Budesonide/ Formoterol Fumarate Dihydrate

Registered South African indications:

• Asthma
  - Where use of a combination (inhaled corticosteroid and long acting beta-2 agonist) is appropriate (80/4.5 (µg/inh))
  - To achieve overall asthma control, including the prevention and relief of symptoms as well as the reduction of the risk of exacerbations (160/4.5 (µg/inh))
  - Where continued use of a high dose combination (inhaled corticosteroid and long-acting beta-2-agonist) is appropriate (320/9 (µg/inh))
• Chronic obstructive pulmonary disease (COPD)

Contraindications

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to inhaled lactose
• Children <12 years

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to lactose (which contains small amounts of milk protein)

Cautions

South African recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Abrupt withdrawal
• Severe exacerbation
• Severe cardiovascular disorders
  - Including heart rhythm abnormalities
• Diabetes mellitus
• Untreated hypokalaemia
• Thyrotoxicosis
• COPD patients
• Adolescents (growth)
• Switching from oral steroids
• Previous prolonged treatment with highest recommended dose of inhaled corticosteroids
• Previous need of high dose emergency corticosteroid therapy
• Galactose intolerance
  - Galactosaemia
• Lapp lactase deficiency
• Fructose intolerance
• Glucose-galactose malabsorption

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Fertility
• Renal impairment
• Hepatic impairment
• Abrupt withdrawal
• Initiation during an exacerbation, or in significantly worsening or acutely deteriorating asthma
• COPD patients with a pre-bronchodilator FEV₁ >50% predicted normal and with a post-bronchodilator FEV₁ <70% predicted normal
• Risk factors for pneumonia in patients with COPD
  - Current smoking
  - Older age
  - Low body mass index
  - Severe COPD
• Previous prolonged treatment with high dose inhaled corticosteroids
• High doses for prolonged periods
  - Coexisting risk factors for osteoporosis
• Adrenal function impairment from previous systemic steroid therapy
• Switching from oral steroids
• Rapid dose reduction of budesonide/ formoterol or supplementary systemic steroids
• Thyrotoxicosis
• Phaeochromocytoma
• Diabetes mellitus
• Untreated hypokalaemia
• Hypertrophic obstructive cardiomyopathy
• Idiopathic subvalvular aortic stenosis
• Severe hypertension
• Aneurysm
• Severe cardiovascular disorders
  - Ischaemic heart disease
  - Tachyarrhythmias
  - Severe heart failure
• QT prolongation or risk factors thereof
• Immunosuppression(See additional prescribing points)
• Active or quiescent pulmonary tuberculosis
• Unstable asthma
• Acute severe asthma
• Fungal and viral infections in the airways
• Coadministration with agents which can induce hypokalaemia or potentiate a hypokalaemic effect

Forms avail. in SA and covered in this monograph: inh

South African registered indications and dosages

Asthma
- Anti-inflammatory reliever therapy in mild disease for the relief of asthma symptoms when they occur, and to prevent allergen- or exercise-induced bronchoconstriction (or to prevent symptoms in those circumstances recognised by the patient to precipitate an asthma attack)

Budesonide/ Formoterol
160/4.5 (µg/inh)

• Inhaled (inh): Initial: 1 inhalation, as needed; Max: 12 inhalations/24hrs can be used temporarily

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Medical practitioner should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the dose frequency

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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. A total daily dose of  >8 inhalations is normally not needed. Patients using >8 inhalations daily should be reassessed for alternative explanations of persisting symptoms

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- Anti-inflammatory and reliever plus maintenance therapy when maintenance treatment with a combination of inhaled corticosteroid and long-acting beta-2-agonist is required

Budesonide/ Formoterol
80/4.5 (µg/inh)

• Inhaled (inh): Maintenance: 2 inhalations, dly; Taken as: 1 inhalation in the morning and evening OR 2 inhalations in either the morning or the evening: Max: 12 inhalations/24hrs can be used temporarily 

160/4.5 (µg/inh)

• Inhaled (inh): Reliever: 1 inhalation, as needed; In response to symptoms and for the prevention of allergen- or exercise-induced bronchoconstriction to control asthma
• Inhaled (inh): Maintenance: 2 inhalations, dly; Taken as: 1 inhalation in the morning and evening OR 2 inhalations in either the morning or the evening; Max: 12 inhalations/24hrs can be used temporarily
  OR
• Inhaled (inh): Maintenance: 2 inhalations, 12hrly may be appropriate; Max: 12 inhalations/24hrs can be used temporarily

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160/4.5 (µg/inh): Medical practitioner should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the dose frequency

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Not more than 6 inhalations should be taken on any single occasion

