PROAIR RESPICLICK(ALBUTEROL SULFATE)POWDER, METERED;INHALATION用于急性哮喘症状治疗的首款也是唯一一款呼吸驱动的、干粉抢救吸入器
2015年4月，美国FDA批准ProAir RespiClick（硫酸沙丁胺醇）吸入粉雾剂用于12岁及以上可逆阻塞性呼吸道疾病患者支气管痉挛治疗或预防；及用于12岁及以上患者运动诱发性支气管痉挛(EIB)预防。这款产品是一种呼吸驱动的、多剂量、干粉、短效β-受体激动剂(SABA)吸入器。它有望在2015年第二季度上市供患者使用。
“ProAir RespiClick是获FDA批准用于急性哮喘症状治疗的首款也是唯一一款呼吸驱动的、干粉抢救吸入器，”辛辛那提大学医学院免疫、过敏及风湿病科Bernstein博士称。“ProAir RespiClick的批准是非常重要的，因为它不再需要吸入期间手与呼吸之间的协调。”
此次批准基于一个由8项临床试验组成的综合性临床开发项目，它旨在评价ProAir RespiClick用于成年与青少年（12岁及以上年龄）哮喘及EIB患者的安全性与有效性。
临床试验结果显示，ProAir® RespiClick既安全又有效，不良事件与先前的沙丁胺醇吸入器相一致。与安慰剂相比，在大于1%的ProAir RespiClick治疗患者中发生的最常见不良事件是背痛、身体酸痛、胃部不适、窦性头痛和尿路感染。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use PROAIR RESPICLICK safely and effectively. See full prescribing information for PROAIR RESPICLICK.
PROAIR RESPICLICK (albuterol sulfate) inhalation powder, for oral
inhalation use
Initial U.S. Approval: 1981
INDICATIONS AND USAGE
PROAIR RESPICLICK inhalation powder is a beta2-adrenergic agonist indicated for:
• Treatment or prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease. ( 1.1)
• Prevention of exercise-induced bronchospasm in patients 12 years of age and older. ( 1.2)
DOSAGE AND ADMINISTRATION
For oral inhalation only
• Treatment or prevention of bronchospasm in adults and adolescents age 12 and older: 2 inhalations every 4 to 6 hours. In some patients, 1 inhalation every 4 hours may be sufficient. ( 2.1)
• Prevention of exercise-induced bronchospasm in adults and adolescents age 12 and over: 2 inhalations 15 to 30 minutes before exercise. ( 2.2)
• PROAIR RESPICLICKdoes not require priming. ( 2.3)
• Do not use with a spacer or volume holding chamber. ( 2.3)
• Keep the inhaler clean and dry at all times. Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. Never wash or put any part of the inhaler in water. ( 2.3)
• Discard when the dose counter displays 0 or after the expiration date on the product, whichever comes first. ( 2.3)
DOSAGE FORMS AND STRENGTHS
Inhalation powder: PROAIR RESPICLICK is a dry powder inhaler that meters 117 mcg of albuterol sulfate (equivalent to 97 mcg of albuterol base) from the device reservoir and delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouthpiece per actuation. The inhaler is supplied for 200 inhalation doses. (3)
CONTRAINDICATIONS
• Patients with hypersensitivity to albuterol. ( 4)
• Patients with severe hypersensitivity to milk proteins. ( 4)
WARNINGS AND PRECAUTIONS
• Life-threatening paradoxical bronchospasm may occur. Discontinue PROAIR RESPICLICK immediately and treat with alternative therapy. ( 5.1)
• Need for more doses of PROAIR RESPICLICK than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2)
• PROAIR RESPICLICK is not a substitute for corticosteroids. ( 5.3)
• Cardiovascular effects may occur. Use with caution in patients sensitive to sympathomimetic drugs and patients with cardiovascular or convulsive disorders. ( 5.4, 5.7)
• Excessive use may be fatal. Do not exceed recommended dose. ( 5.5)
• Immediate hypersensitivity reactions may occur. Discontinue PROAIR RESPICLICK immediately. ( 5.6)
• Hypokalemia and changes in blood glucose may occur. ( 5.7, 5.8)
ADVERSE REACTIONS
Most common adverse reactions (≥1% and >placebo) are back pain, pain, gastroenteritis viral, sinus headache, and urinary tract infection. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Teva Respiratory, LLC at 1-888-482-9522 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
• Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect. ( 7)
• Beta-blockers: May decrease effectiveness of PROAIR RESPICLICK and produce severe bronchospasm. Patients with asthma should not normally be treated with beta-blockers. ( 7.1)
• Diuretics, or non-potassium sparing diuretics: May potentiate hypokalemia or ECG changes. Consider monitoring potassium levels. ( 7.2)
• Digoxin: May decrease serum digoxin levels. Consider monitoring digoxin levels. ( 7.3)
• Monoamine oxidase (MAO) inhibitors and tricyclic antidepressants: May potentiate effect of albuterol on the cardiovascular system. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants. ( 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 4/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Bronchospasm
PROAIR RESPICLICK (albuterol sulfate) inhalation powder is indicated for the treatment or prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease.
