Fluticasone

Fluticasone belongs to the pharmacological class of Corticosteroids.

Fluticasone has been approved for relieving symptoms and also for the treatment and maintenance of episodes of asthma, allergic rhinitis, and nasal polyp.

Fluticasone is slightly absorbed and rapidly metabolized. The nasal bioavailability is found to be 0.50%, and oral bioavailability is found to be 1.26%. The inhalation bioavailability of fluticasone was found to be 13.9%. Fluticasone achieved a steady state mean volume of distribution was found to be 661L.

Both Fluticasone furoate and Fluticasone propionate have been found to be cleared from hepatic metabolism by cytochrome P450 3A4. Both are found to be hydrolyzed at the 5-S-fluoromethyl carbothioate group, thereby forming an inactive metabolite. The major route of elimination for Fluticasone furoate is ≥90% in the feces, and 1-2% in the urine, whereas the significant way of elimination for Fluticasone propionate, is mainly in the feces with <5% eliminated in the urine

The common side effects associated with Fluticasone are nausea, headache, diarrhea, dizziness, dryness, etc.

Fluticasone is available in the form of Oral Inhalation, Topical, and Nasal Inhalation. Fluticasone is available in the U.S., Canada, E.U., India, Australia, and Japan.

Fluticasone belongs to the pharmacological class of Corticosteroids.

The exact mechanism of action of the fluticasone furoate and propionate is unknown. But the in vitro experiments show that Fluticasone furoate is activated by glucocorticoid receptors, inhibiting the nuclear factor kappa b and also inhibiting lung eosinophilia in rats. Fluticasone propionate is said to perform a similar activity but is not stated to affect nuclear factor kappa b.

Fluticasone has been approved for relieving symptoms and also for the treatment and maintenance of episodes of asthma. Allergic rhinitis and nasal polyp.

The onset of the therapeutic effect occurs within 12 hours of the fluticasone medication. The elimination half-life of fluticasone was found to be 7.8 hours.

Fluticasone can be used in the treatment of:

• Asthma
• Allergic Rhinitis
• Nasal Polyp

Fluticasone is approved for use in the following clinical indications:

• Asthma
• Allergic Rhinitis
• Nasal Polyp

Oral Inhalation

1. It should be made sure that the cap is closed before starting to use the inhaler.
2. The inhaler is held upright, and opens the cap until it "clicks."
3. The medication is inhaled via mouth as directed by the physician, usually twice daily (in the morning and evening, 12 hours apart).
4. Each dose is inhaled to get the drug into the lungs.
5. One may or may not taste/feel the drug when one inhales it. Either is normal.
6. The air should not be breathed out of the device. Close the cap firmly after each use.

Topical

To be applied at the site of application as per the direction of the physician.

Nasal Inhalation

1. The nostrils should be blown gently, then 1 nostril should be closed with your finger.
2. The Head is bent forward slightly, and the nozzle is kept carefully into your other nostril.
3. Air is breathed out of the nose slowly, and the fingers pressed down onto the widest part of the nozzle to squirt the spray once into the nostril.
4. Air is breathed out of the mouth.
5. Follow steps three and four again to squirt a second spray (if needed).
6. The same process is repeated in the other nostril.

Asthma

In adults

It is indicated for maintenance treatment of asthma as prophylactic therapy

One inhalation PO qDay; not to exceed one inhalation every 24 hr

Starting dose is based on asthma severity

Recommended starting dose: 100 mcg/day

May increase to 200 mcg/day after two weeks if the patient does not respond to 100 mcg/day

It is indicated for once-daily maintenance treatment of asthma as prophylactic therapy in children aged ≥5 years

Not to exceed 200 mcg qDay

In pediatric

<5 years: Safety and efficacy not established

5-11 years: 50 mcg inhaled PO qDay

≥12 years:

One inhalation PO qDay; not to exceed one inhalation every 24 hr

Starting dose is based on asthma severity

Recommended starting dose: 100 mcg/day

This may increase to 200 mcg/day after two weeks if the patient does not respond to 100 mcg/day

Not to exceed 200 mcg qDay

Oral Inhalation, Topical, and Nasal Inhalation

• Dosage Adjustments in Pediatric Patients:

No dosage adjustments are needed for patients under five years of age as it is not recommended.

Smoking cessation and maintaining health are a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol should be avoided in the patient, especially with an underlying liver disorder or liver dysfunction

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions need to be individualized as per the patient's requirements.

Fluticasone may be contraindicated under the following conditions:

• Hypersensitivity to the ingredients of the medication

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Local Nasal Effects

Epistaxis

In clinical trials of two to twenty-six weeks duration, epistaxis was observed more frequently in subjects treated with Fluticasone nasal spray than those who received a placebo.

Nasal Ulceration

Postmarketing reports of nasal ulceration had been reported in patients who were treated with Fluticasone nasal spray .

