Is salmeterol a steroid?

Salmeterol Oral Inhalation

Salmeterol comes as a dry powder to inhale by mouth using a specially designed inhaler. When salmeterol is used to treat asthma or COPD, it is usually used twice a day, in the morning and evening, about 12 hours apart. Use salmeterol at around the same times every day. When salmeterol is used to prevent breathing difficulties during exercise, it is usually used at least 30 minutes before exercise but not more often than once every 12 hours. If you are using salmeterol twice a day on a regular basis, do not use another dose before exercising. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use salmeterol exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor.

Do not use salmeterol to treat sudden attacks of asthma or COPD. Your doctor will prescribe a short-acting beta agonist medication such as albuterol (Accuneb, Proair, Proventil, Ventolin) to use during attacks. If you were using this type of medication on a regular basis before you began treatment with salmeterol, your doctor will probably tell you to stop using it regularly but to continue to use it to treat sudden attacks of asthma symptoms. Follow these directions carefully. Do not change the way you use any of your medications without talking to your doctor.

Do not use salmeterol if you have asthma or COPD that is quickly getting worse. If you have any of the following signs of worsening asthma or COPD, call your doctor immediately:

  • your breathing gets worse
  • your short-acting inhaler does not work as well as it did in the past
  • you need to use more puffs than usual of your short-acting inhaler or use it more often
  • you need to use four or more puffs per day of your short-acting inhaler for two or more days in a row
  • you use more than one canister (200 inhalations) of your short-acting inhaler during an 8-week period
  • your peak-flow meter (home device used to test breathing) results show your breathing problems are worsening
  • you have asthma and your symptoms do not improve after you use salmeterol regularly for one week

Salmeterol controls the symptoms of asthma and other lung diseases but does not cure these conditions. Do not stop using salmeterol without talking to your doctor. If you suddenly stop using salmeterol, your symptoms may worsen.

Before you use the salmeterol inhaler the first time, ask your doctor, pharmacist, or respiratory therapist to show you how to use it. Practice using the inhaler while he or she watches.

To use the inhaler, follow these steps:

  1. If you will be using a new inhaler for the first time, remove it from the box and the foil wrapper. Fill in the blanks on the inhaler label with the date that you opened the pouch and the date 6 weeks later when you must replace the inhaler.
  2. Hold the inhaler in one hand, and put the thumb of your other hand on the thumbgrip. Push your thumb away from you as far as it will go until the mouthpiece appears and snaps into position.
  3. Hold the inhaler in a level, horizontal position with the mouthpiece toward you. Slide the lever away from you as far as it will go until it clicks.
  4. Every time the lever is pushed back, a dose is ready to inhale. You will see the number in the dose counter go down. Do not waste doses by closing or tilting the inhaler, playing with the lever, or advancing the lever more than once.
  5. Hold the inhaler level and away from your mouth, and breathe out as far as you comfortably can.
  6. Keep the inhaler in a level, flat position. Put the mouthpiece to your lips. Breathe in quickly and deeply though the inhaler, not through your nose.
  7. Remove the inhaler from your mouth, and hold your breath for 10 seconds or as long as you comfortably can. Breathe out slowly.
  8. You will probably taste or feel the salmeterol powder released by the inhaler. Even if you do not, do not inhale another dose. If you are not sure you are getting your dose of salmeterol, call your doctor or pharmacist.
  9. Put your thumb on the thumbgrip and slide it back toward you as far as it will go. The device will click shut.

Serevent Diskus

SIDE EFFECTS

LABA, including salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death. Data from a large 28-week placebo-controlled US trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients .

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.

Clinical Trials Experience In Asthma

Adult and Adolescent Subjects Aged 12 Years and Older

Two multicenter, 12-week, placebo-controlled clinical trials evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 12 years and older with asthma. Table 1 reports the incidence of adverse reactions in these 2 trials.

