Fluticasone propionate

Fluticasone propionate is a synthetic trifluorinated glucocorticoid which exhibits antiallergic, anti-inflammatory, and antipruritic effects. ^[1,2] It is available as sprays, inhalers, nasal, and topical therapies for various inflammatory indications. ^[1]

Pharmacological Class: Corticosteroids

• Oral fluticasone is indicated for treating asthma and has an off label use for chronic obstructive lung disease (COPD) and eosinophilic esophagitis
• Nasal fluticasone is indicated for treating allergic and non-allergic rhinitis, nasal polyps, and allergies
• Topical fluticasone is indicated for treating atopic dermatitis, inflammatory and pruritic dermatoses^[1,2,4] 

It shows a direct local effect of vasoconstriction and anti-inflammatory activity. It suppresses the initial inflammatory events such as vascular permeability, vasodilation, and leukocyte emigration. It also  reduces inflammatory cells such as monocytes, macrophages, mast cells, eosinophils, and dendritic cells and the number of cytokines.

It also stimulates beta-2 receptors on airway smooth muscle and minimizes mucus gland secretions. It also increases the anti-inflammatory effects of annexin-1, secretory leukoprotease inhibitor (SLPI), mitogen-activated kinase phosphatase-1 (MKP-1), glucocorticoid-induced leucine zipper protein (GILZ), and I-kappa B-alpha and inhibitor of nuclear factor (NF)-kappa B.^[4] 

Recommended starting dosages for allergic and non-allergic rhinitis, nasal polyps, and allergies:

• Adults: 200 mcg/day
• Adolescents and children aged four years and older: 100 mcg/day

Recommended starting dosages for asthma:

• Patients aged 12 years and older: 100 mcg twice daily up to a maximum dose of 1,000 mcg twice daily
• Patients aged 4 to 11 years: 50 mcg twice daily up to a maximum dose of 100 mcg twice daily^[3] 

Absorption 

The oral bio-availability is <1% while the intranasal bio-availability is <2%. The intranasal exposure leads to the majority of the dosage being swallowed. Topical absorption is very low but can alter depending on various factors including skin integrity and the presence of disease or inflammation.

Volume of distribution

The volume of distribution of intravenous fluticasone propionate is about 4.2 l/kg.

Protein binding

It is 99% protein-bound in serum while the topical fluticasone propionate is only 91% protein-bound in serum.

Metabolism
It is cleared by cytochrome P450 3A4 via hepatic metabolism. It is hydrolyzed at the FIVE-S-fluoromethyl carbothioate group, leading to the formation of an inactive metabolite.

Route of elimination

It is predominantly eliminated in the feces with <5% excreted in the urine.

Half-life
The half-life for intravenous fluticasone propionate is 7.8 hours.

Clearance

The clearance of fluticasone propionate is 1093mL/min. The total blood clearance is quite elevated (average: 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total.^[1,3]   

• It is contraindicated in individuals with hypersensitivity to this medicine
• Its use is also contraindicated as a primary therapy of acute bronchospasm^[4] 

Concomitant use of strong CYP3A4 inhibitors (such as voriconazole, ritonavir,  itraconazole, atazanavir, clarithromycin, indinavir, ketoconazole, telithromycin, lopinavir) with fluticasone propionate is not recommended, as its coadministration can raise the risk of systemic corticosteroid noxious effects.^[3] 

Most common adverse reactions (>3%) observed in clinical trials are:

• Headache
• Pharyngitis
• Nasal burning/nasal irritation
• Nausea/vomiting
• Cough
• Epistaxis

Adverse events reported during post-approval usage of intranasal fluticasone propionate:

• General Disorders and Administration Site Conditions: Bronchospasm, urticaria,  skin rash, pruritus, angioedema, edema of the face and tongue, dyspnea, wheezing, and anaphylaxis/anaphylactoid reactions
• Eye Disorders: Blurred vision, dryness and irritation, cataracts, conjunctivitis, glaucoma, and raised intraocular pressure
• Ear and Labyrinth Disorders: Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, irritation and dryness in throat, hoarseness, nasal ulcer, sore throat, voice alterations, and cough

Adverse events observed with systemic and local use:

• Nasal septal perforation, epistaxis, impaired wound healing, nasal ulceration, and Candida albicans infection
• Hypercorticism and adrenal suppression
• Glaucoma and cataracts
• Effect on growth 
• Immunosuppression 

