Fluticasone Furoate/ Umeclidinium/ Vilanterol

Registered South African indications:

• Chronic obstructive pulmonary disease (COPD)

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Severe milk-protein allergy (South African manufacturer recommendations)

Cautions
South African recommendations

• Pregnancy
• Breastfeeding
• Moderate to severe hepatic impairment
• Asthma
• Acute use
• Unstable or life-threatening cardiovascular disease
• Heart rhythm abnormalities
• Hypothyroidism
• Uncorrected hypokalaemia
• High dosages
• Hypoxia 
• Acidosis
• Pulmonary tuberculosis 
• Chronic or untreated infections
• Narrow-angle glaucoma 
• Urinary retention
• Risk factors for pneumonia in patients with chronic obstructive pulmonary disease (COPD)
  - Smokers
  - History of prior pneumonia
  - Low body mass index (BMI)
  - Severe chronic obstructive pulmonary disease (COPD)
• Diabetes mellitus
  - History of diabetes mellitus
• Coadministration with other medicines that cause hypokalaemia and cardiac dysrhythmias
• Galactose intolerance e.g. galactosaemia
• Lapp lactase deficiency 
• Glucose-galactose malabsorption 
• Fructose intolerance

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Moderate to severe hepatic impairment
• Asthma
• Acute use
• Deterioration of chronic obstructive pulmonary disease (COPD)
• Unstable or life-threatening cardiovascular disease
• High doses for prolonged periods
• Seizure disorders
• Thyrotoxicosis
• Unusually responsive to beta₂-adrenergic agonists
• Pulmonary tuberculosis 
• Chronic or untreated infections
• Narrow-angle glaucoma 
• Urinary retention
• Risk factors associated with pneumonia in patients with chronic obstructive pulmonary disease (COPD)
  - Smoking
  - Elderly
  - Low body mass index (BMI)
  - Severe chronic obstructive pulmonary disease (COPD) 
• Diabetes mellitus
  - History of diabetes mellitus
• Coadministration with other medicinal products that also have the potential to cause hypokalaemia
• Galactose intolerance
• Total lactase deficiency 
• Glucose-galactose malabsorption

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

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Chronic obstructive pulmonary disease (COPD)
- Maintenance treatment to prevent and relieve symptoms

Fluticasone Furoate/ Umeclidinium/ Vilanterol
92/55/22 (μg)

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

Fluticasone furoate/ umeclidinium/ vilanterol is for oral inhalation only. After inhalation, the patient should rinse their mouth with water without swallowing. Dose should be administered at the same time each day

Instructions for use: See additional prescribing points. Instructions for the 30 dose (30 day supply) inhaler also apply to the 14 dose (14 day supply) inhaler

Indications and dosages registered in other jurisdictions

Chronic obstructive pulmonary disease (COPD) - moderate to severe
- Maintenance treatment in patients who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting beta₂-agonist or a combination of a long-acting beta₂-agonist and a long-acting muscarinic antagonist

Fluticasone Furoate/ Umeclidinium/ Vilanterol
92/55/22 (μg)

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

 For inhalation use only. After inhalation, the patient should rinse their mouth with water without swallowing. Dose should be administered at the same time each day

If a dose is missed the next dose should be inhaled at the usual time the next day

Instructions for use: See additional prescribing points. Instructions for the 30 dose (30 day supply) inhaler also apply to the 14 dose (14 day supply) inhaler

Not indicated for use in children

Pregnancy
South African recommendations

• Caution; positive evidence of risk in animal studies
• Safety in pregnancy is not established
• There are insufficient data from the use of fluticasone furoate/ umeclidinium/ vilanterol in pregnant women. Animal studies have shown reproductive toxicity after administration of beta₂-agonists or corticosteroids

Recommendations in other jurisdictions

• Caution
• There are limited data from the use of fluticasone furoate/umeclidinium/vilanterol in pregnant women
• Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant. Administration of fluticasone furoate/ umeclidinium/ vilanterol to pregnant women should only be considered if the expected benefit to the mother justifies the potential risk to the foetus

Breastfeeding

• Caution 
• Safety in breastfeeding is not established 
• It is unknown whether fluticasone furoate, umeclidinium, vilanterol or their metabolites are excreted in human milk. However, other corticosteroids, muscarinic antagonists and beta₂-agonists are detected in human milk
• A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue fluticasone furoate/ umeclidinium/ vilanterol therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility 
South African recommendations