Table 1: Adverse Reactions With SEREVENT DISKUS With ≥ 3 Incidence and More Common Than Placebo in Adult and Adolescent Subjects With Asthma

Adverse Event Percent of Subjects
Placebo
(n = 152)
SEREVENT DISKUS 50 mcg Twice Daily
(n = 149)
Albuterol Inhalation Aerosol 180 mcg 4 Times Daily
(n = 150)
Ear, nose, and throat
Nasal/sinus congestion, pallor 6 9 8
Rhinitis 4 5 4
Neurological
Headache 9 13 12
Respiratory
Asthma 1 3 < 1
Tracheitis/bronchitis 4 7 3
Influenza 2 5 5

Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥ 3% in the group treated with SEREVENT DISKUS and were more common than in the placebo group.

Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred at ≥ 3% but were more common in the placebo group. However, throat irritation has been described at rates exceeding that of placebo in other controlled clinical trials.

Additional Adverse Reactions

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with SEREVENT DISKUS compared with subjects treated with placebo include the following: contact dermatitis, eczema, localized aches and pains, nausea, oral mucosal abnormality, pain in joint, paresthesia, pyrexia of unknown origin, sinus headache, and sleep disturbance.

Pediatric Subjects Aged 4 to 11 Years

Two multicenter, 12-week, controlled trials have evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 4 to 11 years with asthma. Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common than in the placebo group.

Table 2: Adverse Reaction Incidence in Two 12-Week Pediatric Clinical Trials in Subjects With Asthma

Adverse Event Percent of Subjects
Placebo
(n = 215)
SEREVENT DISKUS 50 mcg Twice Daily
(n = 211)
Albuterol Inhalation Aerosol 200 mcg 4 Times Daily
(n = 115)
Ear, nose, and throat
Ear signs and symptoms 3 4 9
Pharyngitis 3 6 3
Neurological
Headache 14 17 20
Respiratory
Asthma 2 4 < 1
Skin
Skin rashes 3 4 2
Urticaria 0 3 2

The following events were reported at an incidence of greater than 1% in the salmeterol group and with a higher incidence than in the albuterol and placebo groups: gastrointestinal signs and symptoms, lower respiratory signs and symptoms, photodermatitis, and arthralgia and articular rheumatism.

In clinical trials evaluating concurrent therapy of salmeterol with inhaled corticosteroids, adverse events were consistent with those previously reported for salmeterol, or with events that would be expected with the use of inhaled corticosteroids.

Laboratory Test Abnormalities

Elevation of hepatic enzymes was reported in > 1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

Two multicenter, 24-week, placebo-controlled US trials evaluated twice-daily doses of SEREVENT DISKUS in subjects with COPD. For presentation (Table 3), the placebo data from a third trial, identical in design, subject entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 trials (total N = 341 for salmeterol and 576 for placebo).

Table 3: Adverse Reactions With SEREVENT DISKUS With ≥ 3% Incidence in US Controlled Clinical Trials in Subjeci ts With Chronic Obstructive Pulmonary Diseasea

Adverse Event Percent of Patients
Placebo
(n = 576)
SEREVENT DISKUS 50 mcg Twice Daily
(n = 341)
Cardiovascular
Hypertension 2 4
Ear, nose, and throat
Throat irritation 6 7
Nasal congestion/blockage 3 4
Sinusitis 2 4
Ear signs and symptoms 1 3
Gastrointestinal
Nausea and vomiting 3 3
Lower respiratory
Cough 4 5
Rhinitis 2 4
Viral respiratory infection 4 5
Musculoskeletal
Musculoskeletal pain 10 12
Muscle cramps and spasms 1 3
Neurological
Headache 11 14
Dizziness 2 4
Average duration of exposure (days) 128.9 138.5
a Table 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common in the group receiving SEREVENT DISKUS than in the placebo group.

Other adverse reactions occurring in the group receiving SEREVENT DISKUS that occurred at a frequency of ≥ 1% and were more common than in the placebo group were as follows: anxiety; arthralgia and articular rheumatism; bone and skeletal pain; candidiasis mouth/throat; dental discomfort and pain; dyspeptic symptoms; edema and swelling; gastrointestinal infections; hyperglycemia; hyposalivation; keratitis and conjunctivitis; lower respiratory signs and symptoms; migraines; muscle pain; muscle stiffness, tightness, and rigidity; musculoskeletal inflammation; pain; and skin rashes.

Adverse reactions to salmeterol are similar in nature to those seen with other selective beta2-adrenoceptor agonists, e.g., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm; headache; tremor; nervousness; and paradoxical bronchospasm.

