Indacaterol/ Glycopyrronium/ Mometasone Furoate

Registered South African indications:

• Asthma
  - Maintenance treatment of asthma and reduction of exacerbations in those not adequately controlled with a maintenance combination of a long-acting beta₂-agonist and an inhaled corticosteroid

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment (eGFR<30ml/min/1.73m²)
  - End-stage renal disease requiring dialysis
• Severe hepatic impairment
• Deterioration of disease
• Acute asthma
• Acute episodes of bronchospasm for which a short-acting bronchodilator is required
• Withdrawal of treatment without medical practitioner supervision
• Cardiovascular disorders
  - Coronary artery disease
  - Acute myocardial infarction
  - Cardiac dysrhythmias
  - Hypertension
• Seizure disorders
• Hyperthyroidism
• Unusual responsiveness to beta₂-adrenergic agonists
• Known or suspected QT prolongation
• Pre-existing hypokalaemia
• Hypoxia
• Diabetes mellitus
• Narrow-angle glaucoma
• Urinary retention
• Pulmonary tuberculosis
• Chronic or untreated infections
• Human immunodeficiency virus (HIV)
• Coadministration with agents affecting QT interval
• Lactose intolerance
• Galactose intolerance e.g. galactosaemia
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Fructose intolerance
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment (eGFR<30ml/min/1.73m²)
  - End-stage renal disease requiring dialysis
• Severe hepatic impairment
• Low body weight (LBW) (<35kg)
  - Including LBW (<35kg) and low absolute GFR 45ml/min/1.73m²
• Deterioration of disease
• Acute asthma
• Acute episodes of bronchospasm for which a short-acting bronchodilator is required
• Withdrawal of treatment without medical practitioner supervision
• Abrupt withdrawal
• Cardiovascular disorders
  - Coronary artery disease
  - Acute myocardial infarction
  - Cardiac arrhythmias
  - Hypertension
• Seizure disorders
• Thyrotoxicosis
• Unusual responsiveness to beta₂-adrenergic agonists
• Unstable ischaemic heart disease
• History of myocardial infarction in last 12 months
• New York Heart Association (NYHA) class III/IV left ventricular failure
• Arrhythmia
• Uncontrolled hypertension
• Cerebrovascular disease
• History of long QT syndrome
• Known or suspected prolongation of QT interval
• Hypokalaemia
• Hypoxia
• Type I and Type II diabetes mellitus (including uncontrolled Type II diabetes mellitus)
• Narrow-angle glaucoma
• Urinary retention
• Pulmonary tuberculosis
• Chronic or untreated infections
• Coadministration with agents known to prolong QT interval
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

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

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Asthma
- Maintenance treatment of asthma and reduction of exacerbations in those not adequately controlled with a maintenance combination of a long-acting beta₂-agonist and an inhaled corticosteroid

Indacaterol/ Glycopyrronium/ Mometasone Furoate
150/50/80 (μg)

• Inhaled (cps): 1 cap, dly

150/50/160 (μg)

• Inhaled (cps): 1 cap, dly; Max: 1 inhalation/24hrs

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Patients should be given the strength of indacaterol/ glycopyrronium/ mometasone furoate containing the appropriate mometasone furoate dosage for the severity of their disease and should be regularly reassessed by a healthcare professional

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Patients usually experience an improvement in lung function within 5 minutes of inhaling indacaterol/ glycopyrronium/ mometasone furoate. However, the patient should be informed that regular daily use is necessary to maintain control of asthma symptoms and that use should be continued even when asymptomatic

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If a dose is missed, it should be taken as soon as possible. Patients should be instructed not to take more than one dose in a day

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International manufacturer recommendations

Asthma
- Maintenance therapy of asthma in those not adequately controlled with a maintenance combination of a long-acting beta₂-agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year

Indacaterol/ Glycopyrronium/ Mometasone Furoate
150/50/160 (μg)

• Inhaled (cps): 1 cap, dly; Max: 1 inhalation/24hrs

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Treatment should be administered at the same time of the day each day. It can be administered irrespective of the time of the day. If a dose is missed, it should be taken as soon as possible. Patients should be instructed not to take more than one dose in a day