Candida Infection

In clinical trials with fluticasone propionate which was administered intranasally, the development of local infections of pharynx and the nose with Candida albicans had occurred. When such an infection develops, it might be required to treat with appropriate local therapy and discontinuation of Fluticasone nasal spray. Patients using Fluticasone nasal spray over several months or longer should be examined periodically for the evidence of infections caused by Candida infection or other signs of adverse effects on the nasal mucosa.

Nasal Septal Perforation

Postmarketing reports of nasal septal perforation had been reported in patients who were treated with

Fluticasone nasal spray.

Impaired Wound Healing

As corticosteroids have inhibitory effects on the wound healing, patients who had experienced recent nasal traumanasal ulcers or nasal surgery should avoid using Fluticasone nasal spray until healing has occurred.

Immunosuppression

Persons who are using drugs which suppress the immune system are more susceptible to many infections than healthy individuals. Measles and chickenpox, for example, can have a more fatal or serious course in susceptible children or adults using corticosteroids. In such children or adults who had not had these diseases or been properly immunized, some care should be taken to avoid exposure.

Hypercorticism and Adrenal Suppression

Fluticasone will often help control asthma symptoms with less suppression of hypothalamic-pituitary-adrenal function than the therapeutically similar oral doses of prednisone.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) had been observed with long-term administration of products which contain inhaled corticosteroids. The clinical significance of small changes in bone mineral density with regard to long-term outcomes is unknown.

Effect on Growth

Orally inhaled corticosteroids might cause a reduction in growth velocity when it is administered to pediatric patients. Monitor the growth of pediatric patients receiving Fluticasone routinely. To minimize the systemic effects of Fluticasone, each patient's dose should be titrated to the lowest dose that can effectively control his/her symptoms.

Glaucoma and Cataracts

Glaucoma is also called increased intraocular pressure, and cataracts have been reported following the administration of inhaled corticosteroids, including Fluticasone. Therefore, close monitoring should be done in patients with a history of increased glaucoma, with a change in vision or intraocular pressure, and/or cataracts.

Systemically administered corticosteroids have been found to appear in human milk and could interfere with endogenous corticosteroid production, suppress growth, or cause other untoward effects. Hence caution should be exercised when corticosteroids are administered to nursing women.

Pregnancy Category C

There are found to be no sufficient data on the use of Fluticasone in pregnant women to inform a drug-associated risk. In animals studies teratogenicity characteristic of corticosteroids caused decreased fetal skeletal variations and bosy weight which were observed in mice,rats and rabbits with subcutaneously administered maternal toxic doses of fluticasone propionate five times, equivalent to and less than the MRHDID on a mcg/m2 basis, respectively.However, fluticasone propionate had been administered via nose-only inhalation to rats had caused decreased fetal body weight but did not induce teratogenicity at a maternally toxic dose equivalent to the MRHDID in a mcg/m2 basis. Experience with oral corticosteroids suggested that rodents are more prone to teratogenic effects from corticosteroids as comapred to humans. In the U.S. general population, the estimated risk of major miscarriage and birth defects in clinically recognized pregnancies were found to be 2% to 4% and 15% to 20%, respectively.

No sufficient scientific evidence traceable regarding the use and safety of Fluticasone in concurrent use with any particular food.

The adverse reactions related to Fluticasone can be categorized as:

Common

• Tenderness or pain around the eyes and cheekbones
• Sore throat
• Stuffy or runny nose
• Tightness of the chest
• Bloody nose
• Cough
• Fever
• Headache
• Muscle aches
• Troubled breathing
• Unusual tiredness or weakness

Less common

• Loss of vision
• Blurred vision
• Change in vision

Rare

• Swelling or puffiness of the eyelids or around the lips, eyes, face,or tongue
• Redness of the skin
• Skin rash, itching, hives or welts
• Difficulty with swallowing
• Dizziness
• Fast heartbeat
• Large, hive-like swelling on the various parts of the body such ashands, legs, feet, face, eyelids, lips, tongue, throat, or sex organs

The clinically relevant drug interactions of Fluticasone is briefly summarized here:

Inhibitors of Cytochrome P450 3A4

Fluticasone propionate is a substrate of enzyme CYP3A4. The use of strong CYP3A4 inhibitors such as, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, atazanavir, clarithromycin, lopinavir, nefazodone, voriconazole, saquinavir, ketoconazole, telithromycin, conivaptan, with Fluticasone nasal spray is not recommended as increased systemic corticosteroid adverse effects might occur.

Ritonavir

A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects had shown that ritonavir which is a strong CYP3A4 inhibitor can significantly increase plasma fluticasone propionate exposure, which in turn resulting in significantly reduced serum cortisol concentrations . During post marketing use, there had been reported of clinically significant drug interactions in patients who received fluticasone propionate products, including Fluticasone, with ritonavir, resulting in systemic corticosteroid effects which including Cushing's syndrome and adrenal suppression.