Laboratory Abnormalities

There were no clinically relevant changes in these trials. Specifically, no changes in potassium were noted.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of salmeterol. 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 salmeterol or a combination of these factors.

In extensive US and worldwide postmarketing experience with salmeterol, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating , but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.

Cardiovascular

Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) and anaphylaxis.

Non-Site Specific

Very rare anaphylactic reaction in patients with severe milk protein allergy.

Respiratory

Reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking; oropharyngeal irritation.

Read the entire FDA prescribing information for Serevent Diskus (Salmeterol Xinafoate)

What is Salmeterol Xinafoate?

It is very important that your doctor check your or your child’s progress at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects.

Tell your doctor if you are also using other medicines for your COPD. Your doctor may want you to stop using the medicine and use it only during a severe COPD attack. Follow your doctor’s instructions on how you should take your medicine.

This medicine should not be used if you are having a severe COPD attack, or if symptoms of COPD attack has already started. Your doctor may prescribe another medicine for you to use in case of an acute COPD attack. If the other medicine does not work as well, tell your doctor right away.

This medicine should only be used as an additional treatment for patients who cannot be treated with other asthma medicines (such as inhaled corticosteroids) or for asthma patients that require two medicines, including salmeterol. Ask your doctor if you have any questions.

Although this medicine decreases the number of asthma episodes, it may increase the chance for a severe asthma attack when they do occur. Be sure to read about these risks in the Medication Guide and talk to your doctor or pharmacist about any questions or concerns you may have.

You should not use this medicine if your asthma attack has already started. Your doctor will prescribe another medicine (eg, a short-acting inhaler) for you to use in case of an acute asthma attack. Make sure you understand how to use the short-acting inhaler. Talk to your doctor if you need instructions.

Do not use any other asthma medicine or medicine for breathing problems without checking first with your doctor. This medicine should not be used with other inhalers that contain arformoterol (Brovana™), budesonide and formoterol combination (Symbicort®), fluticasone and salmeterol combination (Advair® Diskus®, Advair® HFA), formoterol (Foradil® Aerolizer®, Perforomist™), or indacaterol (Arcapta® Neohaler®).

Tell your doctor if you are using or have used medicine for depression (eg, MAO inhibitor, TCA) within the past 2 weeks.

Talk to your doctor or get medical care right away if:

  • Your or your child’s symptoms do not improve after using this medicine for 1 week or if they become worse.
  • Your short-acting inhaler does not seem to be working as well as usual and you or your child need to use it more often (eg, you use 1 whole canister of the short-acting inhaler in 8 weeks time, or you need to use 4 or more inhalations of the short-acting inhaler in 24 hours or for 2 or more days in a row).
  • You or your child have a big decrease in your peak flow when measured as directed by your doctor.

Do not change your dose or stop using your medicine without first asking your doctor.

Your doctor may want you to carry a medical identification (ID) card stating that you or your child are using this medicine. The card will say that you may need additional medicine during an emergency, a severe asthma attack or other illness, or unusual stress.

This medicine may cause paradoxical bronchospasm, which means your breathing or wheezing will get worse. Paradoxical bronchospasm may be life-threatening. Check with your doctor right away if you or your child are having a cough, difficulty with breathing, shortness of breath, or wheezing after using this medicine.

If you or your child develop a skin rash, hives, or any allergic reaction (including anaphylaxis) to this medicine, check with your doctor right away.

Check with your doctor right away if you or your child have chest pain, a fast heartbeat, nervousness, shaking of the hands or feet, noisy breathing, a feeling of choking, or tightness or irritation of the throat while using this medicine.

Hypokalemia (low potassium in the blood) may occur while you are using this medicine. Check with your doctor right away if you or your child have more than one of the following symptoms: convulsions (seizures), decreased urine, dry mouth, increased thirst, irregular heartbeat, loss of appetite, mood changes, muscle pain or cramps, nausea or vomiting, numbness or tingling in the hands, feet, or lips, shortness of breath, or unusual tiredness or weakness.

This medicine may affect blood sugar levels. If you or your child are diabetic and notice a change in the results of your blood or urine sugar tests, check with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter ) medicines and herbal or vitamin supplements.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2- agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits plateletactivating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.

