenergic agents. |
| Xanthine derivatives and diuretics | T | Concomitant treatment with xanthine derivatives or nonpotassium sparing diuretics may potentiate the possible hypokalaemic effect of beta2-agonists (see WARNINGS AND PRECAUTIONS). | Caution should be exercised when considering the coadministration of ZENHALE with xanthine derivatives or non-potassium sparing diuretics. |
| Monoamine oxidase inhibitors, macrolides, tricyclic antidepressants and drugs known to prolong the QTc interval | T | Action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc-interval have an increased risk of ventricular arrhythmia (see WARNINGS AND PRECAUTIONS). | Formoterol, as other beta2-agonists, should be administered with caution to patients being treated with these drugs. |
| Beta-adrenergic receptor antagonists | T | Beta-adrenergic blockers may weaken or antagonize the effect of formoterol. | ZENHALE should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. |
| Anesthesia with halogenated hydrocarbons | T | There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons. | Caution should be exercised in case of a planned operation with halogenated hydrocarbon anaesthetics. |
Legend: C=Case Study; CT = Clinical Trial; T = Theoretical
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