Symbicort

Beta-adrenergic blockers (including eye drops) can weaken or inhibit the effect of formoterol.

Budesonide and formoterol have not been observed to interact with any other drug used in the treatment of asthma.

The metabolism of budesonide is primarily mediated by the enzyme CYP3A4. CYP3A4 inhibitors like ritonavir and azole antifungals (e.g., ketoconazole and itraconazole), increase the systemic exposure to budesonide. Therefore, concomitant use of budesonide and ritonavir or azole antifungals should be avoided unless the potential benefit outweighs the risk of systemic corticosteroid side-effects.

There are no special dosage requirements for elderly patients.

When starting a patient on SYMBICORT, the dose should first be selected so that effective symptom control is obtained. Subsequently, the dose should be adjusted to the lowest dose at which symptom control is maintained.

The dosage of SYMBICORT should be individualized according to disease severity. Patients should be regularly reassessed so that the dosage of SYMBICORT they are receiving remains optimal.

There are two strategies for the treatment of asthma with SYMBICORT:

SYMBICORT is not currently recommended for children younger than 12 years of age due to the limited clinical data in this age group.

1-2 inhalations SYMBICORT 100 TURBUHALER twice daily or 2 inhalations once daily. Additional doses can be used as needed to provide rapid symptom relief and improved asthma control as follows. Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion. The maximum recommended total daily dose is 8 inhalations.

or

1-2 inhalations SYMBICORT 200 TURBUHALER twice daily or 2 inhalations once daily. Additional doses can be used as needed to provide rapid symptom relief and improved asthma control as follows. Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion. The maximum recommended total daily dose is 8 inhalations.

With SYMBICORT maintenance therapy, patients use SYMBICORT TURBUHALER as a daily maintenance dose and a separate fast-acting inhaled bronchodilator (e.g., formoterol, terbutaline or salbutamol) for symptom relief. Patients should be advised to have a fast-acting bronchodilator available at all times.

There are no data available for the use of SYMBICORT in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism an increased exposure can be expected in patients with severe liver disease (see Warnings and Precautions, Hepatic/Biliary/Pancreatic and Action and Clinical Pharmacology, Pharmacokinetics, Excretion).

2 inhalations SYMBICORT 200 TURBUHALER twice daily. The maximum recommended daily dose is 4 inhalations.

or

1 inhalation SYMBICORT FORTE TURBUHALER twice daily. The maximum recommended daily dose is 2 inhalations.

When treating asthma patients, SYMBICORT should be used only in patients whose conditions are not adequately controlled using low-to-medium dose inhaled corticosteroids or whose disease severity clearly warrants the initiation of treatment with two maintenance therapies (see Warnings and Precautions).

SYMBICORT should not be used in patients whose asthma can be managed by occasional use of short-acting, inhaled beta₂-agonists or for patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled short-acting beta₂-agonists.

It is crucial to inform patients to have a medication for rescue use (e.g., SYMBICORT, formoterol, terbutaline or salbutamol) available at all times to relieve acute asthmatic symptoms. If the patient’s medication for rescue becomes less effective medical attention should be sought.

The patient should be made aware that for optimum benefit, SYMBICORT should be taken regularly, even when they are asymptomatic. Rescue inhalations only need to be taken to relieve acute asthma symptom (see Warnings and Precautions).

A reassessment of asthma therapy should be considered in patients using an increasing number of rescue inhalations for symptom relief without achieving improved asthma control.

SYMBICORT therapy should not be initiated to treat an asthma exacerbation.

If a dose of SYMBICORT is missed, it should be taken as soon as possible; the patient should then resume their regular schedule. A double dose of SYMBICORT should not be taken to make up for doses that are missed.

SYMBICORT therapy should not be initiated to treat acute symptoms of COPD.

Patients use SYMBICORT TURBUHALER both as a daily maintenance dose plus additional inhalations as needed for rapid symptom relief and a timely increase in controller therapy for improved asthma control. Patients should be advised to always have SYMBICORT TURBUHALER available for rescue use. A persistent increase in the use of SYMBICORT as needed indicates a deterioration of asthma control, and the patient's condition should be re-evaluated.

cataract, glaucoma, increased intraocular pressure.

hypercorticism, growth retardation.

Overall Adverse Experiences with ≥3% and More Common Than Placebo in the SYMBICORT Group in Controlled Clinical Trials (0629 and 0670) with SYMBICORT in Patients with COPD

The following adverse reactions have been reported during post-approval use of SYMBICORT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with SYMBICORT.

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.

dysphonia, cough, throat irritation.

angina pectoris, tachycardia, cardiac arrhythmias (e.g. atrial fibrillation, extrasystoles), palpitations.

pyrexia.

dysphonia, oropharyngeal pain, nasal congestion.

