Serehal

Salmeterol is a selective β₂-agonist indicated for reversible airways obstruction in patients with asthma and chronic obstructive pulmonary disease (COPD).

In asthma (including nocturnal asthma and exercise induced symptoms) it is indicated for those treated with inhaled corticosteroids who require a long-acting beta agonist in accordance with current treatment guidelines.

Serehal Accuhaler is not a replacement for inhaled or oral corticosteroids which should be continued at the same dose, and not stopped or reduced, when treatment with Serehal Accuhaler is initiated.

Treatment Of Asthma

Serehal is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in patients aged 4 years and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma. LABA, such as salmeterol, the active ingredient in Serehal, increase the risk of asthma-related death. Use of Serehal for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use Serehal only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serehal) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serehal for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Pediatric and Adolescent Patients

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.

Important Limitation of Use

Serehal is NOT indicated for the relief of acute bronchospasm.

Prevention Of Exercise-Induced Bronchospasm

Serehal is also indicated for prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. Use of Serehal as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of Serehal for the prevention of EIB may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid.

Maintenance Treatment Of Chronic Obstructive Pulmonary Disease

Serehal is indicated for the long-term twice-daily administration in the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis).

Important Limitation of Use

Serehal is NOT indicated for the relief of acute bronchospasm.

Serehal Accuhaler is for inhalation use only.

Serehal Accuhaler should be used regularly. The full benefits of treatment will be apparent after several doses of the drug.

In reversible airways obstruction such as asthma

Adults (including the elderly): One inhalation (50 micrograms) twice daily, increasing to two inhalations (2 x 50 micrograms) twice daily if required.

Children 4 years and over: One inhalation (50 micrograms) twice daily.

The dosage or frequency of administration should only be increased on medical advice.

There are insufficient clinical data to recommend the use of Serehal Accuhaler in children under the age of four.

In chronic obstructive pulmonary disease

Adults (including the elderly): One inhalation (50 micrograms) twice daily.

Children: Not appropriate.

Special patient groups: There is no need to adjust the dose in patients with impaired renal function.

Using the Accuhaler:

The Accuhaler should be used in a standing or sitting position. The device is opened and primed by sliding the lever. The mouthpiece is then placed in the mouth and the lips closed round it. The dose can then be inhaled and the device closed.

Serehal should be administered by the orally inhaled route only.

More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) is not recommended as some patients are more likely to experience adverse effects. Patients using SEREVENT DISKUS should not use additional LABA for any reason.

Asthma

LABA, such as salmeterol, the active ingredient in Serehal, increase the risk of asthma-related death.

Because of this risk, use of Serehal for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid is contraindicated. Use Serehal only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serehal) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serehal for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Pediatric and Adolescent Patients

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma younger than 18 years who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.

For bronchodilatation and prevention of symptoms of asthma, including the symptoms of nocturnal asthma, the usual dosage for adults and children aged 4 years and older is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be reevaluated. If symptoms arise in the period between doses, an inhaled, short-acting beta₂- agonist should be taken for immediate relief.

Exercise-Induced Bronchospasm

Use of Serehal as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of Serehal for the prevention of EIB may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. One inhalation of Serehal at least 30 minutes before exercise has been shown to protect patients against EIB. When used intermittently as needed for prevention of EIB, this protection may last up to 9 hours in adults and adolescents and up to 12 hours in patients aged 4 to 11 years. Additional doses of SEREVENT should not be used for 12 hours after the administration of this drug. Patients who are receiving Serehal twice daily should not use additional SEREVENT for prevention of EIB.

Chronic Obstructive Pulmonary Disease

For maintenance treatment of bronchospasm associated with COPD (including chronic bronchitis and emphysema), the dosage for adults is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart.

Because of the risk of asthma-related death and hospitalization, use of Serehal for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated .

The use of Serehal is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required
• Severe hypersensitivity to milk proteins

The management of asthma should normally follow a stepwise programme.

Serehal should not be used (and is not sufficient) as the first treatment for asthma.

Serehal is not a replacement for inhaled or oral corticosteroids in asthma. Its use is complementary to them. Asthmatic patients must be warned not to stop steroid therapy, and not to reduce it without medical advice, even if they feel better on salmeterol.

Serehal should not be used to treat acute asthma symptoms for which a fast and short-acting inhaled bronchodilator is required. Patients should be advised to have their medicinal product to be used for the relief of acute asthma symptoms available at all times.

Increasing use of bronchodilators, in particular short-acting inhaled β₂-agonists, to relieve symptoms, indicates deterioration of asthma control. In this case, the patient should be instructed to seek medical advice.

Although Serehal may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on Serehal during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Serehal. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Serehal.

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. Consideration should be given to increasing corticosteroid therapy. Under these circumstances daily peak flow monitoring may be advisable. For maintenance treatment of asthma salmeterol should be given in combination with inhaled or oral corticosteroids. Long-acting bronchodilators should not be the only or the main treatment in maintenance asthma therapy.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Serehal. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Serehal should be used.

Paradoxical bronchospasm

As with other inhalational therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and fall in peak expiratory flow rate (PEFR) after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Serehal Accuhaler should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

The pharmacological side effects of beta-₂ agonist treatment, such as tremor, subjective palpitations and headache have been reported, but tend to be transient and to reduce with regular therapy.