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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. A total daily dose of >8 inhalations is not normally needed

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A reassessment of asthma therapy should be considered in patients using an increasing number of budesonide/ formoterol inhalations for symptom relief without achieving improved asthma control within 3 days

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Patients should be advised to have budesonide/ formoterol available for relief of symptoms at all times. A separate inhaler for relief of symptoms is not required
(See additional prescribing points)

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- Maintenance therapy (fixed dose) when maintenance treatment with a combination of inhaled corticosteroid and long acting beta-2 agonist is required, budesonide/ formoterol is taken as a fixed daily dose treatment, with a separate short-acting bronchodilator for relief of symptoms

Budesonide/ Formoterol
80/4.5 (µg/inh)
160/4.5 (µg/inh)

• Inhaled (inh): 1-2 inhalations, 12hrly; Max: 4 inhalations, 12hrly may be required as a maintenance dose or temporarily during worsening of asthma

- Where continued use of a high dose combination (inhaled corticosteroid and long-acting beta-2-agonist) is appropriate

320/9 (µg/inh)

• Inhaled (inh): Initial: 1 inhalation, 12hrly; Max: 2 inhalations, 12hrly may be required as a maintenance dose or temporarily during worsening of asthma

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The dosage of budesonide/ formoterol should be individualised according to disease severity. When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained

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Patients should be advised to have their separate short-acting bronchodilator available for relief of symptoms at all times. Increasing use of a separate rapid acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy

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Patients who are on maintenance therapy for asthma should be advised to have their separate short-acting bronchodilator available for relief of symptoms at all times

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Chronic obstructive pulmonary disease (COPD) - moderate to severe
- With frequent symptoms and a history of exacerbations

Budesonide/ Formoterol
160/4.5 (µg/inh)

• Inhaled (inh): 2 inhalations, 12hrly; Max: 4 inhalations/24hrs

320/9 (µg/inh)

• Inhaled (inh): 1 inhalation, 12hrly: Max: 2 inhalations/24hrs 

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If patients take budesonide/ formoterol as a maintenance therapy, for an optimal benefit they should be instructed that it must be used even when they are asymptomatic

Paed. forms avail. in SA and covered in this monograph: inh

South African registered indications and dosages

Medical practitioners should closely follow the growth of adolescents taking long-term corticosteroids by any route, and weigh the benefits of the corticosteroid therapy against the possible risk of growth suppression

Asthma
- Anti-inflammatory reliever therapy in mild disease for the relief of asthma symptoms when they occur, and to prevent allergen- or exercise-induced bronchoconstriction (or to prevent symptoms in those circumstances recognised by the patient to precipitate an asthma attack)

Budesonide/ Formoterol
160/4.5 (µg/inh)

Younger than 12 years

• Not established for use

Between 12-17 years

• See adult dosage

- Anti-inflammatory and reliever plus maintenance therapy when maintenance treatment with a combination of inhaled corticosteroid and long-acting beta-2-agonist is required

Budesonide/ Formoterol
80/4.5 (µg/inh)

Younger than 12 years

• Not established for use

Between 12-17 years

• See adult dosage

- Maintenance therapy (fixed dose) when maintenance treatment with a combination of inhaled corticosteroid and long acting beta-2 agonist is required, budesonide/ formoterol is taken as a fixed daily dose treatment, with a separate short-acting bronchodilator for relief of symptoms

Budesonide/ Formoterol
80:4.5 (µg/inh)
160:4.5 (µg/inh)

Younger than 12 years

• Not established for use

Between 12-17 years

• Inhaled (inh): 1-2 inhalations, 12hrly; Max: 4 inhalations, 12hrly may be required temporarily during worsening of asthma

320/9 (µg/inh)

Younger than 12 years

• Not established for use

Between 12-17 years

• Inhaled (inh): 1 inhalations, 12hrly; Max: 2 inhalations, 12hrly may be required temporarily during worsening of asthma

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When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained

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Maintenance (fixed dose): Patients should be advised to have their separate rapid-acting bronchodilator available for rescue use at all times. Increasing use of rapid-acting bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy

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Not established for use for chronic obstructive pulmonary disease (COPD) in children below 18 years

Pregnancy 

South African recommendations

• Caution; positive evidence of risk in animal studies
• There are no adequate data from the use of formoterol in pregnant women. In animal studies formoterol has caused adverse effects in reproduction studies at very high systemic exposure levels
• Corticosteroids are teratogenic in animals

