Use of Ozone-Depleting Substances. Direct final rule.

The Food and Drug Administration (FDA, the Agency, or we) is amending its regulation on uses of ozone-depleting substances (ODSs), including chlorofluorocarbons (CFCs), to remove the designation for certain products as "essential uses" under the Clean Air Act. Essential-use products are exempt from the ban by FDA on the use of CFCs and other ODS propellants in FDA-regulated products and from the ban by the Environmental Protection Agency (EPA) on the use of ODSs in pressurized dispensers. The products that will no longer constitute an essential use are: Sterile aerosol talc administered intrapleurally by thoracoscopy for human use and metered-dose atropine sulfate aerosol human drugs administered by oral inhalation. FDA is taking this action because alternative products that do not use ODSs are now available and because these products are no longer being marketed in versions that contain ODSs.

Flunisolide hydrofluoroalkane with integrated spacer for treating asthma: an updated review.

Flunisolide hydrofluoroalkane (HFA) with integrated spacer is the most recent reformulated inhaled corticosteroid (ICS) for asthma available in the United States. It is the only product that combines a corticosteroid extrafine aerosol with a built-in spacer. The potential clinical benefit of the flunisolide HFA formulation and its integrated spacer for treating persistent asthma was assessed through a comprehensive review of the published literature and data from the past 10 years focusing on (1) flunisolide, the molecule, and the impact of the HFA reformulation; (2) updated information on the anti-inflammatory response to flunisolide HFA, particularly in the distal airways; and (3) the usefulness of an integrated spacer. Flunisolide HFA was found effective and safe in clinical studies and comparable with the chlorofluorocarbon (CFC) formulation, but at about one-third the dose of flunisolide CFC, likely reflecting both the device and the particle size of the reformulated product. Compared with the CFC formulation, the extrafine aerosol and smaller particle size of flunisolide HFA substantially increased pulmonary deposition and decreased oropharyngeal deposition. The integrated spacer further enhanced the pulmonary/oropharyngeal deposition ratio. Examination of lung biopsy specimens indicated a favorable anti-inflammatory response to flunisolide HFA in peripheral airways. Pediatric studies showed no significant effects on growth. The data indicate that flunisolide HFA is a safe and effective maintenance therapy for asthma patients. The integrated spacer may provide an added advantage for patients, especially those who may be more likely to experience adverse effects of ICSs, both local and systemic, including children susceptible to adverse effects on growth.

Use of ozone-depleting substances; removal of essential-use designation (flunisolide, etc.). Final rule.

The Food and Drug Administration (FDA), after consultation with the Environmental Protection Agency (EPA), is amending FDA's regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil used in oral pressurized metered-dose inhalers (MDIs). The Clean Air Act requires FDA, in consultation with the EPA, to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. FDA has concluded that there are no substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil as products that do not release ODSs, and therefore they will no longer be essential uses of ODSs as of the effective dates of this rule. MDIs for these active moieties containing an ODS may not be marketed after the relevant effective date.

Safety and efficacy of HFA-134a beclomethasone dipropionate extra-fine aerosol over six months.

OBJECTIVE: To compare the systemic safety and efficacy of hydrofluoroalkane beclomethasone dipropionate (HFA-BDP) extra-fine aerosol 800 microg/day with chlorofluorocarbon (CFC)-BDP 1500 microg/day. DESIGN: Six-month, randomized, parallel-group, double-blind, double-dummy study. PATIENTS: Patients (n=141) with moderate to severe asthma adequately controlled by CFC-BDP 1000 microg/day to 2000 microg/day. INTERVENTIONS: Patients received CFC-BDP 1500 microg/day during a two-week run-in period and were then randomized to either HFA-BDP (n=70) or CFC-BDP (n=71). RESULTS: Similar proportions of HFA-BDP and CFC-BDP patients had a 24 h urinary free cortisol values below the reference range at month 6 (15% versus 25%, P=0.35). Measures of adrenocorticotrophic hormone stimulation and morning plasma cortisol levels were also similar in each group. The frequency of skin bruising and oral candidiasis was low for both treatments. No change in intraocular pressure was reported for either treatment. Pulmonary function was similar in both groups; however, the onset of the first asthma exacerbation or increased asthma symptoms tended to be earlier for CFC-BDP than for HFA-BDP (P=0.076); 27% of CFC-BDP patients reported increased asthma symptoms, compared with 14% of HFA-BDP patients (P=0.095). CONCLUSIONS: HFA-BDP 800 microg/day has a systemic adverse event profile comparable to that of CFC-BDP 1500 microg/day, and further control of asthma symptoms may be achieved after a switch from CFC-BDP 1500 microg/day to HFA-BDP 800 microg/day.