1.2 Exercise-Induced Bronchospasm
PROAIR RESPICLICK is indicated for the prevention of exercise-induced bronchospasm in patients 12 years of age and older.
2 DOSAGE AND ADMINISTRATION
2.1 Bronchospasm
For treatment of acute episodes of bronchospasm or prevention of symptoms associated with bronchospasm, the recommended dosage for adults and adolescents 12 years and older is 2 inhalations repeated every 4 to 6 hours. More frequent administration or a larger number of inhalations is not recommended. In some patients, 1 inhalation every 4 hours may be sufficient.
2.2 Exercise-Induced Bronchospasm
For prevention of exercise-induced bronchospasm, the recommended dosage for adults and adolescents 12 years of age or older is 2 inhalations 15 to 30 minutes before exercise.
2.3 Administration Information
Administer PROAIR RESPICLICK by oral inhalation only.
Priming:PROAIR RESPICLICK inhaler does not require priming.
Do not use PROAIR RESPICLICK with a spacer or volume holding chamber.
Cleaning:
• Keep the inhaler clean and dry at all times. Never wash or put any part of your inhaler in water.
• Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed.
Dose Counter: The PROAIR RESPICLICK inhaler has a dose counter attached to the actuator. When the patient receives the inhaler, the number 200 will be displayed. The dose counter will count down each time the inhaler is actuated. When the dose counter reaches 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Discard PROAIR RESPICLICK 13 months after opening the foil pouch, when the dose counter displays 0 or after the expiration date on the product, whichever comes first [see Patient Counseling Information (17.8)]. 
3 DOSAGE FORMS AND STRENGTHS
Inhalation powder: PROAIR RESPICLICK is a multi-dose breath-actuated dry powder inhaler that meters 117 mcg of albuterol sulfate (equivalent to 97 mcg of albuterol base) from the device reservoir and delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouth piece per actuation. Each inhaler is supplied for 200 inhalation doses. PROAIR RESPICLICK inhalation powder is supplied as a white dry powder inhaler with a red cap in a sealed foil pouch.
4 CONTRAINDICATIONS
Use of PROAIR RESPICLICKis contraindicated in patients with a history of hypersensitivity to albuterol and/or severe hypersensitivity to milk proteins. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate. There have been reports of anaphylactic reactions in patients using inhalation therapies containing lactose [see Warnings and Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Paradoxical Bronchospasm
PROAIR RESPICLICK can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, PROAIR RESPICLICK should be discontinued immediately and alternative therapy instituted.
5.2 Deterioration of Asthma
Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of PROAIR RESPICLICK, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, eg, corticosteroids.
5.3 Use of Anti-Inflammatory Agents
The use of beta-adrenergic-agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, eg, corticosteroids, to the therapeutic regimen.
