Flovent® HFA Inhalation Aerosol is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.
Flovent HFA Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm.
Flovent Dosage and Administration
Flovent HFA should be administered by the orally inhaled route only in patients aged 4 years and older. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.
After asthma stability has been achieved, it is always desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control. The safety and efficacy of Flovent HFA when administered in excess of recommended dosages have not been established.
The recommended starting dosage and the highest recommended dosage of Flovent HFA, based on prior asthma therapy, are listed in Table 1.
| NOTE: In all patients, it is desirable to titrate to the lowest effective dosage once asthma stability is achieved. | ||
| Previous Therapy | Recommended Starting Dosage | Highest Recommended Dosage |
| Adult and adolescent patients (aged ≥12 years) | 88 mcg twice daily 88-220 mcg twice dailya 440 mcg twice daily | 440 mcg twice daily 440 mcg twice daily 880 mcg twice daily |
Bronchodilators alone Inhaled corticosteroids Oral corticosteroidsb | ||
| Pediatric patients (aged 4-11 years)c | 88 mcg twice daily | 88 mcg twice daily |
a Starting dosages above 88 mcg twice daily may be considered for patients with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for the specific agent.
b For patients currently receiving chronic oral corticosteroid therapy, prednisone should be reduced no faster than 2.5 to 5 mg/day on a weekly basis beginning after at least 1 week of therapy with Flovent HFA. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency [see Warnings and Precautions (5.4)]. Once prednisone reduction is complete, the dosage of Flovent HFA should be reduced to the lowest effective dosage.
c Recommended pediatric dosage is 88 mcg twice daily regardless of prior therapy. A valved holding chamber and face mask may be used to deliver Flovent HFA to young patients.
Flovent HFA should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face.
Dosage Forms and Strengths
Flovent HFA is an inhalation aerosol. Each actuation delivers 44, 110, or 220 mcg of fluticasone propionate from the actuator. Flovent HFA 44 mcg is supplied in 10.6-g pressurized aluminum canisters, and Flovent HFA 110 mcg and Flovent HFA 220 mcg are supplied in 12-g pressurized aluminum canisters. Each canister contains 120 metered inhalations and is fitted with a counter and a dark orange oral actuator with a peach strapcap.
Contraindications
The use of Flovent HFA is contraindicated in the following conditions:
- Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions (5.2)]
- Hypersensitivity to any of the ingredients of Flovent HFA contraindicates their use [see Warnings and Precautions (5.6), Adverse Reactions (6.2), Description (11)]
Warnings and Precautions
Local Effects
In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with Flovent HFA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with Flovent HFA continues, but at times therapy with Flovent HFA may need to be interrupted. Patients should rinse the mouth after inhalation of Flovent HFA [see Adverse Reactions (6.1)].
Acute Asthma Episodes
Flovent HFA is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with Flovent HFA. During such episodes, patients may require therapy with oral corticosteroids.
Immunosuppression
Persons who are using 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 susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, 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 a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
Because of the potential for worsening infections, inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
Transferring Patients From Systemic Corticosteroid Therapy
Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to Flovent HFA. In a clinical trial of 168 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose on a weekly basis following initiation of treatment with Flovent HFA. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed short-acting beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although inhaled corticosteroids may provide control of asthma symptoms during these episodes, in recommended doses they supply less than normal physiological amounts of glucocorticoid (cortisol) systemically and do NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
Transfer of patients from systemic corticosteroid therapy to Flovent HFA may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function).
Hypercorticism and Adrenal Suppression
Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of Flovent HFA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing Flovent HFA.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with Flovent HFA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when Flovent HFA is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of Flovent HFA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma.
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and bronchospasm, may occur after administration of Flovent HFA [see Contraindications (4)].
Reduction in Bone Mineral Density
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.
Effect on Growth
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients [see Use in Specific Populations (8.4)]. Monitor the growth of pediatric patients receiving Flovent HFA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including Flovent HFA, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2)].
Glaucoma and Cataracts
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including fluticasone propionate. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
Paradoxical Bronchospasm
As with other inhaled medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with Flovent HFA, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with Flovent HFA should be discontinued immediately and alternative therapy instituted.
Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors
The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Flovent HFA is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Eosinophilic Conditions and Churg-Strauss Syndrome
In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established.