Small airway asthma therapy, challenges, and the future.

The clinical significance of small airway pathology makes these passages an important therapeutic target in asthma. Conventional chlorofluorocarbon-based formulations of inhaled corticosteroids for asthmatic inflammation produce aerosols with a relatively large particle size, and as such, offer poor access to the small airways. New corticosteroid formulations use hydrofluoroalkane propellants with a smaller average particle size, allowing better access to the distal lung. By extending the delivery of this medication to the peripheral lung and by increasing the efficiency of lung targeting, these new corticosteroid formulations provide more effective treatment at reduced drug doses.

Equivalent efficacy and safety of a new HFA-134a formulation of BDP compared with the conventional CFC in adult asthmatics.

The present study demonstrates the equivalent efficacy for BDP 500 microg bid given via MDI with the new HFA-134a propellant (Chiesi Farmaceutici S.p.A., Parma) compared to a conventional CFC propellant (Becotide, Allen & Hanburys, UK). One hundred and sixteen adult patients with stable mild to moderate asthma (FEV1 > or = 60% of predicted normal) entered a 2-week run-in period where they maintained their own inhaled corticosteroids and were then assigned to a 12-week treatment with the test drug in a randomized, multicentre, double-blind, double-dummy, parallel-group design. Ninety-one patients completed the study period. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of daytime and nighttime asthma attacks, number of nighttime awakenings, and clinical symptoms were recorded daily by patients on a diary card. Pulmonary function tests (FEV1, FVC, PEFR, MEF50 and FEF25) were completed at study entry, at the start of treatment and every 2 weeks thereafter. Morning (08.00-10.00 AM) serum cortisol was measured at the start and at the end of treatment. Adverse events were collected for the total study period. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV1 (the 95% CI of the treatments' difference was within the 5% of the LSM of BDP CFC). The other secondary pulmonary function tests measured at the clinic visit showed a satisfactory asthma control, albeit without statistically significant differences between groups. Decreases in the use of rescue salbutamol and in clinical symptoms were also reported in both groups, with no differences between them. Adverse events were reported in 81.4% of patients in the BDP HFA group and in 82.5% in the CFC group. There were 73 and 59 adverse drug reactions in the two groups, respectively; the difference was mainly due to differences in taste. No drug-related serious adverse events were reported in either group. No difference was seen for morning serum cortisol between baseline and end of treatment, or between groups. In conclusion, the BDP-HFA 134a formulation proved to be statistically equivalent to the standard BDP CFC product over 12 weeks in adult patients with mild to moderate asthma.

Switching from conventional to extrafine aerosol beclomethasone dipropionate therapy in children: a 6-month, open- label, randomized trial.