5.4 Cardiovascular Effects
PROAIR RESPICLICK, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of PROAIR RESPICLICK at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, PROAIR RESPICLICK, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
5.5 Do Not Exceed Recommended Dose
Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
5.6 Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. PROAIR RESPICLICK contains small amounts of lactose, which may contain trace levels of milk proteins. Hypersensitivity reactions including anaphylaxis, angioedema, pruritus, and rash have been reported with the use of therapies containing lactose (lactose is an inactive ingredient in PROAIR RESPICLICK). The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving PROAIR RESPICLICK.
5.7 Coexisting Conditions
PROAIR RESPICLICK, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
5.8 Hypokalemia
As with other beta-agonists, PROAIR RESPICLICK may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
6 ADVERSE REACTIONS
Use of PROAIR RESPICLICK may be associated with the following:
• Paradoxical bronchospasm [see Warnings and Precautions (5.1)]
• Cardiovascular Effects [see Warnings and Precautions (5.4)]
• Immediate hypersensitivity reactions [see Warnings and Precautions (5.6)]
• Hypokalemia [see Warnings and Precautions (5.8)
6.1 Clinical Trials Experience
A total of 1120 subjects were treated with PROAIR RESPICLICK during the clinical development program. The most common adverse reactions (≥1% and >placebo) were back pain, pain, gastroenteritis viral, sinus headache, and urinary tract infection. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults and Adolescents 12 years of Age and Older: The adverse reaction information presented in Table 1 below concerning PROAIR RESPICLICK is derived from the 12-week blinded treatment period of three studies which compared PROAIR RESPICLICK 180 mcg four times daily with a double-blinded matched placebo in 653 asthmatic patients 12 to 76 years of age.
Table 1: Adverse Reactions Experienced by Greater Than or Equal to 1.0% of Patients in the PROAIR RESPICLICK Group and Greater Than Placebo in three 12-Week Clinical Trials 1

Preferred Term	Number (%) of patients
	PROAIR RESPICLICK 180 mcg QID N=321	Placebo N=333
Back pain	6 (2%)	4 (1%)
Pain	5 (2%)	2 (<1%)
Gastroenteritis viral	4 (1%)	3 (<1%)
Sinus headache	4 (1%)	3 (<1%)
Urinary tract infection	4 (1%)	3 (<1%)

In a long-term study of 168 patients treated with PROAIR RESPICLICK for up to 52 weeks (including a 12-week double-blind period), the most commonly reported adverse events greater than or equal to 5% were upper respiratory infection, nasopharyngitis, sinusitis, bronchitis, cough, oropharyngeal pain, headache, and pyrexia.
In a small cumulative dose study, tremor, palpitations, and headache were the most frequently occurring (≥5%) adverse events.
6.2 Postmarketing Experience
In addition to the adverse reactions reported from clinical trials with PROAIR RESPICLICK, the following adverse events have been reported during use of other inhaled albuterol sulfate products: Urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), rare cases of aggravated bronchospasm, lack of efficacy, asthma exacerbation (potentially fatal), muscle cramps, and various oropharyngeal side-effects such as throat irritation, altered taste, glossitis, tongue ulceration, and gagging. 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.
In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as: angina, hypertension or hypotension, palpitations, central nervous system stimulation, insomnia, headache, nervousness, tremor, muscle cramps, drying or irritation of the oropharynx, hypokalemia, hyperglycemia, and metabolic acidosis.
7 DRUG INTERACTIONS
Other short-acting sympathomimetic bronchodilators should not be used concomitantly with PROAIR RESPICLICK. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
7.1 Beta Blockers
Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROAIR RESPICLICK, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, eg, as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic-blocking agents in patients with asthma. In this setting, consider cardioselective beta-blockers, although they should be administered with caution.
7.2 Diuretics
The ECG changes and/or hypokalemia which may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium sparing diuretics. Consider monitoring potassium levels.
7.3 Digoxin
Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and PROAIR RESPICLICK.