• Avoid use in individuals with recent nasal trauma, nasal surgery, or nasal ulcers.
• Hypersensitivity reactions (like rash, anaphylaxis, urticaria, angioedema, contact dermatitis) have been noted after treatment with fluticasone propionate nasal spray Therefore, discontinue the nasal spray use if there is an occurrence of such reactions
• Use with caution in patients having a history of cataracts, raised intraocular pressure, and/or glaucoma
• Ocular herpes simplex infection may occur as potential worsening of infections therefore it should be used cautiously in individuals with existing tuberculosis, parasitic, fungal, viral, or  bacterial infection
• Regular and elevated dosage can cause adrenal suppression and hypercorticism in susceptible people. Slowly discontinue the spray, if such alterations are observed
• Monitor the growth of pediatric patients receiving the nasal spray regularly as it may cause a decline in growth velocity when given to the pediatric patients^[3] 

Study compares tolerability and safety of fluticasone propionate tablet to treat eosinophilic oesophagitis 

A study demonstrated efficacy and safety of APT-1011, a new oral disintegrating tablet formulation of fluticasone, in adolescents and adults with eosinophilic oesophagitis. Two dosing regimens of APT-1011 were given orally to patients for over eight weeks.

The effect of APT-1011 on clinical symptoms of eosinophilic oesophagitis, endoscopic appearance, and oesophageal mucosal eosinophil count/eosinophilia was determined. The major outcomes was determination of safety and tolerability. The exploratory outcomes were assessment of histologic and endoscopic measures.

APT-1011 therapy led to an elevated decrease in oesophageal eosinophil counts, eosinophilic oesophagitis Endoscopic Reference Score, patient global assessment, and symptom-based eosinophilic oesophagitis activity index from baseline to end of therapy (Week 8) in comparison with placebo. No mortality, serious or severe treatment-emergent adverse events (TEAEs), and discontinuations from the trial associated with TEAE were witnessed.

In one individual allocated to 1.5 mg APT-1011, a decline in cortisol was noted, but without any proof of adrenal insufficiency. Exploratory efficacy outcomes illustrated improvement in symptoms, endoscopic and histologic findings. Thus, APT-1011, a new orally disintegrating tablet formulation of fluticasone is safe and well-tolerated and thus offers an effective therapeutic strategy to manage patients suffering from eosinophilic oesophagitis.^[5] 

Fluticasone propionate found to improve nasal symptoms of seasonal allergic rhinitis

In a randomized trial, fluticasone propionate aqueous nasal spray 200 mcg used as needed (FP200PRN) was found to effectively treat nasal symptoms (nasal congestion, rhinorrhea, nasal itching, and sneezing) linked with seasonal allergic rhinitis in patients 12 years and older.

This study was carried out to explore the efficacy and safety of four weeks treatment with FP200PRN in 241 patients suffering from seasonal allergic rhinitis. Fluticasone propionate was also found to have a minimized occurrence of side effects in comparison with regular once-daily usage.^[6] 

1. Fluticasone propionate. Drug bank. Accession no: DB00588. Available online from: https://go.drugbank.com/drugs/DB00588 [Last accessed on: 4 June 2021]
2. Fluticasone propionate. PubChem. CID 5311101. Available online from: https://pubchem.ncbi.nlm.nih.gov/compound/Fluticasone [Last accessed on: 4 June 2021]
3. Fluticasone propionate.  FDA LABEL. Available online from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020121s045lbl.pdf [Last accessed on: 4 June 2021]
4. Remien K, Bowman A. Mechanism of Action. Available online from: https://www.ncbi.nlm.nih.gov/books/NBK542161/ [Last accessed on: 4 June 2021]
5. Hirano I, Safroneeva E, Roumet MC, Comer GM, Eagle G, Schoepfer A, Falk GW. Randomised clinical trial: the safety and tolerability of fluticasone propionate orally disintegrating tablets versus placebo for eosinophilic oesophagitis. Alimentary pharmacology & therapeutics. 2020 Apr;51(8):750-9.
6. Dykewicz MS, Kaiser HB, Nathan RA, Goode-Sellers S, Cook CK, Witham LA, et al. Fluticasone propionate aqueous nasal spray improves nasal symptoms of seasonal allergic rhinitis when used as needed (prn). Annals of Allergy, Asthma & Immunology. 2003 Jul 1;91(1):44-8.