Budesonide/ Glycopyrronium/ Formoterol Fumarate Dihydrate

Registered South African indications:

• Maintenance treatment to relieve symptoms and prevent exacerbations in adult patients with chronic obstructive pulmonary disease (COPD)

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product

South African recommendations

Caution in the following patient groups:

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment

Deterioration of disease

• If patients find the treatment ineffective, despite taking the highest recommended dose, medical attention must be sought. Sudden and progressive deterioration in control of COPD is potentially life threatening and the patient should undergo urgent medical assessment
• In this situation, consideration should be given to the need for increased therapy such as a course of oral corticosteroids or antibiotic treatment if an infection is present

Transfer from oral therapy

• Particular care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time
• Patients who have required high dose corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress
• Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery

Paradoxical bronchospasm

• Administration of this combination product may cause paradoxical bronchospasm. If this occurs, treatment should be stopped and other treatments considered

Not for acute use

• Budesonide/ glycopyrronium/ formoterol fumarate dihydrate is not indicated for the treatment of acute episodes of bronchospasm, or to treat an acute COPD exacerbation (i.e. as a rescue therapy)

Cardiovascular effects

• Caution should be observed in patients with thyrotoxicosis and in patients with a severe cardiovascular disorder, such as ischaemic heart disease, tachydysrhythmias or severe heart failure. Caution should be observed when treating patients with a prolonged QTc-interval

Systemic effects

• Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhaled corticosteroid treatments than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma
• Potential effects on bone density should be considered particularly in patients on high doses for prolonged periods that have co-existing risk factors for osteoporosis. Long-term studies with inhaled budesonide in adults at daily doses of 800 micrograms (metered dose) have not shown any significant effects on bone mineral density

Hypokalaemia and hyperglycaemia

• Metabolic effects of hyperglycaemia and hypokalaemia may be observed with high doses of β₂ adrenergic agonists. The decrease in serum potassium is usually transient, not requiring supplementation

Anticholinergic activity

• Due to its anticholinergic activity, budesonide/ glycopyrronium/ formoterol fumarate dihydrate should be used with caution in patients with symptomatic prostatic hyperplasia, urinary retention or narrow-angle glaucoma

Renal impairment

• Formal pharmacokinetic studies using this combination product have not been conducted in patients with renal impairment. As glycopyrronium is predominantly renally excreted, patients with severe renal impairment (creatinine clearance of <30ml/min) should be treated with budesonide/ glycopyrronium/ formoterol fumarate dihydrate only if the expected benefit outweighs the potential risk

Hepatic impairment

• As budesonide and formoterol are primarily eliminated via hepatic metabolism an increased exposure can be expected in patients with severe hepatic impairment. In patients with severe hepatic impairment, this combination product should be used only if the expected benefit outweighs the potential risk

Pneumonia

• Medical practitioners should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections can overlap with the symptoms of COPD exacerbations

Effects on ability to drive and use machines

• No studies on the effects on the ability to drive and use machines have been performed. Based on the pharmacological profile, this combination product is expected to have no or negligible influence on the ability to drive and use machines

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

South African registered indications and dosages

Maintenance treatment to relieve symptoms and prevent exacerbations in adult patients with chronic obstructive pulmonary disease (COPD)

Budesonide/ Glycopyrronium/ Formoterol Fumarate Dihydrate
160/7.2/5 (μg)

• Inhaled (inh): 2 inhalations, twice daily in the morning and evening; Admin. should be by oral inhalation only; Max: 2 inhalations/24hrs

---

Missed dose
If a dose is missed, it should be taken as soon as possible, and the next dose should be taken at the usual time. A double dose should not be taken to make up for a forgotten dose

---

Method of Administration
For oral inhalation use
For detailed instructions, refer to the product patient leaflet
Patients should be instructed how to administer the product correctly and advised to read the instructions for use carefully
Patients who find it difficult to co-ordinate actuation with inhalation may use this inhaler with a spacer to ensure proper administration of the product

Not established for children below 18 years

Pregnancy

South African recommendations

• Caution
• There are no adequate data on the use of budesonide/ glycopyrronium/ formoterol fumarate dihydrate in pregnant women
• Data on the use of inhaled budesonide in more than 2 500 exposed pregnancies indicate no increased teratogenic risk associated with budesonide. Single-dose studies in humans found that very small amounts of glycopyrronium passed the placental barrier
• There are no adequate data from use of formoterol or glycopyrronium in pregnant women. No animal reproductive toxicology studies have been conducted with this combination product. Budesonide has been shown to induce embryofoetal toxicity in rats and rabbits, a class effect of glucocorticoids. At very high doses/systemic exposure levels, formoterol caused implantation losses as well as decreases in birth weight and early postnatal survival, whereas glycopyrrolate had no significant effects on reproduction
• Budesonide/ glycopyrronium/ formoterol fumarate dihydrate should only be used during pregnancy if the expected benefits outweigh the potential risks