7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants
PROAIR RESPICLICK should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the cardiovascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects: Pregnancy Category C:
There are no adequate and well-controlled studies of PROAIR RESPICLICK or albuterol sulfate in pregnant women. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. PROAIR RESPICLICK should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately eight-tenths of the maximum recommended human dose (MRHD) for adults on a mg/m2 basis and in 10 of 108 (9.3%) fetuses at approximately 8 times the MRHD. Similar effects were not observed at approximately one-thirteenth of the MRHD. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).
In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 630 times the MRHD.
In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 65 times the MRHD.
Non-Teratogenic Effects: A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.
8.2 Labor and Delivery
Because of the potential for beta-agonist interference with uterine contractility, use of PROAIR RESPICLICK for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. PROAIR RESPICLICK has not been approved for the management of pre-term labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol.
8.3 Nursing Mothers
Plasma levels of albuterol after inhaled therapeutic doses are very low in humans, but it is not known whether the components of PROAIR RESPICLICK are excreted in human milk.
Caution should be exercised when PROAIR RESPICLICK is administered to a nursing woman. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of PROAIR RESPICLICK by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of PROAIR RESPICLICK for the treatment or prevention of bronchospasm in children 12 to 17 years of age and older with reversible obstructive airway disease is based on two 12-week clinical trials in 318 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, one long-term safety study in children 12 years of age and older, and one single-dose crossover study comparing doses of 90 and 180 mcg with albuterol sulfate inhalation aerosol (ProAir® HFA) in 71 patients [see Clinical Studies (14.1)]. The safety and effectiveness of PROAIR RESPICLICK for treatment of exercise-induced bronchospasm in children 12 years of age and older is based on one single-dose crossover study in 38 patients age 16 and older with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies (14.2)]. The safety profile for patients ages 12 to 17 was consistent with the overall safety profile seen in these studies.
The safety and effectiveness of PROAIR RESPICLICK in pediatric patients below the age of 12 years have not been established. Overall, 120 children with asthma ages 4 to 11 years have participated in the PROAIR RESPICLICK clinical program, including 76 patients evaluated in 2 single-dose crossover clinical trials comparing PROAIR RESPICLICK to ProAir HFA at doses up to 180 mcg.
8.5 Geriatric Use
Clinical studies of PROAIR RESPICLICK did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions (5.4, 5.7)].
All beta2-adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
10 OVERDOSAGE
The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, eg, seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia.
Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of PROAIR RESPICLICK.
Treatment consists of discontinuation of PROAIR RESPICLICK together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of PROAIR RESPICLICK.
11 DESCRIPTION
The active ingredient of PROAIR RESPICLICK inhalation powder is albuterol sulfate, a racemic salt of albuterol. Albuterol sulfate is a beta2-adrenergic agonist. It has the chemical name α1-[(tert-butylamino) methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1) (salt), and the following chemical structure:

The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C13H21NO3)2•H2SO4. Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate is the official U.S. Adopted Name in the United States, and salbutamol sulfate is the recommended World Health Organization international nonproprietary name.
PROAIR RESPICLICK is an inhalation-driven, multi-dose inhalation powder (dry powder inhaler) for oral inhalation only. It contains a formulation blend of albuterol sulfate with alpha-lactose monohydrate. Each actuation provides a metered dose of 2.6 mg of the formulation containing 117 mcg of albuterol sulfate (equivalent to 97 mcg of albuterol base) and lactose from the device reservoir. Under standardized in vitro test conditions with fixed flow rates ranging from 58 to 71 L/min, and with a total air volume of 2 L, the PROAIR RESPICLICK inhaler delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) with lactose from the mouthpiece. The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. In a study that investigated the peak inspiratory flow rate (PIFR) in asthma (n=27, ages 12 to 17 years old and n=50, ages 18 to 45 years old) and COPD (n=50, over 50 years old) patients, the mean PIFR achieved by subjects was >60 L/min (range = 31 to 110 L/min.), indicating that patients would be able to achieve the required inspiratory flow to operate the MDPI device correctly. The inhaler is provided for 200 actuations (inhalations).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Albuterol sulfate is a beta2-adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta2-adrenergic receptors on airway smooth muscle. Activation of beta2-adrenergic receptors leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3',5’‑adenosine monophosphate (cyclic AMP). This increase of cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta2-adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions (5.4)].
Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes [see Warnings and Precautions (5.4)].
12.2 Pharmacodynamics
In a pharmacodynamic (PD) trial conducted in 47 patients, the PD and safety profiles were similar for PROAIR RESPICLICK and ProAir HFA. Comparable changes from baseline in the PD measures (serum glucose and potassium concentrations, QTcB, QTcF, heart rate, systolic blood pressure, and diastolic blood pressure) were observed following cumulative dose administration up to 1440 mcg of both PROAIR RESPICLICK and ProAir HFA. The overall safety, efficacy and PD profile of PROAIR RESPICLICK and ProAir HFA were comparable.
In a single-dose Phase 2 study also assessing PD, 71 patients using PROAIR RESPICLICK had bronchodilator efficacy that was significantly greater than placebo and comparable to that of ProAir HFA at administered doses of 90 and 180 mcg in adolescent and adult subjects with persistent asthma.
Cardiac Electrophysiology
As with other beta2-adrenergic agonists, PROAIR RESPICLICK prolonged QT intervals following a 1440 mcg cumulative dose. The prolongation was comparable to that of ProAir HFA.
12.3 Pharmacokinetics
Absorption
Albuterol was rapidly absorbed into the systemic circulation with peak plasma concentrations occurring at half an hour following single- or multiple-dose oral inhalation(s) of PROAIR RESPICLICK. In a cumulative dose study, the AUC0-t was comparable between PROAIR RESPICLICK group and ProAir HFA group; Cmax value was approximately one-third higher in PROAIR RESPICLICK group than ProAir HFA group.
Distribution
The volume of distribution has not been determined for PROAIR RESPICLICK. Published literature suggests that albuterol exhibits low in vitro plasma protein binding (10%).
Elimination
The accumulation ratio (~1.6 fold) was observed following one week QID dosing. The corresponding effective half-life was approximately 5 hours, which was consistent with the elimination half-life following both single- or multiple-dose administration.
Metabolism
Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3.
Excretion
The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.
Specific Populations
Age: No pharmacokinetic studies for PROAIR RESPICLICK have been conducted in neonates or elderly subjects.
Sex: The influence of sex on the pharmacokinetics of PROAIR RESPICLICK has not been studied.
Race: The influence of race on the pharmacokinetics of PROAIR RESPICLICK has not been studied.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of PROAIR RESPICLICK to patients with renal impairment [see Use in Specific Populations (8.5)].
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of PROAIR RESPICLICK has not been evaluated.
Drug Interaction Studies: In vitro and in vivo drug interaction studies have not been conducted with PROAIR RESPICLICK. Known clinically significant drug interactions are outlined in Drug Interactions (7).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2‑year study in Sprague-Dawley rats, albuterol sulfate caused a dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately 15 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18‑month study in CD‑1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 1,600 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In a 22‑month study in Golden Hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 210 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay.
Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 310 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
13.2 Animal Toxicology and/or Pharmacology
Preclinical: Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when β‑agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.
14 CLINICAL STUDIES
14.1 Bronchospasm Associated with Asthma
Adult and Adolescent Patients 12 Years of Age and Older
In two 12-week, randomized, double-blind, placebo-controlled studies of identical design (Study 1 and Study 2), PROAIR RESPICLICK (153 patients) was compared to a matched placebo dry powder inhaler (163 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. Patients were maintained on inhaled corticosteroid treatment. Serial FEV1 measurements, shown below in Figure 1 as average of the mean changes from test-day baseline at Day 1 and Day 85, demonstrated that two inhalations of PROAIR RESPICLICK produced significantly greater improvement in FEV1 AUC0‑6hr over the pre-treatment value than placebo in Study 1. Consistent results were observed in Study 2.