Pharmacodynamics

Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium . The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50-mcg doses of salmeterol inhalation powder (n = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Also, pediatric patients receiving 50-mcg doses of salmeterol inhalation powder (n = 67) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 3 months of therapy, and no clinically significant dysrhythmias were noted.

In 24-week clinical studies in patients with COPD, the incidence of clinically significant abnormalities on the predose ECGs at Weeks 12 and 24 in patients who received salmeterol 50 mcg was not different compared with placebo.

No effect of treatment with salmeterol 50 mcg was observed on pulse rate and systolic and diastolic blood pressure in a subset of patients with COPD who underwent 12-hour serial vital sign measurements after the first dose (n = 91) and after 12 weeks of therapy (n = 74). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar for patients receiving either salmeterol or placebo .

Concomitant Use of SEREVENT DISKUS With Other Respiratory Medications

Short-Acting Beta2-Agonists: In two 12-week repetitive-dose clinical trials in adult and adolescent subjects with asthma (N = 149), the mean daily need for additional beta2-agonist in subjects using SEREVENT DISKUS was approximately 1/ inhalations/day. Twenty-six percent (26%) of the subjects in these trials used between 8 and 24 inhalations of short-acting betaagonist per day on 1 or more occasions. Nine percent (9%) of the subjects in these trials averaged over 4 inhalations/day over the course of the 12-week trials. No increase in frequency of

cardiovascular events was observed among the 3 subjects who averaged 8 to 11 inhalations/day; however, the safety of concomitant use of more than 8 inhalations/day of short-acting beta2- agonist with SEREVENT DISKUS has not been established. In 29 subjects who experienced worsening of asthma while receiving SEREVENT DISKUS during these trials, albuterol therapy administered via either nebulizer or inhalation aerosol (1 dose in most cases) led to improvement in FEV1 and no increase in occurrence of cardiovascular adverse events.

In 2 clinical trials in subjects with COPD, the mean daily need for additional beta2- agonist for subjects using SEREVENT DISKUS was approximately 4 inhalations/day. Twentyfour percent (24%) of subjects using SEREVENT DISKUS averaged 6 or more inhalations of albuterol per day over the course of the 24-week trials. No increase in frequency of cardiovascular adverse reactions was observed among subjects who averaged 6 or more inhalations per day.

Methylxanthines: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by subjects receiving salmeterol has not been completely evaluated. In 1 clinical trial in subjects with asthma, 87 subjects receiving SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 subjects receiving SEREVENT Inhalation Aerosol without theophylline. Resting heart rates were slightly higher in the subjects on theophylline but were little affected by therapy with SEREVENT Inhalation Aerosol.

In 2 clinical trials in subjects with COPD, 39 subjects receiving SEREVENT DISKUS concurrently with a theophylline product had adverse event rates similar to those in 302 subjects receiving SEREVENT DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with SEREVENT DISKUS did not alter the observed adverse event profile.

Cromoglycate: In clinical trials, inhaled cromolyn sodium did not alter the safety profile of salmeterol when administered concurrently.

Pharmacokinetics

Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1- hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect.

Absorption

Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses.

Distribution

The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

Metabolism

Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces.

An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to a-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of a-hydroxysalmeterol in vitro.

Elimination

In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only).

The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (greater than 99%) and has a long elimination half-life of 11 days.

Drug Interactions

Inhibitors of Cytochrome P450 3A4: Ketoconazole: In a placebocontrolled crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 ) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist-mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

Animal Toxicology And/Or Pharmacology

Preclinical

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 beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

Clinical Studies

Asthma

The initial trials supporting the approval of SEREVENT DISKUS for the treatment of asthma did not require the regular use of inhaled corticosteroids. However, for the treatment of asthma, SEREVENT DISKUS is currently indicated only as concomitant therapy with an inhaled corticosteroid .

In 2 randomized doubleblind trials, SEREVENT DISKUS was compared with albuterol inhalation aerosol and placebo in adolescent and adult subjects with mild-to-moderate asthma (protocol defined as 50% to 80% predicted FEV1, actual mean of 67.7% at baseline), including subjects who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week period with no change in effectiveness over this time period (see Figure 1). There were no gender- or age-related differences in safety or efficacy. No development of tachyphylaxis to the bronchodilator effect was noted in these trials. FEV1 measurements (mean change from baseline) from these two 12-week trials are shown in Figure 1 for both the first and last treatment days.

