Flonase®

Fluticasone Propionate

Corticosteroid for Nasal Use

GlaxoSmithKline

http://www.gsk.com/index.htm

Flonase Monograph PDF download here.

 

CPS:PIS_m217200

Date of Preparation: June 14, 2001

Date of Revision: December 10, 2003

 

 

Pharmacology

Fluticasone is a potent anti-inflammatory steroid. When administered intranasally in therapeutic doses, it has a direct anti-inflammatory action on the nasal mucosa, the mechanism of which is not yet completely defined.

     The onset of action is not immediate, and 2 to 3 days treatment may be required before maximum relief is obtained. This is because the anti-inflammatory activities of glucocorticoids are related to specific steroid effects, which involve several biochemical events, including protein synthesis.

     Following intranasal dosing of fluticasone (200 µg/day), steady-state maximum plasma concentrations were not quantifiable in most subjects (<0.01 ng/mL). The highest C_max observed was 0.017 ng/mL. Direct absorption in the nose is negligible due to the low aqueous solubility with the majority of the dose being eventually swallowed. When administered orally the systemic exposure is <1% due to poor absorption and pre-systemic metabolism. The total systemic absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible.

     In clinical trials, no hypothalamic-pituitary-adrenal (HPA) axis effects have been observed. Following intranasal dosing of fluticasone (200 µg/day), no significant change in 24-hour serum cortisol AUC was found compared to placebo (ratio 1.01; 90% CI: 0.9 to 1.14).

 

Indications

For the treatment of seasonal allergic rhinitis including hay fever, and perennial rhinitis poorly responsive to conventional treatment. In patients with allergic rhinitis, fluticasone is also indicated for the management of associated sinus pain and pressure.

     Regular usage is essential for full therapeutic benefit, since maximum relief may not be obtained until after 2 to 3 days of treatment.

 

Contraindications

In patients with a history of hypersensitivity to any of its ingredients, and in patients with untreated fungal, bacterial, or tuberculosis infections of the respiratory tract.

 

Warnings

In patients previously on systemic steroids, either over prolonged periods or in high doses, the replacement with a topical corticosteroid can be accompanied by symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression and, in severe cases, adrenal insufficiency may occur, necessitating the temporary resumption of systemic steroid therapy.

     Careful attention must be given to patients with asthma or other clinical conditions in whom a rapid decrease in systemic steroids may cause a severe exacerbation of their symptoms.

     A drug interaction study of intranasal fluticasone propionate in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.

 

Precautions

 

General

Patients should be informed that the full effect of fluticasone therapy is not achieved until 2 to 3 days of treatment have been completed. Treatment of seasonal rhinitis should, if possible, start before the exposure to allergens.

     Although fluticasone will control seasonal allergic rhinitis in most cases, an abnormally heavy challenge of summer allergens may in certain instances necessitate appropriate additional therapy.

     Under most circumstances, treatment with corticosteroids should not be stopped abruptly but tapered off gradually. Patients should be advised to inform subsequent physicians of prior use of corticosteroids.

Steroid Replacement by Fluticasone: The replacement of a systemic steroid with fluticasone must be gradual and carefully supervised by the physician. The guidelines under Dosage should be followed in all such cases.

Effect on Infection: Corticosteroids may mask some signs of infection and new infections may appear. A decreased resistance to localized infections has been observed during corticosteroid therapy; this may require treatment with appropriate therapy or stopping the administration of fluticasone.

     Patients who are on drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in nonimmune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled i.m. immunoglobulin (IG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Systemic Effects: Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism, suppression of HPA function, and/or reduction of growth velocity in children or teenagers. Physicians should closely follow the growth of children and adolescents taking corticosteroids, by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed.

     Although systemic effects have been minimal with recommended doses of fluticasone aqueous nasal spray, potential risk increases with larger doses. Therefore, larger than recommended doses of fluticasone aqueous nasal spray should be avoided.

 

Drug Interactions

Under normal circumstances, very low plasma concentrations of fluticasone propionate are achieved after intranasal dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions involving fluticasone propionate are unlikely.

     A drug interaction study of intranasal fluticasone propionate in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.

     This study has shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. However, there have been a few case reports during world-wide post-market use of adrenal cortisol suppression associated with concomitant use of azole anti-fungals and inhaled fluticasone propionate. Therefore, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.

