Chemical formula: C₂₂H₂₇F₃O₄S Molecular mass: 444.51 g/mol
Fluticasone interacts in the following cases:
Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled 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 mediated by fluticasone propionate are unlikely.
In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing’s syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects.
In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side-effects. Caution is recommended and long-term treatment with such drugs should, if possible, be avoided.
Co-treatment with other potent CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects.
Other inhibitors of CYP3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Combinations should be avoided unless the benefit outweighs the potential increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors.
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development. The relevance of this finding to human beings has not been established; however, administration of fluticasone during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
There are no adequate data from the use of fluticasone in pregnant women. In animal studies glucocorticoids have been shown to induce malformations including cleft palate and intra-uterine growth retardation. This is not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure. Fluticasone should be used in pregnancy only if the benefits to the mother outweigh the potential risks to the foetus or child.
There are limited data in pregnant women. Administration of fluticasone during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. It is important, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained. Treatment with fluticasone propionate should not be stopped abruptly.
Results from a retrospective epidemiological study did not find an increased risk of major congenital malformations following exposure to fluticasone propionate when compared to other inhaled corticosteroids, during the first trimester of pregnancy.
Reproductive studies in animals have shown only those effects characteristic of glucocorticosteroids at systemic exposures in excess of those seen at the recommended inhaled therapeutic dose. There is inadequate evidence of safety of fluticasone in human pregnancy. Data on a limited number (200) of exposed pregnancies indicate no adverse effects of fluticasone on pregnancy or the health of the foetus/new born child. To date no other relevant epidemological data are available. Administration of corticosteroids to pregnant animals can cause abnormalities of fetal development, including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human fetus. It should be noted, however, that the fetal changes in animals occur after relatively high systemic exposure. Because fluticasone inhaler delivers fluticasone directly to the lungs by the inhaled route it avoids the high level of exposure that occurs when corticosteroids are given by systemic routes. Administration of fluticasone during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.
The excretion of fluticasone propionate into human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration there was evidence of fluticasone propionate in the milk. However, plasma levels in patients following dermal application of fluticasone propionate at recommended doses are likely to be low.
It is unknown whether nasal administered fluticasone is excreted in human breast milk.
Administration of fluticasone to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
The excretion of fluticasone propionate into human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration there was evidence of fluticasone propionate in the breast milk. However, plasma levels in patients following inhaled application of fluticasone propionate at recommended doses are likely to be low.
Administration during lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
There are no data on human fertility. Animal studies indicate no effects of fluticasone propionate on male or female fertility.
Fluticasone has no or negligible influence on the ability to drive and use machines.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10.000 and <1/1000) very rare (<1/10.000, including isolated reports) and not known (cannot be estimated from the available data). Very common, common and uncommon events were generally determined from clinical trial data. The background rates in placebo and comparator groups were not taken into account when assigning frequency categories to adverse events derived from clinical trial data, since these rates were generally comparable to those in the active treatment group. Rare and very rare events were generally derived from spontaneous data.
Very rare: secondary infections (particularly when occlusive dressings are used or when skin folds are involved) have been reported with corticosteroid use.
Very rare: hypersensitivity.
If signs of hypersensitivity appear, application should stop immediately.
Very rare: features of hypercortisolism
Prolonged use of large amounts of corticosteroids, or treatment of extensive areas, can result in sufficient systemic absorption to produce the features of hypercortisolism. This effect is more likely to occur in infants and children, and if occlusive dressings are used. In infants, the napkin may act as an occlusive dressing.
Very rare: dilation of superficial blood vessels
Prolonged and intensive treatment with potent corticosteroid preparations may cause dilation of the superficial blood vessels.
Not known: Vision, blurred
Common: pruritus
Uncommon: local burning
Very rare: Thinning, striae, hypertrichosis, hypopigmentation, allergic contact dermatitis, exacerbation of dermatoses, pustular psoriasis.
Not known: Vascular purpura, skin fragility, peri-oral dermatitis, rosacea, scab, leg ulcer, acne, impaired healing.
Local burning and pruritus have been reported, however in clinical trials the incidence of these adverse reactions was generally comparable to placebo and comparator groups.
Prolonged and intensive treatment with potent corticosteroid preparations may cause local atrophic changes in the skin such as thinning, striae, hypertrichosis and hypopigmentation.
Exacerbation of the signs and symptoms of the dermatoses and allergic contact dermatitis have been reported with corticosteroid use.
Treatment of psoriasis with a corticosteroid (or its withdrawal) may provoke the pustular form of the disease.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.
The most commonly reported adverse reactions during treatment with fluticasone furoate are epistaxis, nasal ulceration and headache. The most serious undesirable effects are rare reports of hypersensitivity reactions, including anaphylaxis (less than 1 case per 1000 patients).
There were over 2700 patients treated with fluticasone furoate in safety and efficacy studies for seasonal and perennial allergic rhinitis. Paediatric exposure to fluticasone furoate in safety and efficacy studies in seasonal and perennial allergic rhinitis included 243 patients 12 to <18 years, 790 patients 6 to <12 years and 241 patients 2 to <6 years.
Data from large clinical trials were used to determine the frequency of adverse reactions.
The following convention has been used for the classification of frequencies: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10,000 to <1/1000; Very rare <1/10,000.
Rare: Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria.
Common: Headache.
Not known: Transient ocular changes, vision blurred
Very common: Epistaxis*
Common: Nasal ulceration
Uncommon: Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness.
Very rare: Nasal septum perforation
Not known: Growth retardation**
* Epistaxis was generally mild to moderate in intensity. In adults and adolescents, the incidence of epistaxis was higher in longer-term use (more than 6 weeks) than in short-term use (up to 6 weeks).
Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. Growth retardation has been reported in children receiving nasal corticosteroids.
The safety in children under 6 years has not been well established. Frequency, type and severity of adverse reactions observed in the paediatric population are similar to those in the adult population.
* In paediatric clinical studies of up to 12 weeks duration the incidence of epistaxis was similar between patients receiving fluticasone furoate and patients receiving placebo.
** In a one-year clinical study assessing growth in pre-pubescent children receiving 110 micrograms of fluticasone furoate once daily, an average treatment difference of -0.27 cm per year in growth velocity was observed compared to placebo.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.
Very Common: Candidiasis of the mouth and throat
Common: Pneumonia (in COPD patients)
Rare: Oesophageal candidiasis
Hypersensitivity reactions with the following manifestations:
Uncommon: Cutaneous hypersensitivity reactions
Very Rare: Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions
Not known: Vision, blurred
Very Rare: Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma
Very Rare: Hyperglycaemia
Very Rare: Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children)
Not known: Depression, aggression (predominantly in children)
Common: Hoarseness/dysphonia
Very Rare: Paradoxical bronchospasm
Unknown: Epistaxis
Very Rare: Dyspepsia
Common: Contusions
Very Rare: Arthralgia
Hoarseness and candidiasis of the mouth and throat (thrush) occurs in some patients. Such patients may find it helpful to rinse out their mouth with water after using the inhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with fluticasone.
Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma.
As with other inhalation therapy, paradoxical bronchospasm may occur. This should be treated immediately with a fast-acting inhaled bronchodilator. Fluticasone should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.
There was an increased reporting of pneumonia in studies of patients with COPD receiving fluticasone 500 micrograms. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.
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