Figure 1: Serial 12-Hour FEV1 From Two 12-Week Clinical Trials in Subjects With Asthma

Table 4 shows the treatment effects seen during daily treatment with SEREVENT DISKUS for 12 weeks in adolescent and adult subjects with mild-to-moderate asthma.

Table 4: Daily Efficacy Measurements in Two 12-Week Clinical Trials (Combined Data) Parameter Time Placebo

Parameter Time Placebo SEREVENT DISKUS Albuterol Inhalation Aerosol
No. of randomized subjects 152 149 148
Mean AM peak expiratory Baseline 394 395 394
flow (L/min) 12 weeks 396 427a 394
Mean % days with no asthma Baseline 14 13 12
symptoms 12 weeks 20 33 21
Mean % nights with no Baseline 70 63 68
awakenings 12 weeks 73 85a 71
Rescue medications (mean Baseline 4.2 4.3 4.3
no. of inhalations per day) 12 weeks 3.3 1.6b 2.2
Asthma exacerbations (%) 14 15 16
aStatistically superior to placebo and albuterol (P < 0.001).
bStatistically superior to placebo (P < 0.001).

Maintenance of efficacy for periods up to 1 year has been documented.

SEREVENT DISKUS and SEREVENT Inhalation Aerosol were compared with placebo in 2 additional randomized double-blind clinical trials in adolescent and adult subjects with mildto- moderate asthma. SEREVENT DISKUS 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were noted in 2 randomized, single-dose, crossover comparisons of SEREVENT DISKUS and SEREVENT Inhalation Aerosol for the prevention of EIB. Therefore, while SEREVENT DISKUS was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate subjects with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all subjects.

Subjects on Concomitant Inhaled Corticosteroids: In 4 clinical trials in adult and adolescent subjects with asthma (N = 1,922), the effect of adding SEREVENT Inhalation Aerosol to inhaled corticosteroid therapy was evaluated over a 24-week treatment period. The trials compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose.

Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled subjects (aged 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all subjects were switched to beclomethasone dipropionate (BDP) 168 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of BDP to 336 mcg twice daily. As compared with the doubled dose of BDP, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of subjects who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the group receiving SEREVENT Inhalation Aerosol versus 17.9% in the higher-dose beclomethasone dipropionate group).

Two randomized, double-blind, controlled, parallel-group clinical trials (N = 925) enrolled subjects (aged 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior asthma therapy. During the 2- to 4-week run-in period, all subjects were switched to fluticasone propionate 88 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared with the increased (2.5 times) dose of fluticasone propionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reductions in supplemental albuterol use. Fewer subjects receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%).

Table 5 shows the treatment effects seen during daily treatment with SEREVENT Inhalation Aerosol for 24 weeks in adolescent and adult subjects with mild-to-moderate asthma.

Onset of Action: During the initial treatment day in several multiple-dose clinical trials with SEREVENT DISKUS in subjects with asthma, the median time to onset of clinically significant bronchodilatation ( ≥ 15% improvement in FEV1) ranged from 30 to 48 minutes after a 50-mcg dose.

One hour after a single dose of 50 mcg of SEREVENT DISKUS, the majority of subjects had ≥ 15% improvement in FEV1. Maximum improvement in FEV1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most subjects.

Pediatric Subjects

In a randomized, double-blind, controlled trial (N = 449), 50 mcg of SEREVENT DISKUS was administered twice daily to pediatric subjects with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial PEF (36% to 39% postdose increase from baseline) and FEV1 (32% to 33% postdose increase from baseline). Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and inhaled corticosteroids. A second randomized, double-blind, placebocontrolled trial (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS.

Salmeterol Multi-center Asthma Research Trial

The SMART trial was a randomized double-blind trial that enrolled LABA-naive subjects with asthma (average age of 39 years; 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy.

A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (see Table 5 and Figure 2). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%, relative risk: 4.37 ).

Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%, relative risk: 5.82 ). In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%, relative risk: 7.26 ). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (see Table 5).

The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control therapy mitigates the risk of asthmarelated death.