All cause mortality was assessed in COPD trials 0629 and 0670. Of the 1834 patients in the pooled data, there were 56 (3.1%) deaths: 20 (4.4%) in the formoterol group, 14 (3.0%) in the placebo group, 11 (2.4%) in the budesonide group, and 11 (2.4%) in the SYMBICORT group. The most common cause of death overall was COPD (formoterol=9, placebo=7, budesonide=3, and SYMBICORT=3 cases).

tremor, dizziness, headache.

skin bruising.

myalgia, arthralgia, pain in extremity.

influenza, respiratory tract infection, upper respiratory tract infection, rhinitis, pharyngitis, cystitis, oral candidiasis.

hypotension, hypertension.

muscle spasms.

hyperglycemia, hypokalemia.

immediate and delayed hypersensitivity reactions, such as anaphylactic reaction, angioedema, brochospasm, urticaria, rash, dermatitis, pruritus.

oropharyngeal candidiasis, nausea.

behaviour disturbances, sleep disturbances, nervousness, agitation, depression, restlessness.

SYMBICORT (budesonide and formoterol fumarate dihydrate) is indicated for regular treatment of asthma in patients 12 years and older with reversible obstructive airways disease, where the use of a combination product is appropriate. This may include:

• Patients on effective maintenance doses of long-acting beta₂-agonists and inhaled corticosteroids.

  
  

• Patients who are symptomatic on current inhaled corticosteroid therapy.

  
  

When treating asthma patients, SYMBICORT should be used only in patients whose conditions are not adequately controlled using low-to-medium dose inhaled corticosteroids or whose disease severity clearly warrants the initiation of treatment with two maintenance therapies (see Warnings and Precautions).

SYMBICORT should not be used in patients whose asthma can be managed by occasional use of short-acting, inhaled beta₂-agonists or for patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled short-acting beta₂-agonists.

For SYMBICORT there are two treatment approaches:

1. SYMBICORT Maintenance Therapy: SYMBICORT is taken as regular maintenance treatment with a separate rapid-acting bronchodilator as rescue.

   
   

2. SYMBICORT Maintenance and Reliever Therapy: SYMBICORT is taken as regular maintenance treatment and as needed in response to symptoms.

   
   

See Dosage and Administration and Warnings and Precautions.

SYMBICORT TURBUHALER is indicated for the maintenance treatment of moderate to severe COPD including chronic bronchitis and emphysema, in patients with persistent symptoms and a history of exacerbations, where the use of a combination product is considered appropriate.

SYMBICORT TURBUHALER is not indicated for the relief of acute bronchospasm in COPD patients.

See Dosage and Administration and Warnings and Precautions.

Each dry powder inhaler contains: budesonide 100 µg and formoterol fumarate dihydrate 6 µg per dose. Also contains lactose (may contain milk protein residue) which acts as a “carrier”. The amount added does not normally cause problems in lactose-intolerant people. Pack sizes of 60 and 120 doses.

Each dry powder inhaler contains: budesonide 200 µg and formoterol fumarate dihydrate 6 µg per dose. Also contains lactose (may contain milk protein residue) which acts as a “carrier”. The amount added does not normally cause problems in lactose-intolerant people. Pack sizes of 60 and 120 doses.

Due to reversible hyperglycemic effect of beta₂-agonists, additional blood glucose monitoring is recommended initially in diabetic patients.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids.

The incidence of pneumonia and lung infections other than pneumonia have been assessed in two 12-month studies of 1834 patients with COPD. In these two studies, there was a slightly higher incidence of lung infections other than pneumonia (e.g., bronchitis, viral lower respiratory tract infections, etc.) in patients receiving SYMBICORT TURBUHALER 2×200/6 μg bid (13.0%) in comparison with those receiving formoterol 2×6 μg bid (11.4%), budesonide 2×200 μg bid (9.9%), or placebo (8.2%). Pneumonia occurred in 4.1% of patients treated with SYMBICORT TURBUHALER compared with 2.4% treated with formoterol, 3.1% treated with budesonide, and 2.8% treated with placebo (see Adverse Reactions).

There is an enhanced effect of corticosteroids on patients with cirrhosis. Reduced liver function may affect the elimination of corticosteroids. The intravenous pharmacokinetics of budesonide however, are similar in cirrhotic patients and in healthy subjects. The pharmacokinetics after oral ingestion of budesonide were affected by compromised liver function as evidenced by increased systemic availability. This is however, of little importance for budesonide, as after inhalation, the oral contribution to systemic availability is very small (see Dosage and Administration, Special Populations, Hepatic/Renal Impairment and Action and Clinical Pharmacology, Pharmacokinetics, Excretion).

SYMBICORT is not currently recommended in children younger than 12 years of age due to limited clinical data in this age group.