Ketoconazole

Coadministration of orally inhaled fluticasone propionate about 1,000 mcg and ketoconazole about 200 mg once daily had resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and about a 45% decrease in plasma cortisol area under the curve (AUC), but there was found to be no effect on urinary excretion of cortisol.

The common side effects of Fluticasone include the following:

• Headache
• Dryness, stinging, burning or irritation in the nose
• Nausea
• Vomiting
• Diarrhea
• Bloody mucus in nose
• Dizziness

Pregnancy

Pregnancy Category C

There are found to be no sufficient data on the use of Fluticasone in pregnant women to inform a drug-associated risk. In animals studies teratogenicity characteristic of corticosteroids caused decreased fetal skeletal variations and body weight which were observed in mice,rats and rabbits with subcutaneously administered maternal toxic doses of fluticasone propionate five times, equivalent to and less than the MRHDID on a mcg/m2 basis, respectively.However, fluticasone propionate administered via nose-only inhalation to rats had caused decreased fetal body weight but did not induce teratogenicity at a maternally toxic dose equivalent to the MRHDID in a mcg/m2 basis. Experience with oral corticosteroids suggested that rodents are more prone to teratogenic effects from corticosteroids as comapred to humans. In the U.S. general population, the estimated risk of major miscarriage and birth defects in clinically recognized pregnancies were found to be 2% to 4% and 15% to 20%, respectively.

Nursing Mothers

Systemically administered corticosteroids have been found to appear in human milk and could interfere with endogenous corticosteroid production, suppress growth, or cause other untoward effects. Hence caution should be exercised when corticosteroids are administered to nursing women.

Pediatric Use

The effectiveness and safety of Fluticasone nasal spray in children aged 4 years and older had been established. Six hundred fifty subjects aged 4 to 11 years and four hundred and forty subjects aged twelve to seventeen years had been studied in US clinical trials with fluticasone propionate nasal spray. The effectiveness and safety of Fluticasone nasal spray in children younger than four years have not been established.

Effects on growth has been reported in the patients aged 3 to 9 years. The velocity of the growth had been found to be reduced with the constant use of Fluticasone.This has been established in the clinical controlled trials.

Geriatric Use

A limited number of subjects who were aged 65 years and older (n = 129) or 75 years and older (n = 11) had been treated with Fluticasone nasal spray in clinical trials. While the number of subjects were too small to permit separate analysis of safety and efficacy, the adverse reactions reported in this population were found to be similar to those reported in the younger patients. In general, dose selection for an elderly patient should be done cautiously, which is usually starting at the low end of the dose range.

Physicians should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Fluticasone.

Chronic overdosage might result in symptoms of hypercorticism . Intranasal administration of two mg which is 10 times the recommended dose of fluticasone propionate two times a day for seven days was administered to healthy human volunteers. The adverse events reported with fluticasone propionate were found to be similar to placebo, and no clinically significant abnormalities in laboratory safety tests had been observed. Single oral doses up to 16 mg had been studied in human volunteers where no acute toxic effects reported. The Repeat oral doses of 80 mg daily for 10 days in volunteers and repeat oral doses of 10 mg daily for 14 days in patients were found to be well tolerated. Adverse reactions were found to be of mild or moderate severity, and incidences were foudn to be similar in active and placebo treatment groups.

Pharmacodynamics

Systemically, in vitro experiments show Fluticasone furoate activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. Fluticasone propionate performs similar activity but is not stated to affect nuclear factor kappa b11Label. Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin.

Pharmacokinetics

• Absorption

The indirect calculations had indicated that fluticasone propionate when delivered by the intranasal route had an absolute bioavailability averaging about less than 2%. Trials using oral dosing of labeled and unlabeled drug had demonstrated that the oral systemic bioavailability of fluticasone propionate was negligible (<1%) and this was primarily due to incomplete absorption and presystemic metabolism in the gut and liver. After intranasal treatment of patients with rhinitis for three weeks, fluticasone propionate plasma concentrations were found to be above the level of detection i.e.50 pg/mL only when recommended doses had exceeded and then only in occasional samples at low plasma levels.

• Distribution

Followed by intravenous administration, the initial disposition phase for fluticasone propionate was found to be rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution had averaged around 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins had averaged 99%. Fluticasone propionate was found to be weakly and reversibly bound to erythrocytes and was not significantly bound to human transcortin.

• Metabolism

The only circulating metabolite detected in man was the 17β-carboxylic acid derivative of fluticasone propionate, which was formed through the CYP3A4 enzyme pathway. This metabolite had less affinity which is approximately 1/2,000 than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and had negligible pharmacological activity in animal studies.

• Elimination

About less than 5% of a radiolabeled oral dose of Fluticasone was excreted in the urine as metabolites, with the remainder which was found to be excreted in the feces as parent drug and metabolites.

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