Table 5: Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART)

Salmeterol n (%a) Placebo n (%a) Relative Riskb (95% Confidence Interval) Excess Deaths Expressed per 10,000 Subjectsc (95% Confidence Interval)
Total Populationd
Salmeterol: n = 13,176
Placebo: n = 13,179
13 (0.10%) 3 (0.02%) 4.37
(1.25, 15.34)
8
(3, 13)
Caucasian
Salmeterol: n = 9,281
Placebo: n = 9,361
6
(0.07%)
1
(0.01%)
5.82
(0.70, 48.37)
6
(1, 10)
African American
Salmeterol: n = 2,366
Placebo: n = 2,319
7
(0.31%)
1
(0.04%)
7.26
(0.89, 58.94)
27
(8, 46)
a Life-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to study treatment to account for early withdrawal of subjects from the study.
bRelative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthmarelated death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.
c Estimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 patients received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.
d The Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Figure 2: Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment

Exercise-Induced Bronchospasm

In 2 randomized, single-dose, crossover trials in adolescents and adults with EIB (N = 52), 50 mcg of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise. For some subjects, this protective effect against EIB was still apparent up to 8.5 hours following a single dose (see Table 6).

Table 6: Results of 2 Exercise-Induced Bronchospasm Studies in Adolescents and Adults

In 2 randomized trials in children aged 4 to 11 years with asthma and EIB (N = 50), a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many subjects.

Chronic Obstructive Pulmonary Disease

In 2 clinical trials evaluating twice-daily treatment with SEREVENT DISKUS 50 mcg (n = 336) compared with placebo (n = 366) in patients with chronic bronchitis with airflow limitation, with or without emphysema, improvements in pulmonary function endpoints weregreater with salmeterol 50 mcg than with placebo. Treatment with SEREVENT DISKUS did not result in significant improvements in secondary endpoints assessing COPD symptoms in either clinical trial. Both trials were randomized, double-blind, parallel-group trials of 24 weeks’ duration and were identical in design, patient entrance criteria, and overall conduct.

Figure 3 displays the integrated 2-hour postdose FEV1 results from the 2 clinical trials. The percent change in FEV1 refers to the change from baseline, defined as the predose value on Treatment Day 1. To account for subject withdrawals during the trial, Endpoint (last evaluable FEV1) data are provided. Subjects receiving SEREVENT DISKUS 50 mcg had significantly greater improvements in 2-hour postdose FEV1 at Endpoint (216 mL, 20%) compared with placebo (43 mL, 5%). Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment.

Figure 3: Mean Percent Change From Baseline in Postdose FEVi Integrated Data From 2 Trials of Subjects With Chronic Bronchitis and Airflow Limitation

Onset of Action and Duration of Effect

The onset of action and duration of effect of SEREVENT DISKUS were evaluated in a subset of subjects (n = 87) from 1 of the 2 clinical trials discussed above. Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV1 increase of 12% or more and at least 200 mL) occurred at 2 hours. The mean time to peak bronchodilator effect was 4.75 hours. As seen in Figure 4, evidence of bronchodilatation was seen throughout the 12-hour period. Figure 4 also demonstrates that the bronchodilating effect after 12 weeks of treatment was similar to that observed after the first dose. The mean time to peak bronchodilator effect after 12 weeks of treatment was 3.27 hours.

Figure 4: Serial 12-Hour FEV1 on the First Day and at Week 12 of Treatment

About salmeterol inhalers

Type of medicine A long-acting beta2-agonist bronchodilator
Used for Asthma; chronic obstructive pulmonary disease (COPD); and other airways-related problems
Also called Serevent®; Neovent®; Soltel®
There are combination brand inhalers containing salmeterol which are called Seretide®, Sirdupla®, Aloflute®, Combisal; Sereflo®, AirFluSal® Forspiro, Aerivio® Spiromax, Stalpex® and Fusacomb® – these brands also contain a medicine called fluticasone
Available as Metered-dose inhalers and breath-actuated inhalers

Salmeterol is called a bronchodilator because it widens (dilates) your airways. It works by opening up the air passages in your lungs so that air can flow into your lungs more freely. This helps to ease symptoms such as coughing, wheezing and feeling breathless. It is prescribed to relieve airways-related problems in people who have asthma or chronic obstructive pulmonary disease (COPD). Salmeterol is called a long-acting bronchodilator. Its effects are usually felt within 20 minutes and last for around 12 hours.