Not established for use in children below 18 years

Pregnancy

South African manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• Safety in pregnancy has not been established
• Indacaterol and glycopyrronium was not teratogenic in rats or rabbits following subcutaneous administration
• In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate was teratogenic and when used, caused increased foetal malformations and decreased foetal survival and growth
• The indacaterol component may inhibit labour due to a relaxant effect on uterine smooth muscle

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• There are insufficient data from the use of this combination inhaler or its individual components (indacaterol, glycopyrronium and mometasone furoate) in pregnant women to determine whether there is a risk
• Indacaterol and glycopyrronium were not teratogenic in rats and rabbits following subcutaneous or inhalation administration, respectively
• In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate caused increased foetal malformations and decreased foetal survival and growth
• Like other medicinal products containing beta₂-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle
• This medicinal product should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus

Breastfeeding

South African manufacturer recommendations

• Caution 
• Safety in breastfeeding has not been established

International manufacturer recommendations

• Caution; not recommended 
• There is no information available on the presence of indacaterol, glycopyrronium or mometasone furoate in human milk, on the effects on a breastfed infant, or on the effects on milk production
• Other inhaled corticosteroids similar to mometasone furoate are transferred into human milk
• Indacaterol, glycopyrronium and mometasone furoate have been detected in the milk of lactating rats 
• Glycopyrronium reached up to 10-fold higher concentrations in the milk of lactating rats than in the blood of the dam after intravenous administration
• A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility 

• Reproduction studies and other data in animals did not indicate a concern regarding fertility in either males or females

Renal Impairment

South African manufacturer recommendations

• Mild to moderate (eGFR≥30ml/min/1.73 m²): No dose adjustment recommended 
• Severe (eGFR<30ml/min/1.73 m²)/ End-stage renal disease requiring dialysis: Caution; no information available 

International manufacturer recommendations

• Mild to moderate (eGFR≥30ml/min/1.73 m²): No dose adjustment recommended 
• Severe (eGFR<30ml/min/1.73 m²)/ End-stage renal disease requiring dialysis: Caution; no dose adjustment recommended 

Hepatic Impairment 

• Mild or moderate: No dose adjustment recommended 
• Severe: Caution; no information available 

Elderly

• ≥65 years: No dose adjustment recommended 

Low body weight

International manufacturer recommendations

• Total systemic exposure (AUC) for glycopyrronium may be up to 1.8-fold higher in asthma patients with low body weight (35kg) and up to 2.5-fold higher in asthma patients with low body weight (35kg) and low absolute GFR (45ml/min/1.73m²)

Drugs in Sport

• Prohibited - At all times

Central Nervous System Disorders

• Headache
  - Tension headache
• Psychological or behavioural effects
  - Psychomotor hyperactivity
  - Sleep disorders
  - Anxiety
  - Depression or aggression (particularly in children)

Cardiovascular Disorders

• Tachycardia
  - Sinus tachycardia
  - Supraventricular tachycardia
• Increased blood pressure
• Electrocardiographic (ECG) changes
  - Flattening of the T wave
  - Prolongation of QT interval
  - ST-segment depression

Respiratory Disorders

• Nasopharyngitis
• Upper respiratory tract infection
• Asthma (exacerbation)
• Oropharyngeal candidiasis
• Oropharyngeal pain
  - Odynophagia
  - Oropharyngeal discomfort
  - Throat irritation
• Cough
• Dysphonia
• Paradoxical bronchospasm

Gastrointestinal Disorders

• Oral candidiasis
• Gastroenteritis
  - Chronic gastritis
  - Enteritis
  - Gastritis
  - Gastrointestinal inflammation
• Dry mouth
  - Dry throat

Genitourinary Disorders

• Urinary tract infection
  - Asymptomatic bacteriuria
  - Bacteriuria
  - Cystitis
  - Urethritis
  - Viral urinary tract infection
• Dysuria

Endocrine and Metabolic Disorders

• Hyperglycaemia
  - Increased blood glucose
• Hypokalaemia
• Cushing's syndrome
• Cushingoid features
• Adrenal suppression
• Growth retardation in children and adolescents
• Decrease in bone mineral density