Adverse Reactions
Systemic and local corticosteroid use may result in the following:
- Candida albicans infection [see Warnings and Precautions (5.1)]
- Immunosuppression [see Warnings and Precautions (5.3)]
- Hypercorticism and adrenal suppression [see Warnings and Precautions (5.5)]
- Reduction in bone mineral density [see Warnings and Precautions (5.7)]
- Growth effects [see Warnings and Precautions (5.8)]
- Glaucoma and cataracts [see Warnings and Precautions (5.9)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The incidence of common adverse reactions in Table 2 is based upon 2 placebo-controlled US clinical trials in which 812 adult and adolescent patients (457 females and 355 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated twice daily for up to 12 weeks with 2 inhalations of Flovent HFA 44 mcg Inhalation Aerosol, Flovent HFA 110 mcg Inhalation Aerosol, Flovent HFA 220 mcg Inhalation Aerosol (dosages of 88, 220, or 440 mcg twice daily), or placebo.
| Adverse Event | Flovent HFA 88 mcg Twice Daily (n = 203) % | Flovent HFA 220 mcg Twice Daily (n = 204) % | Flovent HFA 440 mcg Twice Daily (n = 202) % | Placebo (n = 203) % |
| Ear, nose, and throat | ||||
| Upper respiratory tract infection | 18 | 16 | 16 | 14 |
| Throat irritation | 8 | 8 | 10 | 5 |
| Upper respiratory inflammation | 2 | 5 | 5 | 1 |
| Sinusitis/sinus infection | 6 | 7 | 4 | 3 |
| Hoarseness/dysphonia | 2 | 3 | 6 | <1 |
| Gastrointestinal | ||||
| Candidiasis mouth/throat & non-site specific | 4 | 2 | 5 | <1 |
| Lower respiratory | ||||
| Cough | 4 | 6 | 4 | 5 |
| Bronchitis | 2 | 2 | 6 | 5 |
| Neurological | ||||
| Headache | 11 | 7 | 5 | 6 |
Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in any of the groups treated with Flovent HFA and were more common than in the placebo group. Less than 2% of patients discontinued from the studies because of adverse reactions. The average duration of exposure was 73 to 76 days in the active treatment groups compared with 60 days in the placebo group.
Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by patients with asthma treated with Flovent HFA compared with patients treated with placebo include the following: rhinitis, rhinorrhea/post-nasal drip, nasal sinus disorders, laryngitis, diarrhea, viral gastrointestinal infections, dyspeptic symptoms, gastrointestinal discomfort and pain, hyposalivation, musculoskeletal pain, muscle pain, muscle stiffness/tightness/rigidity, dizziness, migraines, fever, viral infections, pain, chest symptoms, viral skin infections, muscle injuries, soft tissue injuries, urinary infections.
Fluticasone propionate inhalation aerosol (440 or 880 mcg twice daily) was administered for 16 weeks to 168 patients with asthma requiring oral corticosteroids (Study 3). Adverse reactions not included above, but reported by more than 3 patients in either group treated with Flovent HFA and more commonly than in the placebo group included nausea and vomiting, arthralgia and articular rheumatism, and malaise and fatigue.
In 2 long-term studies (26 and 52 weeks), the pattern of adverse reactions in patients treated with Flovent HFA at dosages up to 440 mcg twice daily was similar to that observed in the 12-week studies. There were no new and/or unexpected adverse reactions with long-term treatment.
Pediatric Patients Aged 4 to 11 Years: Flovent HFA has been evaluated for safety in 56 pediatric patients who received 88 mcg twice daily for 4 weeks. Types of adverse reactions in these pediatric patients were generally similar to those observed in adults and adolescents.
Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors.
Ear, Nose, and Throat: Aphonia, facial and oropharyngeal edema, and throat soreness and irritation.
Endocrine and Metabolic: Cushingoid features, growth velocity reduction in children/adolescents, hyperglycemia, osteoporosis, and weight gain.
Eye: Cataracts.
Gastrointestinal Disorders: Dental caries and tooth discoloration.
Psychiatry: Agitation, aggression, anxiety, depression, and restlessness. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.
Immune System Disorders: Immediate and delayed hypersensitivity reactions, including urticaria, anaphylaxis, rash, and angioedema and bronchospasm, have been reported.