If you have asthma, as well as a salmeterol inhaler, you will also be prescribed a preventer inhaler containing a steroid medicine. Alternatively, there are several brands of salmeterol inhaler which already contain a steroid called fluticasone. You may be prescribed one of these combination brands to help reduce the number of inhalers you need to use each day.

Before using a salmeterol inhaler

Some medicines are not suitable for people with certain conditions, and sometimes a medicine can only be used if extra care is taken. For these reasons, before you start using salmeterol it is important that your doctor knows:

  • If you have an overactive thyroid gland (hyperthyroidism).
  • If you have heart or blood vessel problems, or an irregular heartbeat.
  • If you have high blood pressure (hypertension).
  • If you have high sugar (glucose) levels in your blood (diabetes).
  • If you have been told by a doctor that there are low levels of potassium in your blood.
  • If you are pregnant, trying for a baby or breastfeeding. This is because it is particularly important that your breathing is well controlled if you are pregnant.
  • If you are taking or using any other medicines or inhalers. This includes any medicines you are taking which are available to buy without a prescription, as well as herbal and complementary medicines.
  • If you have ever had an allergic reaction to a medicine.

How to use a salmeterol inhaler

  • Before you start the treatment, read the manufacturer’s printed information leaflet from inside the pack. It will give you more information about salmeterol, diagrams to remind you how to use and clean your inhaler device, and a full list of side-effects which you could experience.
  • Follow your doctor’s instructions carefully and make sure you know how to use the inhaler properly. There are several types of inhaler device. Some of these devices create a spray or ‘puff’ which you breathe in through your mouth; others are activated when you breathe in through the mouthpiece. If you are not sure how to use the device you have been given, ask your nurse, doctor or pharmacist to show you.
  • Use your inhaler regularly, twice each day. Your doctor will tell you how many inhalations to use each time. The directions will also be printed on the label of your inhaler to remind you about what the doctor said to you. Do not use the inhaler more times than the doctor has said.
  • Try to use your inhaler at the same times each day, as this will help you to remember to use it regularly. If you do forget a dose, use the inhaler as soon as you remember (unless it is nearly time for your next dose, in which case leave out the missed dose). Do not take two doses together to make up for a forgotten dose.
  • Your doctor may give you a spacer device to use with some salmeterol inhalers, particularly if you struggle to co-ordinate breathing in and pressing the inhaler device. This helps to make sure that the medicine travels right into your lungs. Your doctor or pharmacist will be able to advise you on using the device.

Getting the most from your treatment

  • If you have asthma, you should receive a written asthma action plan from your nurse or doctor, which will help you to manage your asthma and tell you what to do if you have an asthma attack. Salmeterol will not work quickly enough to relieve an asthma attack that has already started, so your doctor will prescribe another inhaler (a shorter-acting bronchodilator, such as salbutamol) for you to use if you have an attack – make sure that you keep it with you all the time.
  • If you usually use a steroid (preventer) inhaler and have just been prescribed salmeterol, you should continue to use your steroid inhaler as well as salmeterol. You should continue to use both inhalers, even if your symptoms improve. Your doctor will tell you if and when it is appropriate for you to step down your treatment.
  • Try to keep your regular appointments with your doctor. This is so your doctor can review your condition on a regular basis. Your doctor or nurse may also want to check your technique from time to time to make sure you are using your inhaler correctly.
  • Do not smoke. Smoking causes irritation and damage to your lungs and will make your condition worse. Speak with your doctor or practice nurse for further advice if you are having difficulty in stopping smoking.
  • If you find that your symptoms are becoming worse or that you need to use a reliever (rescue) inhaler more regularly, continue to use your inhalers but also contact your doctor or nurse for advice. Also, if your usual dose of salmeterol does not provide relief from your symptoms, speak with your doctor about this as soon as you can.
  • If you have diabetes you may need to check your blood sugar (glucose) more frequently, as salmeterol can affect the levels of sugar in your blood. Your doctor will advise you about this.

Can salmeterol cause problems?