Long-term Effects: During long-term therapy, HPA axis function and hematological status should be assessed.

     The long-term effects of fluticasone in humans are still unknown, in particular, its local effects; the possibility of atrophic rhinitis and/or pharyngeal candidiasis should be kept in mind.

Hypothyroidism and Cirrhosis: There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis.

Use of Corticosteroids and ASA: ASA should be used cautiously in conjunction with corticosteroids in hypothrombinemia.

Effect of Corticosteroids on Wound Healing: In patients who have had recent nasal surgery or trauma, a nasal corticosteroid should be used with caution until healing has occurred, because of the inhibitory effect of corticosteroids on wound healing.

Proper Use of Drug: To ensure proper dosage and administration of the drug, the patient should be instructed by a physician or other health professional in the use of fluticasone (see Information for the Patient).

 

Pregnancy

The safety of fluticasone in pregnancy has not been established. If used, the expected benefits should be weighed against the potential hazard to the fetus, particularly during the first trimester of pregnancy.

     Like other glucocorticosteroids, fluticasone is teratogenic to rodent species. Adverse effects typical of potent corticosteroids are only seen at high systemic exposure levels; direct intranasal application ensures minimal systemic exposure. The relevance of these findings to humans has not yet been established. Infants born of mothers who have received substantial doses of glucocorticosteroids during pregnancy should be carefully observed for hypoadrenalism.

 

Lactation

Glucocorticosteroids are excreted in human milk. It is not known whether fluticasone is excreted in human milk.

     When measurable plasma levels were obtained in lactating laboratory rats following s.c. administration, there was evidence of fluticasone in the breast milk. However, following intranasal administration to primates, no drug was detected in the plasma, and it is therefore unlikely that the drug would be detectable in milk. The use of fluticasone in nursing mothers requires that the possible benefits of the drug be weighed against the potential hazards to the infant.

 

Children

Fluticasone is not presently recommended for children younger than 4 years of age due to limited clinical data in this age group.

     Until greater clinical experience has been gained, the continuous, long-term treatment of children under age 12 is not recommended.

 

Adverse Effects

Adverse reactions in controlled clinical studies with fluticasone have been primarily associated with irritation of the nasal mucous membranes, and are consistent with those expected from application of a topical medication to an already inflamed membrane. The adverse reactions reported by patients treated with fluticasone were similar to those reported by patients receiving placebo.

     The most frequently reported adverse reactions (≥  1% in any treatment group) considered by the investigator to be potentially related to fluticasone or placebo in trials of seasonal allergic rhinitis are listed in  Table 1. These studies, conducted in 948 adults and in 499 children, evaluated 14 to 28 days of treatment with recommended doses of fluticasone compared with placebo.

CPS:Flonase_t1Click here for Table 1

Table 1: Flonase

Adverse Reactions Reported Most Frequently in Clinical Trials of Seasonal Allergic Rhinitis

 

	Adults (age ≥ 12 years)				Children (age 4-11 years)
	Fluticasone 100 µg b.i.d. (n=312) %	Fluticasone 200 µg o.d. (n=322) %	Placebo (n=314) %	Fluticasone 100 µg o.d. (n=167)  %		Fluticasone 200 µg o.d. (n=164) %	Placebo (n=168) %
Nasal Burning	2.2	3.4	2.5	1.8		2.4	1.2
Pharyngitis	1.3	1.6	<1	<1		0	0
Runny Nose	<1	1.6	<1	<1		<1	<1
Blood in Nasal Mucous	0	1.6	<1	0		<1	0
Epistaxis	1.6	2.8	2.2	3.0		3.7	3.6
Sneezing	<1	1.2	2.2	0		<1	0
Crusting in Nostrils	0	0	0	1.2		0	0
Nasal Congestion	0	0	0	0		1.2	0
Nasal Ulcer	<1	0	0	1.2		1.2	1.2
Headache	1.3	2.5	1.9	1.2		1.2	1.2

brdrb

     In two 6-month trials involving 831 patients aged 12 to 75 years with perennial allergic rhinitis, the adverse reactions reported by patients treated with fluticasone were similar in type and incidence to those reported in seasonal trials, with the exception of epistaxis (≤ 13.3%) and blood in nasal mucous (≤ 8.3%). In addition to the events reported most frequently in the seasonal trials, patients receiving fluticasone in the 6-month trials reported nasal soreness (≤ 2.5%), nasal excoriation (≤ 2.0%), sinusitis (≤ 1.6%), and nasal dryness (≤ 1.3%).