• No information available

Recommendations in other jurisdictions

• There are no data on the effects of fluticasone furoate/ umeclidinium/ vilanterol on human fertility. Animal studies indicate no effects of fluticasone furoate, umeclidinium or vilanterol on male or female fertility

Renal Impairment

• No dose adjustment recommended 

Hepatic Impairment 
South African recommendations

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; no dose adjustment recommended 
  Monitor for systemic corticosteroid-related adverse reactions. Umeclidinium has not been studied in patients with severe hepatic impairment

Recommendations in other jurisdictions

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; no dose adjustment recommended 
  Monitor for systemic corticosteroid-related adverse reactions

Elderly

• No dose adjustment recommended 

Drugs in Sport

• Permitted - With warnings
  Prohibited substance: Vilanterol - refer to section S3 (beta-2 agonists) of the world anti-doping agency (WADA) 2022 prohibited list
  All selective and non-selective beta-2 agonists, including all optical isomers, are prohibited except for
  - Inhaled salbutamol: maximum 1600μg over 24 hours in divided doses not to exceed 600μg over 8 hours starting from any dose
  - Inhaled formoterol: maximum delivered dose of 54μg over 24 hours
  - Inhaled salmeterol: maximum 200μg over 24 hours
  - Inhaled vilanterol: maximum 25μg over 24 hours
  Vilanterol, a beta-2-agonist was included in the WADA 2022 monitoring program to assess patterns and prevalence of misuse in- and out-of-competition below the minimum reporting level

Central Nervous System Disorders

• Headache

Cardiovascular Disorders 

• Supraventricular tachyarrhythmia
• Tachycardia
• Atrial fibrillation

Respiratory Disorders 

• Pneumonia
• Upper respiratory tract infection
• Viral respiratory tract infection
• Bronchitis
• Pharyngitis
• Nasopharyngitis
• Rhinitis
• Sinusitis
• Cough
• Oropharyngeal pain 
• Dysphonia

Gastrointestinal Disorders 

• Constipation
• Dry mouth
• Candidiasis of mouth and throat

Genitourinary Disorders

• Urinary tract infection

Musculoskeletal Disorders 

• Arthralgia
• Back pain
• Fractures

Immune, Blood and Lymphatic System Disorders 

• Influenza
• Hypersensitivity reactions
  - Anaphylaxis
  - Angioedema
  - Urticaria
  - Rash

Sensory Disorders 

• Dysgeusia
• Blurred vision 
• Glaucoma
• Eye pain
• Increased intraocular pressure

• Beta-adrenergic blockers (See additional prescribing points)
• Strong CYP3A4 inhibitors
• Ketoconazole
• Ritonavir
• Cobicistat containing products
• Methylxanthine derivatives
• Steroids
• Non-potassium-sparing diuretics
• Other long-acting muscarinic antagonists
• Other long-acting beta₂-adrenergic agonists

• Pulmonary function 
  - Forced expiratory volume (FEV1)
  - Peak flow
• Blood pressure
• Heart rate
• Ophthalmic examination
  - Intraocular pressure
  - Cataracts
• Bone mineral density 

Specific cases may require

• Serum potassium (hypokalemic patients)
• Blood glucose (diabetic patients)

Additional observations

• Signs/symptoms of
  - Oral or systemic infection
  - Hypercortisolism
  - Adrenal suppression

Beta-adrenergic blockers

• Beta-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists, such as vilanterol. If beta-blockers are required, cardioselective beta-blockers should be considered, however, caution should be exercised during concurrent use of both non-selective and selective beta-blockers

Fluticasone furoate/ umeclidinium/ vilanterol is a combination of inhaled synthetic corticosteroid, long-acting muscarinic receptor antagonist and long-acting beta2-adrenergic agonist (ICS/LAMA/LABA). Following oral inhalation, umeclidinium and vilanterol act locally on airways to produce bronchodilation by separate mechanisms and fluticasone furoate reduces inflammation.

Fluticasone furoate
Fluticasone furoate is a corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects chronic obstructive pulmonary disease (COPD) symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (e.g. cytokines and chemokines) involved in inflammation.

Umeclidinium
Umeclidinium is a long-acting muscarinic receptor antagonist (also referred to as an anticholinergic). Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.

Vilanterol
Vilanterol is a selective long-acting, beta₂-adrenergic receptor agonist (LABA). The pharmacologic effects of beta₂- adrenergic agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate 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 and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

COMBINATION PREPARATIONS

Fluticasone Furoate/ Umeclidinium/ Vilanterol

Inhaler 92μg/55μg/22μg

• Trelegy Ellipta (GlaxoSmithKline) originator