Breastfeeding

South African recommendations

• Caution
• A clinical pharmacology study has shown that inhaled budesonide is excreted in breast milk
• However, budesonide was not detected in nursing infant blood samples. Based on pharmacokinetic parameters, the plasma concentration in the child is estimated to be less than 0.17% of the mother’s plasma concentration
• Consequently, no effects due to budesonide are anticipated in breastfed children whose mothers are receiving therapeutic doses of budesonide/ glycopyrronium/ formoterol fumarate dihydrate
• It is not known whether glycopyrronium or formoterol are excreted in human milk. Evidence of transfer of glycopyrronium and formoterol into maternal milk in rats has been reported

Fertility

South African recommendations

• Studies in rats have shown slight reductions in fertility only at dose levels higher than the maximum human exposure to formoterol
• Budesonide and glycopyrronium individually, did not cause any adverse effects on fertility in rats. It is unlikely that budesonide/ glycopyrronium/ formoterol fumarate dihydrate administered at the recommended dose will affect fertility in humans

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  It can also be used at the recommended dose in patients with severe renal impairment or end-stage renal disease requiring dialysis, only if the expected benefit outweighs the potential risk

South African recommendations

• Mild to moderate: No dose adjustment recommended
  Severe: Caution; no dose adjustment recommended
  In patients with severe hepatic impairment, this combination product should be used only if the expected benefit outweighs the potential risk

South African recommendations

• No dose adjustment recommended

Infections and Infestations

Common

• Oral candidiasis
• Pneumonia

Immune System Disorders

Uncommon

• Hypersensitivity

Endocrine Disorders

Very rare

• Signs or symptoms of systemic glucocorticosteroid effects, e.g. hypofunctions of the adrenal gland

Metabolism and Nutrition Disorders

Common

• Hyperglycaemia

Psychiatric Disorders

Common

• Anxiety
• Insomnia

Uncommon

• Depression
• Agitation
• Restlessness
• Nervousness

Very rare

• Abnormal behaviour

Nervous System Disorders

Common

• Headache

Uncommon

• Tremor
• Dizziness

Cardiac Disorders

Common

• Palpitations

Uncommon

• Angina pectoris
• Tachycardia
• Cardiac arrhythmias (atrial fibrillation, supraventricular tachycardia and extrasystoles)

Respiratory, Thoracic and Mediastinal Disorders

Common

• Dysphonia
• Cough

Uncommon

• Throat irritation
• Bronchospasm

Gastrointestinal Disorders

Common

• Nausea

Uncommon

• Dry mouth

Renal and Urinary Disorders

Common

• Urinary tract infection

Uncommon

• Urinary retention

Musculoskeletal and Connective Tissue Disorders

Common

• Muscle spasms

General Disorders and Administration Site Conditions

Uncommon

• Chest pain

• Other anticholinergic and/or long-acting β₂-adrenergic agonist
• Strong CYP3A inhibitors (see Additional Prescribing Points)
• Itraconazole
• Ketoconazole
• HIV protease inhibitors
• Cobicistat-containing products
• Medicines affecting renal excretion mechanisms
• Inhibitors of OCT2 and MATE1
• Cimetidine
• Non-potassium sparing diuretics
• Beta-adrenergic blockers
• Medicinal products known to prolong the QTc-interval

None routine. Specific cases may require

• Blood glucose
• Renal function
• Hepatic function
• Ophthalmic examination
• Bone mineral density

Additional Observations

• Deterioration of disease
• Signs of pneumonia
• Adrenal insufficiency
• Paradoxical bronchospasm
• Cardiovascular status
• Urinary retention

Metabolic interactions

• The metabolism of budesonide is primarily mediated by CYP3A4. Co-treatment with strong CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products, are expected to increase the risk of systemic side effects
• This is of limited clinical importance for short-term (1-2 weeks) treatment, but should be taken into consideration during long-term treatment with a strong CYP3A4 inhibitor

Budesonide, a glucocorticosteroid, and two bronchodilators: glycopyrronium, a long-acting muscarinic antagonist (anticholinergic) and formoterol, a long-acting β₂- adrenergic agonist make up this combination product. The combination of these substances with different mechanisms of action results in increased efficacy compared to use with any of the dual component therapies.

Budesonide

Budesonide, when inhaled, has a rapid (within hours) and dose dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer COPD exacerbations. Inhaled budesonide has less severe adverse effects than systemic corticosteroids.

Glycopyrronium

Glycopyrronium has a rapid onset of action and has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, bronchodilation is induced through inhibition of the M3 receptor at the smooth muscle.

Formoterol

Formoterol has a rapid onset of action. Bronchodilation is induced by causing direct relaxation of airway smooth muscle as a consequence of the increase in cyclic AMP through activation of adenylate cyclase.

As a consequence of the differential density of muscarinic receptors and β₂-adrenoceptors in the central and peripheral airways of the lung, muscarinic antagonists are more effective in relaxing central airways and β2-adrenergic agonists are more effective in relaxing peripheral airways; relaxation of both central and peripheral airways with combination treatment may contribute to its beneficial effects on lung function.