BACKGROUND: In adults with asthma, hydrofluoralkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol provides equivalent asthma control at half the daily dose of conventional chlorofluorocarbon (CFC)-BDP. OBJECTIVE: We sought to compare the efficacy and tolerability of switching from CFC-BDP to HFA-BDP at half the daily dose in children with stable asthma. METHODS: This 6-month, open-label, randomized, multicenter study enrolled 520 children aged 5 to 11 years with well-controlled asthma receiving inhaled CFC-BDP or budesonide 200 to 800 microg/d x. (Four hundred fifty-two patients were using doses within the recommended range of 200-400 microg and were analyzed separately.) During a 4-week run-in period, patients used CFC-BDP plus a spacer (CFC-BDP+S) at approximately the same dose as they were using before study entry. Patients were then randomized in a 1:3 ratio to continue on CFC-BDP+S or switch to HFA-BDP Autohaler at half the daily dose. RESULTS: The change from baseline in morning peak expiratory flow was significantly greater in patients receiving 100-200 microg of HFA-BDP compared with those receiving 200-400 microg of CFC-BDP+S at weeks 7 to 8 (8.5 and 0.4 L/min, respectively; P =.014), with continuing improvement in both groups over 6 months (12.2 and 12.4 L/min, respectively, at month 6). There were no significant differences between treatments in mean change from baseline in FEV(1), percentage of days or nights without asthma symptoms, and daily beta-agonist use over the 6-month treatment period. The proportion of patients who had one or more asthma exacerbations, the incidence of adverse events, and the percentage change from baseline in 24-hour urinary free cortisol levels were similar in the 2 treatment groups. CONCLUSIONS: This study confirms that asthma control can be well maintained in children when switching from CFC-BDP+S to an HFA-BDP Autohaler at doses as low as 100 to 200 microg/d.

Effective control of asthma with hydrofluoroalkane flunisolide delivered as an extrafine aerosol in asthma patients.

BACKGROUND: Inhaled corticosteroids are established as maintenance therapy for persistent asthma. A new aerosol formulation of flunisolide delivers a small particle size by using a hydrofluoroalkane (HFA) propellant with a built-in spacer. OBJECTIVE: To compare efficacy and safety of two different flunisolide formulations, HFA and chlorofluorocarbon (CFC), with placebo treatment over a range of doses. METHODS: The multicenter, randomized, double-blind, placebo-controlled trial consisted of a 2-week, active run-in phase with CFC flunisolide 500 microg, twice daily, followed by 12 weeks of double-blind treatment with placebo, HFA flunisolide (85, 170, or 340 microg, twice daily), or CFC flunisolide (250, 500, or 1,000 microg, twice daily). Patients (N = 669) were nonsmokers, at least 12 years of age, with mild to moderate asthma who were being treated with inhaled corticosteroids. Outcome measures were change from baseline in forced expiratory volume in 1 second (FEV1), peak expiratory flow rate, as needed albuterol use, nocturnal awakenings, and asthma symptoms. RESULTS: After 12 weeks of treatment, patients receiving 170 microg, twice daily, and 340 microg, twice daily, of HFA flunisolide showed a significant (P < 0.01) improvement in percentage increase in FEV1 (12.22% at 170 microg, twice daily, and 14.69% at 340 microg, twice daily) compared with the placebo group (5.35%). At one-third the dose of CFC flunisolide, HFA flunisolide provided similar improvement in pulmonary function versus placebo. Both formulations demonstrated comparable linear dose dependency for the change from baseline in FEV1 without any evidence of cortisol suppression. Outcome values for all seven secondary efficacy measures were numerically superior in patients receiving HFA flunisolide compared with the CFC formulation. Both formulations seemed to be safe and well tolerated. CONCLUSIONS: HFA flunisolide provides comparable efficacy and safety at one-third the dose of CFC flunisolide.

Comparison of 4 analgesic agents for venipuncture.