In experimental animal studies, budesonide was found to cross the placental barrier. Like other glucocorticosteroids, budesonide is teratogenic to rodent species. High doses of budesonide administered subcutaneously produced fetal malformations, primarily skeletal defects, in rabbits, rats and mice. Results from world-wide post marketing experience indicate inhaled budesonide during pregnancy has no adverse effects on the health of the fetus/new born child. Review of published literature of orally inhaled budesonide, including results from a large case control study performed with cases identified from 3 Swedish health registers showed that there was no association between exposure to inhaled budesonide and overall congenital malformations. Results from a similar study performed with intranasal budesonide, using the same 3 Swedish health registers showed that the use of intranasal budesonide was associated with a subgroup “less severe cardiovascular defects”; however, there was no statistically significant association between the use of intranasal budesonide during pregnancy and overall congenital malformations, or overall frequency of cardiovascular defects in the offspring. The safety of formoterol during pregnancy has not yet been established. SYMBICORT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Particular care is needed in asthmatic patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred during and after transfer. For the transfer of patients treated with oral corticosteroids, inhaled corticosteroids should first be added to the existing oral steroid therapy which is then gradually withdrawn.

Patients with adrenocortical suppression should be monitored regularly and the oral steroid reduced cautiously. Some depression of plasma cortisol may occur in a small number of patients on higher doses of inhaled budesonide (for example greater than 800 μg/day). However, in most but not all patients on inhaled budesonide therapy, adrenal function and adrenal reserve remain within normal range. Some patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled budesonide.

After withdrawal from long-term treatment with systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis. Although inhaled budesonide may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies. The physician may consider supplying oral steroids for use in times of stress (e.g. asthma exacerbations, chest infections, surgery).

During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or asthma exacerbation. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning and evening cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level.

There are no well-controlled human studies that have investigated effects of formoterol on preterm labour or labour at term. Because of the potential for beta-agonist interference with uterine contractility, use of SYMBICORT during labour should be restricted to those patients in whom the benefits clearly outweigh the risks.

There is no need to adjust the dose in elderly patients.

As with other inhalation therapy, paradoxical bronchospasm may occur characterized by an immediate increase in wheezing after dosing. In this event, SYMBICORT should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted.

Treatment with inhaled corticosteroids should not be stopped abruptly, but tapered gradually under the supervision of a physician.

In adolescents the severity of asthma may vary with age and periodic reassessment should be considered to determine if continued therapy with SYMBICORT is still indicated.

In common with other beta-adrenergic agents, formoterol can induce reversible metabolic changes (hyperglycemia, hypokalemia).

When beginning treatment with SYMBICORT (budesonide/formoterol fumarate dihydrate), patients who have been taking inhaled beta₂-agonist on a regular basis should be instructed to discontinue the regular use of these drugs.

It is crucial to inform patients with asthma to have medication for rescue use available at all times. Asthma patients should be clearly instructed to use medication for rescue (e.g., SYMBICORT, formoterol, terbutaline, or salbutamol) if they develop asthma symptoms while taking SYMBICORT.

The reliever inhalations of SYMBICORT should be taken in response to symptoms but is not intended for regular prophylactic use before exercise.

Do not exceed recommended dosage of SYMBICORT.

Therapeutic dosages of budesonide may cause the appearance of C. albicans (thrush) in the mouth and throat. The development of pharyngeal and laryngeal candidiasis is a cause for concern because the extent of its penetration into the respiratory tract is unknown. Symptomatic candidiasis can be treated with topical anti-fungal therapy while continuing to use SYMBICORT.

With asthma, a persistent increase in the use of medication for rescue (e.g. SYMBICORT, formoterol, terbutaline or salbutamol), indicates a deterioration of asthma control and the patient's condition should be re-evaluated (see Dosage and Administration).

Asthma or COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If patients find the rescue medication less effective (e.g. increased or persistent use), or exceeds the highest recommended dose of SYMBICORT, medical attention must be sought as this could be indicative of disease deterioration.

Sudden and progressive deterioration in control of asthma or COPD (e.g. exacerbations) is potentially life threatening and the patient should undergo urgent medical assessment. It is recognized that exacerbations are the most frequent cause of medical visits, hospital admissions and mortality among patients with asthma or COPD. With asthma and COPD, consideration should be given to the need for increased therapy with corticosteroids, e.g. a course of oral corticosteroids. Antibiotic treatment should be considered if an infection is present. Treatment with SYMBICORT should not be initiated to treat a severe exacerbation.

As with any asthma or COPD therapy, before introducing SYMBICORT, adequate education on how to use the drug and what to do during periods of worsening disease should be provided to the patient.

Patients who are on drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults on immunosuppressant corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intravenous immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids may mask some signs of infection and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy.