Figure 1: FEV1 as Mean Change from Test-Day, Pre-Dose Baseline in a 12-Week Clinical Trial (Study 1)
In Study 1, 44 of 78 patients treated with PROAIR RESPICLICK achieved a 15% increase in FEV1 within 30 minutes post‑dose on Day 1. The median time to onset was 5.7 minutes, and median duration of effect as measured by a 15% increase was approximately 2 hours. Consistent results were observed in Study 2. In a double‑blind, randomized, placebo–controlled, single‑dose crossover study evaluating PROAIR RESPICLICK and ProAir HFA in 71 adult and adolescent subjects ages 12 and older with persistent asthma, PROAIR RESPICLICK had bronchodilator efficacy that was significantly greater than placebo at administered doses of 90 and 180 mcg.
14.2 Exercise-Induced Bronchospasm
In a randomized, single-dose, crossover study in 38 adult and adolescent patients with exercise-induced bronchospasm (EIB), two inhalations of PROAIR RESPICLICK taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as the maintenance of FEV1 within 80% of post-dose, pre-exercise baseline values) in 97% (37 of 38) of patients as compared to 42% (16 of 38) of patients when they received placebo.
Patients who participated in these clinical trials were allowed to use concomitant steroid therapy.
16 HOW SUPPLIED/STORAGE AND HANDLING
PROAIR RESPICLICK inhalation powder is supplied as a white dry powder inhaler with a red cap sealed in a foil pouch in boxes of one. Each inhaler contains 0.65g of the formulation and provides 200 actuations (NDC 59310-580-20).
Store at room temperature (between 15° and 25°C; 59° and 77°F). Avoid exposure to extreme heat, cold, or humidity.
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Using PROAIR RESPICLICK)
Patients should be given the following information:
Frequency of Use
The action of PROAIR RESPICLICK should last for 4 to 6 hours. Instruct patients to not use PROAIR RESPICLICK more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of PROAIR RESPICLICK without consulting the physician. If patients find that treatment with PROAIR RESPICLICK becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual, they should seek medical attention immediately.
Caring for and Storing the Inhaler
Instruct patients to not open their inhaler unless they are taking a dose. Repeated opening and closing the cover without taking medication will waste medication and may damage the inhaler.
Advise patients to keep their inhaler dry and clean at all times. Never wash or put any part of the inhaler in water. Patient should replace inhaler if washed or placed in water.
Routine maintenance is not required. If the mouthpiece needs cleaning, instruct patients to gently wipe the mouthpiece with a dry cloth or tissue as needed.
Instruct patients to store the inhaler at room temperature and to avoid exposure to extreme heat, cold, or humidity.
Instruct patients to never take the inhaler apart.
Inform patients that PROAIR RESPICLICK has a dose counter attached to the actuator. When the patient receives the inhaler, the number 200 will be displayed. The dose counter will count down each time the mouthpiece cap is opened and closed. The dose counter window displays the number of actuations left in the inhaler in units of two (eg, 200, 198, 196, etc). When the counter displays 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Inform patients to discard PROAIR RESPICLICK when the dose counter displays 0 or after the expiration date on the product, whichever comes first.
Paradoxical Bronchospasm
Inform patients that PROAIR RESPICLICK can produce paradoxical bronchospasm. Instruct patients to discontinue PROAIR RESPICLICK if paradoxical bronchospasm occurs.
Concomitant Drug Use
Inform patients that, while they are taking PROAIR RESPICLICK, they should take other inhaled drugs and asthma medications only as directed by a physician.
Common Adverse Events
Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, and nervousness.
Pregnancy
Inform patients who are pregnant or nursing that they should contact their physician about the use of PROAIR RESPICLICK.
General Information on Use
Effective and safe use of PROAIR RESPICLICK includes an understanding of the way that it should be administered. Do not use a spacer or volume holding chamber with PROAIR RESPICLICK. Patients should be instructed on the proper use of the inhaler. See the FDA-approved Patient Information and Patient Instructions for Use. Discard PROAIR RESPICLICK 13 months after opening the foil pouch, when the dose counter displays 0 or after the expiration date on the product, whichever comes first.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9324e2eb-26fd-4f14-9f10-e5aa467306f4