This study compared pain on application, pain on venipuncture, cost, and convenience of 4 analgesic agents used for venipuncture. A convenience sample of 280 preoperative subjects was assigned randomly to 1 of 4 groups. Group 1 received 2.5% lidocaine--2.5% prilocaine cream (LPC) topically, Group 2 received dichlorotetrafluoroethane spray (DCTF), Group 3 received 0.5% lidocaine subcutaneously, and group 4 received normal saline with 0.9% benzyl alcohol (BA) subcutaneously. A 7-point verbal descriptor scale measured pain on application, and a 100-mm visual analogue scale measured pain on venipuncture. Cost was measured and compared on unit-dose basis. Convenience was measured with a questionnaire survey completed by the investigators. There was no significant difference (P < .05) among the groups for age, sex, ASA physical status, or difficulty of venipuncture. There was a significant difference in pain on application for all 4 agents (P < .05). The DCTF had the highest pain on application score (1.7 +/- 0.1), while the LPC had no pain on application (0.0 +/- 0). Lidocaine had a higher pain on application score (1.08 +/- 0.1) than the BA (0.52 +/- 0.1) but a lower score than DCTF. Lidocaine (1.3 +/- 0.3) was significantly less painful (P < .05) on venipuncture than LPC (2.18 +/- 0.3) and DCTF (2.5 +/- 0.3) but was not significantly different than BA (1.92 +/- 0.3). (All scores are given as mean +/- SEM.) There was a significant difference in cost and convenience among the 4 agents, with BA and lidocaine being the least expensive analgesic agents. Lidocaine, DCTF, and BA were equally convenient to use, while LPC was the least convenient, (P < .05). Lidocaine had low pain on venipuncture and low cost and convenience of use, but it was less than ideal in terms of pain on application. The BA had all the qualities of an ideal analgesic agent for venipuncture in this sample and should be considered as an analgesic agent for venipuncture.

Comparable bronchodilation with hydrofluoroalkane-134a (HFA) albuterol and chlorofluorocarbons-11/12 (CFC) albuterol in children with asthma.

This was an open-label, parallel group, randomized, age-stratified, multicenter study designed to compare the safety and efficacy of regular use of albuterol formulated in hydrofluoroalkane-134a (HFA albuterol) and albuterol formulated in chlorofluorocarbons-11/12 (CFC albuterol) in children with asthma. Children age 4-11 years using a short-acting inhaled beta2-agonist for 6 months to manage stable asthma, and with a prestudy forced expiratory volume in 1 sec (FEV1) of >50% predicted after withholding short-acting inhaled beta2-agonists for at least 6 hr, an increase in FEV1 > or = 12% within 30 min after two puffs of CFC albuterol, and the capability to comply with medication withholding requirements were eligible for study entry. After screening evaluation, patients entered a minimum 7-day run-in period. On study day 1 spirometry and a baseline 12-lead electrocardiogram (ECG) were performed, pulse and blood pressure were measured, and patients self-administered two puffs of their randomized study drug, either HFA albuterol or CFC albuterol. Serial spirometry was performed over 6 hr after study drug dosing. Pulse and blood pressure were measured just prior to each spirometry and a 12-lead ECG was performed at 60 min postdose. Patients took two puffs of their study drug four times a day for 4 weeks. At study week 4, study day 1 procedures were repeated. Patients maintained a daily diary of morning (A.M.) and evening (P.M.) peak expiratory flow (PEF), daytime asthma symptom scores, nighttime asthma sleep disturbance scores, and study drug use. Demographics and baseline characteristics of the 63 patients randomized to HFA albuterol (33) and CFC albuterol (30) were similar. No significant differences were found between the HFA albuterol and CFC albuterol treatment groups for any of the primary or secondary FEV1 efficacy variables either at study day 1 or study week 4. No significant differences were noted between treatment groups for A.M. and P.M. PEF, individual asthma symptom scores, nighttime asthma sleep disturbance scores, and rescue study drug use over the 4-week study. No significant differences were found between the two treatment groups for change from predose in heart rate, systolic and diastolic blood pressure, and 12-lead ECG intervals at either study day 1 or study week 4. Adverse event reporting was similar for the two treatment groups. In this study, with regular use of HFA albuterol in children with asthma, there was a similar safety profile and comparable bronchodilator efficacy as with CFC albuterol.

Proventil HFA prevents exercise-induced bronchoconstriction in children.