A clinical pharmacology study has shown that inhaled budesonide is excreted in breast milk. It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of SYMBICORT to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

There is an enhanced effect of corticosteroids on patients with hypothyroidism.

Although clinically not significant, 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.

No clinically significant effect on the cardiovascular system is usually seen after the administration of inhaled formoterol in recommended doses, but the cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood pressure, heart rate, excitement) can occur after use of formoterol. Formoterol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines.

With beta-adrenergic agonist bronchodilators, changes in systolic and/or diastolic blood pressure, pulse rate, and electrocardiograms have been noted. No clinically important differences have been observed with SYMBICORT within the recommended dosages.

Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for formoterol and 3 L/kg for budesonide.

After the administration of budesonide, formoterol or the fixed combination, pharmacokinetic parameters, for the respective substances, were comparable. Specifically, for budesonide, AUC was slightly higher, rate of absorption more rapid and maximal plasma concentration higher after administration of the fixed combination. For formoterol, maximal plasma concentration was slightly lower after administration of the fixed combination.

SYMBICORT and the monoproducts (PULMICORT TURBUHALER and OXEZE TURBUHALER) were bioequivalent with regard to systemic bioavailability of budesonide and formoterol.

Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after inhalation via TURBUHALER ranged from 32 to 44% of the delivered dose (25 to 30% of the metered dose). The systemic bioavailability is about 49% of the delivered dose and 38% of the metered dose.

Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 minutes after inhalation. In studies the mean lung deposition of formoterol after inhalation via TURBUHALER ranged from 28-49% of the delivered dose (21-37% of the metered dose). Because of the low therapeutic dose, systemic levels of formoterol are low or undetectable after inhalation.

SYMBICORT contains formoterol fumarate dihydrate and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. In asthma, SYMBICORT can offer a more convenient regime for patients requiring concurrent long-acting beta₂-agonist and inhaled corticosteroid therapy—dosing with SYMBICORT may be adjusted to meet the condition of the patients' disease. SYMBICORT can be used both as a maintenance and reliever medication in asthma, due to the rapid bronchodilator effect of formoterol and the anti-inflammatory effects of budesonide.

The major part of a dose of formoterol is eliminated via hepatic metabolism followed by renal excretion. After inhalation 8-13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and the late elimination half-life averages 17 hours.

Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are excreted in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.

Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates).

Budesonide undergoes an extensive degree (≈90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxy-budesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. There are no indications of any metabolic interactions or any displacement reactions between formoterol and budesonide.

Budesonide is a potent synthetic glucocorticosteroid with strong topical and weak systemic effects. Budesonide has a high local anti-inflammatory potency and it is rapidly biotransformed in the liver. This favorable separation between topical anti-inflammatory activity and systemic effect is due to strong glucocorticosteroid receptor affinity and an effective first pass metabolism with a short half-life. The anti-anaphylactic and anti-inflammatory effects of budesonide manifest themselves as decreased bronchial obstruction in the early as well as the late phase allergic reactions. When administered by inhalation at therapeutic doses, it has a direct, potent anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically. Budesonide has also been shown to decrease airway reactivity to both direct and indirect challenge in hyperreactive patients. Therapy with inhaled budesonide has been effective when used for prevention of exercise-induced asthma.

The respective mechanisms of action of budesonide and formoterol are discussed below.

Formoterol is a potent, selective, fast and long-acting beta₂-adrenergic stimulant used for the prevention and relief of asthma symptoms. Formoterol produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in as rapidly as short-acting bronchodilators (salbutamol, terbutaline), within 1-3 minutes after inhalation, and has a duration of 12 hours after a single dose. Formoterol offers more effective protection against carbachol, histamine- or methacholine-induced bronchoconstriction than other short (e.g., salbutamol) and long-acting (e.g., salmeterol) beta₂-agonists. Formoterol provides dose-related benefits in pulmonary function and in bronchoprotective effects against methacholine, histamine and AMP challenges, indicating a dose-related reduction in airways responsiveness to both direct and indirect stimuli and a greater protection against asthma triggers such as allergens and exercise.

Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 year old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. The pharmacokinetics of formoterol in children has not been studied.

In clinical trials in asthma and COPD, combination treatment with formoterol and budesonide improved symptoms and lung function, and reduced exacerbations.

In asthma, the effect on lung function of SYMBICORT was clinically equivalent to that of the free combination of budesonide and formoterol in separate inhalers in adults and exceeded that of budesonide alone in adults and adolescents. There was no sign of attenuation of the anti-asthmatic effect over time. SYMBICORT and the short-acting bronchodilator salbutamol have been shown to have similarly rapid onsets of effect. The combination of budesonide and formoterol does not mask the onset or severity of exacerbations.