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the more common ones associated with salmeterol. The best place to find a full list of the side-effects which can be associated with your medicine, is from the manufacturer’s printed information leaflet supplied with the medicine. Alternatively, you can find examples of some manufacturers’ information leaflets in the reference section below. Speak with your doctor or pharmacist if any of the following continue or become troublesome.

Common salmeterol inhaler side-effects (these affect less than 1 in 10 people) What can I do if I experience this?
Muscle cramps, feeling shaky, being aware of your heartbeat If troublesome, discuss it with your doctor or clinic
Headache Drink plenty of water and ask a pharmacist to recommend a suitable painkiller. If the headaches continue, let your doctor know

If you experience any other symptoms which you think may be due to the inhaler, please speak with your doctor or pharmacist for further advice.

How to store salmeterol

  • Keep all medicines out of the reach and sight of children.
  • Store in a cool, dry place, away from direct heat and light.

Important information about all medicines

If you buy any medicines, check with a pharmacist that they are safe to take with your other medicines.

Never take more than the prescribed dose. If you suspect that you or someone else might have taken an overdose of this medicine, go to the accident and emergency department of your local hospital. Take the container with you, even if it is empty.

If you are having an operation or dental treatment, tell the person carrying out the treatment which medicines you are taking.

This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.

Do not keep out-of-date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.

If you have any questions about this medicine ask your pharmacist.

Inhaled steroids with and without regular salmeterol for asthma: serious adverse events

Review question

Is it safe to add regular salmeterol to inhaled corticosteroid (ICS) for adults or children with asthma?

Background

Another Cochrane Review found that using regular salmeterol without regular ICS for adults with asthma led to an increase in serious adverse events (death or admission to hospital). We wanted to find out if more adverse (harmful) effects occur when people take regular salmeterol in addition to ICS. We looked only at adverse effects – deaths, being admitted to hospital and life-threatening effects. We did not look at the benefits of taking salmeterol for other outcomes. We updated this review in 2018 because of new evidence from large randomised trials of salmeterol in combination with ICS, in 11,679 adults and 6208 children with asthma.

Study characteristics

In total, we have included 41 studies in 27,951 adults and eight studies in 8453 children. Almost all studies used a combination inhaler to deliver salmeterol with ICS and compared this with the same dose of ICS for an average of six months.

Key results

We did not find a difference in the risk of death or serious adverse events in either adults or children.

Eleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 adults taking regular ICS at the same dose. For every 1000 adults treated for 25 weeks, researchers reported one death on ICS alone and a corresponding risk on salmeterol and ICS of one death (95% confidence Interval (CI) 0 to 2 deaths). No deaths in any studies were attributed to asthma, and researchers reported no deaths at all among children.

A non-fatal serious adverse event of any cause occurred in 332 adults on regular salmeterol with ICS compared to 282 adults on regular ICS alone. For every 1000 adults treated for 25 weeks, 21 serious adverse events occurred on ICS alone, and the corresponding risk on salmeterol and ICS was 23 adults (95% CI 20 to 27).

A total of 65 of 4229 children on regular salmeterol with ICS suffered a serious adverse event of any cause compared to 62 of 4224 children on regular ICS alone. For every 1000 children treated for 23 weeks, 15 serious adverse events occurred on ICS alone, and the corresponding risk on salmeterol and ICS was also 15 children (95% CI 11 to 22).

Quality of the evidence

Reviewers assessed the overall risk of bias for all-cause events as low. The two new large studies performed independent assessment to identify the cause of asthma-related serious adverse events. This makes current data on asthma events more reliable than previously reported.

Conclusions

Trials reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. The risk of dying from asthma while receiving either treatment was therefore very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS.

We can now say that the worst-case estimate (safety margin) from this review is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to ICS alone). These possible risks must be weighed against the benefits experienced by people who take combination treatment.

People monitored in the new trials took over 90% of their prescribed treatment. This is much more than the average amount of medication that people take outside a trial. Therefore the effects shown in trials may be different from the effects experienced by people at home who are not taking their inhalers as prescribed.

Because very few people die of asthma, trials would have to be very large to detect differences in the death rate. Therefore it is probably not feasible to find out if adding salmeterol to ICS causes more deaths among participants in randomised controlled trials – as these trials would be very large, difficult to run, and expensive. It might be better to use case-control studies or to review asthma deaths (e.g. from medical records).

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