Short-acting inhaled beta2-agonists used just prior to exercise are an effective method for preventing exercise-induced bronchoconstriction (EIB) in children. This was a randomized, single-blind, placebo-controlled, four-period crossover study that compared the effectiveness of albuterol formulated in hydrofluoroalkane-134a (HFA) to albuterol formulated in chlorofluorocarbons (CFCs) and to placebo in protecting asthmatic children age 6-11 from EIB. Patients self-administered either HFA albuterol, two different CFC albuterol products, or placebo 30 min prior to exercise challenge. Spirometry was performed predose and 5, 10, 15, 30, 45, 60, 75, and 90 min after the exercise challenge was completed. The smallest percent change from the predose forced expiratory volume in 1 sec (FEV1) after exercise challenge was similar for the three active treatments, and each of the active treatments was significantly better than placebo. Each active treatment had significantly fewer patients unprotected from EIB (unprotected defined as having >20% fall in FEV1 after exercise challenge) than placebo. Changes in heart rate, blood pressure and electrocardiogram (ECG) intervals were similar for the three active treatments following exercise. HFA albuterol is as effective as albuterol products formulated in CFCs and more effective than placebo in protecting asthmatic children from EIB.

Health-related quality of life in moderate asthma: 400 microg hydrofluoroalkane beclomethasone dipropionate vs 800 microg chlorofluorocarbon beclomethasone dipropionate. The Study Group.

OBJECTIVE: To compare the effect of hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP; 400 microg/d) with that of chlorofluorocarbon (CFC) BDP (800 microg/d) on asthma health-related quality of life in a 12-week, parallel-group, multicenter study. BACKGROUND: HFA-BDP is a new CFC-free preparation of BDP, which was developed as a result of CFCs being phased out from metered dose inhalers. METHODS: Following 7 to 12 days of prednisone, 30 mg/d, 347 adults with moderate asthma were randomized to receive either 400 microg/d HFA-BDP, 800 microg/d CFC-BDP, or HFA placebo for 12 weeks (all other oral and inhaled steroids were withdrawn). Patients completed the Asthma Quality of Life Questionnaire (AQLQ), and clinical asthma status was measured at the end of a run-in period, at randomization (after oral steroid treatment), and at the end of the study treatment. RESULTS: Sixty-one patients withdrew, 43 due to worsening asthma (33 placebo; 5 HFA-BDP; 5 CFC-BDP). There was a deterioration in the AQLQ score (- 0.81) in the placebo group, and the difference between this and the stability observed in both the HFA-BDP group (+ 0.13) and the CFC-BDP group (- 0.03) was statistically significant (p

Equivalence of asthma control with new CFC-free formulation HFA-134a beclomethasone dipropionate and CFC-beclomethasone dipropionate.

The study was designed to test for equivalence of asthma control between a new aerosol formulation of beclomethasone dipropionate (BDP) incorporating a chlorofluorocarbon-(CFC) free, hydrofluoroalkane propellant (HFA-134a) and the conventional beclomethasone aerosol formulated in CFC propellants. Sixty-eight asthmatic patients entered an eight-week, randomised, double-blind crossover study. All patients, previously stabilised on BDP, were randomised to receive the same dose of BDP from each of the study treatments. Statistically significant equivalence was demonstrated between HFA-BDP and CFC-BDP for asthma control parameters: FEV1, morning and evening PEF, sleep disturbance, wheeze and cough, morning breathlessness and bronchodilator use. Such equivalence was also demonstrated for safety parameters. To conclude, it has been demonstrated that HFA-BDP achieves a level of asthma control that is clinically and statistically equivalent to CFC-BDP in terms of efficacy and safety, at total daily doses ranging from 200 micrograms to 600 micrograms in asthma patients previously stabilised on inhaled CFC-BDP.

Practical application of a first-aid treatment for burns and scalds.

This study examined the use of a first-aid treatment for burns and scalds sustained at The Fire Service College in Gloucestershire. One hundred and eight treatments were carried out. Questionnaires and assessments were completed for each patient and used to evaluate the effectiveness of treatment. The results suggest that the product used is a practical and effective first-aid treatment for burns.