Musculoskeletal Disorders

• Musculoskeletal pain
  - Back pain
  - Musculoskeletal chest pain
  - Myalgia
  - Neck pain
• Muscle spasms

Skin and Subcutaneous Tissue Disorders

• Rash
  - Drug eruption
  - Papular rash
  - Pruritic rash
• Pruritus
  - Eye pruritus
  - Genital pruritus

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Drug eruption
  - Drug hypersensitivity
  - Rash
  - Pruritic rash
  - Urticaria
• Angioedema
  - Difficulties in breathing or swallowing
  - Swelling of the tongue, lips and face
• Pyrexia
• Candidiasis

Sensory Disorders

• Cataract
• Glaucoma
• Visual disturbance
• Blurred vision
• Central serous chorioretinopathy (CSCR)

• QT prolonging agents
• Monoamine oxidase inhibitors
• Tricyclic antidepressants
• Hypokalaemic agents
• Methylxanthine derivatives
• Steroids
• Non-potassium-sparing diuretics
• Beta-adrenergic blockers
  (See additional prescribing points)
• Strong CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Nelfinavir
• Ritonavir
• Cobicistat
• Long-acting muscarinic antagonists
• Long-acting beta₂-adrenergic agonists

None routine. Specific cases may require

• Pulmonary function
  - Forced expiratory volume (FEV₁)
  - Peak flow
• Serum glucose
• Serum potassium
• Hepatic function
• Bone mineral density
• Blood pressure
• Heart rate
• CNS stimulation
• Hypothalamic-pituitary-adrenal axis suppression
• Ophthalmic examination (chronic users)

Additional observations

• Monitor
  - Symptom relief
  - Increased use of short-acting beta-₂ adrenergic agonists
• Signs and symptoms
  - Oral candidiasis
  - Possible eosinophilic conditions (including eosinophilic granulomatosis with polyangiitis [formerly known as Churg-Strauss syndrome])
  - Hypersensitivity reactions
  - Urinary retention

Administration directions

• For inhalation use only. Indacaterol/ glycopyrronium/ mometasone furoate capsules MUST NOT BE SWALLOWED
• Patients should be instructed on how to administer the medicinal product correctly
• The capsules must be administered only using the provided inhaler
• The inhaler provided with each new prescription should be used
• Indacaterol/ glycopyrronium/ mometasone furoate should be administered at the same time of the day each day
• It can be administered irrespective of the time of the day
• The capsules must always be stored in the blister to protect from moisture and light, and only removed immediately before use
• After inhalation, patients should rinse their mouth with water without swallowing

Beta-adrenergic blockers

• Beta-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists
• Therefore, this medicinal product should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use
• Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution

Indacaterol
Indacaterol is a long-acting beta₂-adrenergic agonist for once-daily administration. The pharmacological effects of beta₂-adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human beta₂-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.

Glycopyrronium
Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anti-cholinergic). Glycopyrronium works by blocking the broncho-constrictor action of acetylcholine on airway smooth muscle cells thereby dilating the airways. Of the five known muscarinic receptor subtypes (M1-5), only subtypes M1-3 have a defined physiological function in the human lung. Glycopyrronium is a high affinity muscarinic receptor antagonist of these three receptor subtypes. It demonstrated 4- to 5-fold selectivity for the human M3 and M1 receptors over the human M2 receptor in competition binding studies. It has a rapid onset of action, as evidenced by observed receptor association/dissociation kinetic parameters and by the onset of action after inhalation in clinical studies. The long duration of action can be partly attributed to sustained drug concentrations in the lungs as reflected by the prolonged terminal elimination half-life of glycopyrronium after inhalation.

Mometasone furoate
Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. It is likely that much of the mechanism for the effects of mometasone furoate lies in its ability to inhibit the release of mediators of the inflammatory cascade. In vitro, mometasone furoate inhibits the release of leukotrienes (LT) from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of LT production and an extremely potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+ T-cells.

COMBINATION PREPARATIONS

Indacaterol/ Glycopyrronium/ Mometasone furoate

Capsules, lung admin 150μg/50μg/80μg

• Zimbus Breezhaler (Novartis) originator

Capsules, lung admin 150μg/50μg/160μg

• Zimbus Breezhaler (Novartis) originator