Respiratory: Asthma exacerbation, chest tightness, cough, dyspnea, immediate and delayed bronchospasm, paradoxical bronchospasm, pneumonia, and wheeze.
Skin: Contusions, cutaneous hypersensitivity reactions, ecchymoses, and pruritus.
Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate [see Warnings and Precautions (5.12)].
Drug Interactions
Strong Cytochrome P450 3A4 Inhibitors
Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Flovent HFA is not recommended because increased systemic corticosteroid adverse effects may occur.
A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. Coadministration of fluticasone propionate and ketoconazole is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. There are no adequate and well-controlled studies with Flovent HFA in pregnant women. Flovent HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Teratogenic Effects: Subcutaneous studies in mice at a dose approximately 0.1 times the maximum recommended human daily inhalation dose (MRHD) in adults on a mg/m2 basis and in the rat at a dose approximately 0.5 times the MRHD in adults on a mg/m2 basis revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.
In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose approximately 0.04 times the MRHD in adults on a mg/m2 basis. However, no teratogenic effects were reported at oral doses up to approximately 3 times the MRHD in adults on a mg/m2 basis. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.
Nursing Mothers
It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate (approximately 0.05 times the MRHD in adults on a mg/m2 basis) resulted in measurable radioactivity in milk.
Since there are no data from controlled trials on the use of Flovent HFA by nursing mothers, caution should be exercised when Flovent HFA is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of Flovent HFA in children 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. The safety and effectiveness of Flovent HFA in children younger than 4 years have not been established. Use of Flovent HFA in patients aged 4 to 11 years is supported by evidence from adequate and well-controlled studies in adults and adolescents 12 years and older, pharmacokinetic studies in patients aged 4 to 11 years, established efficacy of fluticasone propionate formulated as Flovent® DISKUS® (fluticasone propionate inhalation powder) and Flovent® ROTADISK® (fluticasone propionate inhalation powder) in patients aged 4 to 11 years, and supportive findings with Flovent HFA in a study conducted in patients aged 4 to 11 years.
Effects on Growth: Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known.
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including Flovent HFA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including Flovent HFA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.
Since a cross study comparison in adolescent and adult patients (aged 12 years and older) indicated that systemic exposure of inhaled fluticasone propionate from Flovent HFA would be higher than exposure from Flovent ROTADISK, results from a study to assess the potential growth effects of Flovent ROTADISK in pediatric patients (aged 4 to 11 years) are provided.
A 52-week placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder (Flovent ROTADISK) at 50 and 100 mcg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this study, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year.
The clinical significance of these growth data is not certain. 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. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma.
Children Younger Than 4 Years:Pharmacokinetics:[see Clinical Pharmacology (12.3)].
Pharmacodynamics: A 12-week, double-blind, placebo-controlled, parallel-group study was conducted in children with asthma aged 1 to less than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week treatment period with 88 mcg of Flovent HFA twice daily (n = 73) and with placebo (n = 42) were calculated. The mean and median change from baseline in urine cortisol over 12 hours were -0.7 and 0.0 mcg for Flovent HFA and 0.3 and -0.2 mcg for placebo, respectively.
In a 1-way crossover study in children aged 6 to less than 12 months with reactive airways disease (N = 21), serum cortisol was measured over a 12-hour dosing period. Patients received placebo treatment for a 2-week period followed by a 4-week treatment period with 88 mcg of Flovent HFA twice daily with an AeroChamber Plus® Valved Holding Chamber (VHC) with face mask. The geometric mean ratio of serum cortisol over 12 hours (AUC0-12 hr) following Flovent HFA (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72, 1.27).
Safety: Flovent HFA administered as 88 mcg twice daily has been evaluated for safety in 239 pediatric patients aged 1 to less than 4 years in a 12-week, double-blind, placebo-controlled study. Treatments were administered with an AeroChamber Plus VHC with face mask. In pediatric patients aged 1 to less than 4 years receiving Flovent HFA, the following events occurred with a frequency greater than 3% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection, vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection.
Flovent HFA administered as 88 mcg twice daily has also been evaluated for safety in 23 pediatric patients aged 6 to 12 months in an open-label placebo-controlled study. Treatments were administered with an AeroChamber Plus VHC with face mask for 2 weeks with placebo followed by 4 weeks with active drug. There was no discernable difference in the types of adverse events reported between patients receiving placebo compared to the active drug.