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• No clinical data are available on concomitant treatment with formoterol and budesonide and exposed pregnancies
• Data from an embryo-foetal development study in the rat showed no evidence of any additional effect from the combination
• There are no adequate data from the use of formoterol in pregnant women. In animal studies, formoterol has caused adverse effects in reproduction studies at very high systemic exposure levels
• Data on approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide
• In animal studies, glucocorticosteroids have been shown to induce malformations. This is not likely to be relevant for humans given recommended doses
• Animal studies have also identified an involvement of excess prenatal glucocorticoids in increased risks for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range
• During pregnancy, budesonide/ formoterol inhaler should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used

Breastfeeding

South African recommendations

• Caution; not recommended 
• Safety in breastfeeding has not been demonstrated
• A clinical pharmacology study has shown that inhaled budesonide is excreted in breast milk
• Women using the budesonide/ formoterol inhaler should not breastfeed their infants

Recommendations in other jurisdictions

• Caution; not recommended 
• Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the breastfeeding child are anticipated
• 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 inhaled budesonide/ formoterol to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child

Fertility 

South African recommendations

• There are no animal studies on the effect of the budesonide/ formoterol combination on fertility

Recommendations in other jurisdictions

• There is no data available on the potential effect of budesonide on fertility
• Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure

Renal Impairment

• Caution; no information available 

Hepatic Impairment

• Caution; no information available
  As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver diseases

Elderly

• No dose adjustment recommended 

Porphyria Information

• NP - Not porphyrinogenic 

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders 

• Anxiety
• Aggression
• Depression
• Behavioural changes (predominantly in children)
• Sleep disorders
• Psychomotor hyperactivity
• Headache
• Tremor
• Dizziness

• Taste disturbances

Cardiovascular Disorders

• Palpitations
• Tachycardia
• Cardiac arrhythmias
  - Atrial fibrillation
  - Supraventricular tachycardia
  - Extrasystoles
• Angina pectoris
• Prolongation of QTc-interval
• Variations in blood pressure

Respiratory Disorders 

• Cough
• Mild irritation in the throat
• Paradoxical bronchospasm
  - Wheezing
  - Shortness of breath
• Dyspnoea
  - Hoarseness
• Candida infections in the oropharynx (See additional prescribing points)
• Pneumonia (in COPD patients)

Gastrointestinal Disorders

• Nausea

Endocrine and Metabolic Disorders

• Cushing's syndrome
• Adrenal suppression
• Growth retardation
• Decrease in bone mineral density
• Hypokalaemia
• Hyperglycaemia
• Increased insulin levels

Musculoskeletal  Disorders

• Decreased bone density
• Muscle cramps

Skin and Subcutaneous Tissue Disorders

• Bruises

Immune, Blood and Lymphatic System Disorder

• Hypersensitivity reactions (Immediate and delayed)
  - Exanthema
  - Urticaria
  - Pruritus
  - Dermatitis
  - Angioedema
  - Anaphylactic reaction
• Increased free fatty acids
• Increased glycerol
• Increased ketone bodies

Sensory Disorders

• Cataract
• Glaucoma
• Blurred vision

• Inhaled beta-2 agonists
• CYP3A4 inhibitors (See additional prescribing points)
• Itraconazole
• Ketoconazole
• Voriconazole
• Posaconazole
• Clarithromycin
• Telithromycin
• Nefazodone
• Cobicistat
• HIV protease inhibitors
• Beta-adrenergic blockers
• Quinidine
• Disopyramide
• Procainamide
• Phenothiazines
• Antihistamines
• Terfenadine
• Tricyclic antidepressants
• Levodopa
• Levothyroxine
• Oxytocin
• Alcohol
• Xanthine derivatives
• Steroids
• Diuretics
• Monoamine oxidase inhibitors
• Furazolidone
• Procarbazine
• Anticholinergic agents
• Digitalis glycosides
• QT prolonging agents
• Halogenated hydrocarbons

None routine. Specific cases may require

• Pulmonary function
  - Forced expiratory volume (FEV₁)
  - Peak flow
• Growth in paediatric patients
• Bone mineral density
• Blood pressure
• Heart rate
• Serum glucose
• Serum potassium
• HPA axis function

Additional observations

• Symptom relief
• Increased use of short-acting beta-adrenergic agonists (may be a sign of asthma or COPD deterioration)
• CNS stimulation

South African recommendations

When asthma control is achieved, the dose should be titrated to the lowest effective dose achieving symptom control

Dosages

Asthma
- Anti-inflammatory reliever therapy (patients with mild disease)

• The formoterol component provides fast onset of effect (within 1-3 minutes) with long-acting (at least 12 hours after a single dose) bronchodilation in reversible airways obstruction
• Patients should be advised to always have budesonide/ formoterol inhaler available for relief of symptoms
• Clinical studies have demonstrated that budesonide/ formoterol anti-inflammatory reliever therapy provides significant reductions in severe exacerbations and was statistically superior on daily asthma symptom control compared to a short-acting beta-2-agonist therapy alone