     Infrequent adverse reactions (incidence of 0.1% to 1% and greater than placebo) reported by patients receiving fluticasone at the recommended daily dose of 200 µg (or 100 µg/day for children 4 to 11 years of age) in the aforementioned clinical trials included pharyngeal irritation, nasal stinging, nausea and vomiting, unpleasant smell and taste, and sinus headache (0.3%); lacrimation, eye irritation, xerostomia, cough, urticaria, and rash (0.2%); and nasal septum perforation (0.1%).

Postmarketing Surveillance: The following events have been identified during postapproval use of fluticasone in clinical practice.

 

General

headache and hypersensitivity reactions including angioedema, skin rash, edema of the face or tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea and anaphylaxis/anaphylactic reactions have been reported.

Ear, Nose and Throat

alteration or loss in sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice changes.

 

Eye

dryness and irritation of the eyes, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure, and cataracts.

 

Overdose

 

 

Symptoms

Like any other nasally administered corticosteroid, acute overdosing is unlikely in view of the total amount of active ingredient present. However, when used chronically in excessive doses or in conjunction with other corticosteroid formulations, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of fluticasone should be discontinued slowly, consistent with accepted procedures for discontinuation of chronic steroid therapy (see Dosage).

     The restoration of HPA axis function may be slow. During periods of pronounced physical stress (i.e., severe infections, trauma, surgery) a supplement with systemic steroids may be advisable.

 

 

Treatment

See Symptoms.

 

Dosage

See Warnings.

     The therapeutic effects of corticosteroids, unlike those of decongestants, are not immediate. Since the effect of fluticasone depends on its regular use, patients must be instructed to take the nasal inhalation at regular intervals and not, as with other nasal sprays, as they feel necessary.

Adults and Children 12 years of age and older: The usual dosage is 2 sprays (50 µg each) in each nostril once a day (total daily dosage, 200 µg). Some patients with severe rhinitis may benefit from 2 sprays in each nostril every 12 hours. The recommended maximum daily dose is 400 µg (4 sprays in each nostril).

Children 4 to 11 years of age: The usual dosage is 1 or 2 (50 µg/actuation) sprays in each nostril in the morning (100 or 200 µg/day). The recommended maximum daily dose is 200 µg (2 sprays in each nostril).

     The safety and efficacy of fluticasone in children below 4 years of age have not been established and, therefore, fluticasone is not recommended in this patient population.

     Until greater clinical experience has been gained, the continuous, long-term treatment of children under age 12 is not recommended.

     An improvement of symptoms usually becomes apparent within a few days after the start of therapy. However, symptomatic relief may not occur in some patients for as long as 2 weeks. Fluticasone should not be continued beyond three weeks in the absence of significant symptomatic improvement.

     In the presence of excessive nasal mucous secretion or edema of the nasal mucosa, the drug may fail to reach the site of action. In such cases it is advisable to use a nasal vasoconstrictor for 2 to 3 days prior to starting treatment with fluticasone. Patients should be instructed on the correct method of use, which is to blow the nose, then insert the nozzle carefully into the nostril, compress the opposite nostril and actuate the spray while inspiring through the nose, with the mouth closed (see Information for the Patient).

     Careful attention must be given to patients previously treated for prolonged periods with systemic corticosteroids when transferred to fluticasone. Initially, fluticasone and the systemic corticosteroid must be given concomitantly, while the dose of the latter is gradually decreased. The usual rate of withdrawal of the systemic steroid is the equivalent of 1 mg of prednisone every 4 days if the patient is under close supervision. If continuous supervision is not feasible, the withdrawal of the systemic steroid should be slower, approximately 1 mg of prednisone (or equivalent) every 10 days. If withdrawal symptoms appear, the previous dose of the systemic steroid should be resumed for a week before further decrease is attempted.

 

Supplied

Each 100 mg of spray delivered by the metered nasal adaptor (1 actuation), contains: micronised fluticasone propionate 50 µg. Nonmedicinal ingredients: benzalkonium chloride, dextrose, microcrystalline cellulose and carboxymethylcellulose sodium, phenylethyl alcohol, polysorbate 80 and purified water. Amber glass bottles containing sufficient formulation for 120 metered sprays (16 g net weight). Store between 4 and 30°C. Shake gently before use.