In Vitro Testing of Dose Delivery With Holding Chambers: In vitro dose characterization studies were performed to evaluate the delivery of Flovent HFA via holding chambers with attached face masks. The studies were conducted with 2 different holding chambers (AeroChamber Plus VHC and AeroChamber Z-STAT Plus™ VHC) and face masks (small and medium size) at inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively. The mean delivered dose of fluticasone propionate through the holding chambers with face masks was lower than the 44 mcg of fluticasone propionate delivered directly from the actuator mouthpiece. The results were similar through both holding chambers (see Table 3 for data for the AeroChamber Plus VHC). The fine particle fraction (approximately 1 to 5 μm) across the flow rates used in these studies was 70% to 84% of the delivered dose, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for Flovent HFA delivered without a holding chamber typically represents 42% to 55% of the delivered dose measured at the standard flow rate of 28.3 L/min. These data suggest that, on a per kilogram basis, young children receive a comparable dose of fluticasone propionate when delivered via a holding chamber and face mask as adults do without their use.
| Age | Face Mask | Flow Rate (L/min) | Holding Time (seconds) | Mean Medication Delivery Through AeroChamber Plus VHC (mcg/actuation) | Body Weight 50th Percentile (kg)a | Medication Delivered per Actuation (mcg/kg)b |
6 to 12 Months | Small | 4.9 | 0 2 5 10 | 8.3 6.7 7.5 7.5 | 7.5-9.9 | 0.8-1.1 0.7-0.9 0.8-1.0 0.8-1.0 |
2 to 5 Years | Small | 8.0 | 0 2 5 10 | 7.3 6.8 6.7 7.7 | 12.3-18.0 | 0.4-0.6 0.4-0.6 0.4-0.5 0.4-0.6 |
2 to 5 Years | Medium | 8.0 | 0 2 5 10 | 7.8 7.7 8.1 9.0 | 12.3-18.0 | 0.4-0.6 0.4-0.6 0.5-0.7 0.5-0.7 |
| >5 Years | Medium | 12.0 | 0 2 5 10 | 12.3 11.8 12.0 10.1 | 18.0 | 0.7 0.7 0.7 0.6 |
a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50th percentile weight for boys and girls at the ages indicated.
b A single inhalation of Flovent HFA in a 70-kg adult without use of a valved holding chamber and face mask delivers approximately 44 mcg, or 0.6 mcg/kg.
Geriatric Use
Of the total number of patients treated with Flovent HFA in US and non-US clinical trials, 173 were 65 years or older, 19 of which were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
Formal pharmacokinetic studies using Flovent HFA have not been conducted in patients with hepatic impairment. Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.
Renal Impairment
Formal pharmacokinetic studies using Flovent HFA have not been conducted in patients with renal impairment.
Overdosage
Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)]. Inhalation by healthy volunteers of a single dose of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Doses of 1,320 mcg administered to healthy human volunteers twice daily for 7 to 15 days were also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.
No deaths were seen in mice given an oral dose of 1,000 mg/kg (approximately 2,300 and 11,000 times the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis). No deaths were seen in rats given an oral dose of 1,000 mg/kg (approximately 4,600 and 22,000 times the MRHD in adults and children aged 4 to 11 years, respectively, on a mg/m2 basis).
Flovent Description
The active component of Flovent HFA 44 mcg Inhalation Aerosol, Flovent HFA 110 mcg Inhalation Aerosol, and Flovent HFA 220 mcg Inhalation Aerosol is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9 - difluoro - 11β,17 - dihydroxy - 16α - methyl - 3 - oxoandrosta - 1,4 - diene - 17β - carbothioate, 17-propionate and the following chemical structure:
Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.
Flovent HFA 44 mcg Inhalation Aerosol, Flovent HFA 110 mcg Inhalation Aerosol, and Flovent HFA 220 mcg Inhalation Aerosol are pressurized metered-dose aerosol units fitted with a counter. Flovent HFA is intended for oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients.
After priming, each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate in 60 mg of suspension (for the 44-mcg product) or in 75 mg of suspension (for the 110- and 220-mcg products) from the valve. Each actuation delivers 44, 110, or 220 mcg of fluticasone propionate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuatio
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