Asthma
- Anti-inflammatory and reliever plus maintenance therapy

• The as needed inhalations provide both rapid relief of symptoms and improved overall asthma control
• Patients should be advised to have budesonide/ formoterol inhaler available for relief of symptoms at all times
• A separate inhaler for relief of symptoms is not required
• Clinical studies have demonstrated that budesonide/ formoterol anti-inflammatory reliever plus maintenance therapy provides clinically meaningful reductions in severe exacerbations while maintaining symptom control, compared to budesonide/ formoterol maintenance therapy with a separate short-acting bronchodilator
• If the patient experiences deteriorating symptoms after taking the appropriate maintenance therapy and additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms

Recommendations in other jurisdictions

• Budesonide/ formoterol is not intended for the initial management of asthma.
• The dosage of the components of budesonide/ formoterol is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the maintenance dose is adjusted.
• If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of β₂ adrenoceptor agonists and/or corticosteroids by individual inhalers should be prescribed
• The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Patients should be regularly reassessed by their prescriber/health care provider so that the dosage of budesonide/ formoterol remains optimal.
• When long-term control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone

Asthma
- Maintenance and reliever therapy

• Patients take a daily maintenance dose of budesonide/ formoterol and in addition take budesonide/ formoterol as needed in response to symptoms. Patients should be advised to always have budesonide/ formoterol available for rescue use
• For patients taking budesonide/ formoterol as reliever, preventative use of budesonide/ formoterol for allergen- or exercise-induced bronchoconstriction should be discussed between physician and patient; the recommended use should take into consideration the frequency of need. In case of frequent need of bronchodilation without corresponding need for an increased dose of inhaled corticosteroids, an alternative reliever should be used
• Maintenance and reliever therapy should especially be considered for patients with:
  • Inadequate asthma control and in frequent need of reliever medication
  • Asthma exacerbations in the past requiring medical intervention
• Close monitoring for dose-related adverse effects is needed in patients who frequently take high numbers of budesonide/ formoterol as-needed inhalations

Asthma 
- Maintenance therapy

Budesonide/ Formoterol
320/9 (µg/inh)

• In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include budesonide/ formoterol given once daily, when in the opinion of the prescriber, a long-acting bronchodilator would be required to maintain control
• Increasing use of a separate rapid-acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy
• Budesonide/ formoterol 320/9 (µg/inh) should be used as maintenance therapy only. Lower strengths (160µg/4.5µg and 80µg/ 4.5µg) are available for the maintenance and reliever therapy regimen

Interactions

• Potent inhibitors of CYP3A4 are likely to markedly increase plasma levels of budesonide and concomitant use should be avoided. If this is not possible the time interval between administration of the inhibitor and budesonide should be as long as possible
• Limited data about this interaction for high-dose inhaled budesonide indicates that marked increases in plasma levels (on average four fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000μg)

Adverse effects

• To minimise the risk of oropharyngeal candida infection, the patient should be instructed to rinse their mouth out with water after inhaling the maintenance dose

Immunosuppression

• Prolonged use of corticosteroids may increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to vaccines
• Avoid use if possible in patients with ocular herpes; active or quiescent tuberculosis infections of the respiratory tract; or untreated viral, fungal, or bacterial or parasitic systemic infections
• Exposure to chickenpox or measles should be avoided; if the patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin or pooled intravenous immunoglobulin may be indicated; if chickenpox develops, treatment with antiviral agents may be considered. If exposure to measles, prophylaxis with pooled intramuscular immunoglobulin may be indicated

Budesonide
Budesonide is a glucocorticosteroid which when inhaled has a dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Inhaled budesonide has less severe adverse effects than systemic corticosteroids. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.

Formoterol
Formoterol is a selective β₂-adrenoceptor adrenergic agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose-dependent, with an onset of effect within 1-3 minutes.

COMBINATION PREPARATIONS

Budesonide/Formoterol Fumarate

Inhaler 80μg/4.5μg 

• Symbicord Turbuhaler 80:4.5μg (AstraZeneca) originator
• Vannair 80:4.5μg (AstraZeneca) originator

Inhaler 160μg/4.5μg 

• Symbicord Turbuhaler 160:4.5μg (AstraZeneca) originator
• Vannair 160:4.5μg (AstraZeneca) originator

Inhaler 320μg/9μg 

• Symbicord Turbuhaler 320:9μg (AstraZeneca) originator