Cardiovascular effects

Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, salmeterol should be used with caution in patients with pre-existing cardiovascular disease.

Thyrotoxicosis

Serehal should be administered with caution in patients with thyrotoxicosis.

Blood glucose levels

There have been very rare reports of increases in blood glucose levels and this should be considered when prescribing to patients with a history of diabetes mellitus.

Hypokalaemia

Potentially serious hypokalaemia may result from β₂-agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics. Serum potassium levels should be monitored in such situations.

Respiratory-related events

Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol compared with placebo. It is not known if this was due to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if asthma symptoms remained uncontrolled or worsen whilst using Serehal.

Ketoconazole

Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment.

Inhaler technique

Patients should be instructed in proper use of their inhaler and their technique checked to ensure optimum delivery of the inhaled medicinal product to the lungs.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Asthma-Related Death

LABA, such as salmeterol, the active ingredient in Serehal, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Because of this risk, use of Serehal for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a longterm asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serehal) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serehal for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Pediatric and Adolescent Patients

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.

The Salmeterol Multi-center Asthma Research Trial (SMART) was a large 28-week placebo-controlled US trial comparing the safety of salmeterol (SEREVENT Inhalation Aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in subjects receiving salmeterol. Given the similar basic mechanisms of action of beta₂-agonists, the findings seen in the SMART trial are considered a class effect.

A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.

The SNS and SMART trials enrolled subjects with asthma. No trials have been conducted that were primarily designed to determine whether the rate of death in patients with COPD is increased by LABA.

Deterioration Of Disease And Acute Episodes

Serehal should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Serehal has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of Serehal in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta₂-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well.

It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting beta₂-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional inhaled corticosteroid or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of Serehal.

Serehal should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta₂- agonist, not Serehal, should be used to relieve acute symptoms such as shortness of breath. When prescribing Serehal, the healthcare provider should also prescribe an inhaled, short-acting beta₂-agonist (e.g., albuterol) for treatment of acute symptoms.

When beginning treatment with Serehal, patients who have been taking oral or inhaled, short-acting beta₂-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

Serehal Is Not A Substitute For Corticosteroids

There are no data demonstrating that Serehal has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout treatment with Serehal in patients receiving oral or inhaled corticosteroids for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they feel better as a result of initiating SEREVENT DISKUS. Any change in corticosteroid dosage should be made ONLY after clinical evaluation.

Excessive Use Of Serehal And Use With Other Long-Acting Beta₂-Agonists

Serehal should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Serehal should not use another medicine containing a LABA (e.g., formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Paradoxical Bronchospasm And Upper Airway Symptoms

As with other inhaled medicines, Serehal can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Serehal, it should be treated immediately with an inhaled, short-acting bronchodilator. Serehal should be discontinued immediately, and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving Serehal.

Cardiovascular And Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Therefore, Serehal, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Salmeterol can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (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. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Serehal. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take Serehal

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur.

Coexisting Conditions

Serehal, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia And Hyperglycemia

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with Serehal at recommended doses.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Asthma-Related Death

Inform patients that salmeterol increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Inform patients that Serehal should not be the only therapy for the treatment of asthma and must only be used as additional therapy when long-term asthma control medications (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Also inform them that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other longterm asthma control drugs mitigates the increased risk of asthma-related death from LABA. Inform patients that when Serehal is added to their treatment regimen they must continue to use their long-term asthma control medication.

Not for Acute Symptoms

Inform patients that Serehal is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta₂-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following:

• Decreasing effectiveness of inhaled, short-acting beta₂-agonists
• Need for more inhalations than usual of inhaled, short-acting beta₂-agonists
• Significant decrease in lung function as outlined by the physician

Tell patients they should not stop therapy with SEREVENT DISKUS without physician/provider guidance since symptoms may recur after discontinuation.

Not a Substitute for Corticosteroids

Advise all patients with asthma that they must also continue regular maintenance treatment with an inhaled corticosteroid if they are taking Serehal.

Serehal should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with Serehal.

Do Not Use Additional Long-Acting Beta₂-Agonists

Instruct patients not to use other LABA.

Immediate Hypersensitivity Reactions

Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Serehal. Patients should discontinue Serehal if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take Serehal.

Risks Associated With Beta-Agonist Therapy

Inform patients of adverse effects associated with beta₂-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Treatment of Exercise-Induced Bronchospasm

Patients using Serehal for the treatment of EIB should not use additional doses for 12 hours. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHDID for adults and children based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHDID for adults and children, respectively, on a mg/m basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHDID for adults and children, respectively, on a mg/m basis). These findings in rodents are similar to those reported previously for other betaadrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHDID for adults on a mg/m basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials with Serehal in pregnant women. Beta₂-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproductive studies are not always predictive of human response, Serehal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking Serehal.

No teratogenic effects occurred in rats at salmeterol doses approximately 160 times the maximum recommended daily inhalation dose (MRHDID) (on a mg/m² basis at maternal oral doses up to 2 mg/kg/day). In pregnant Dutch rabbits administered oral doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/kg/day).

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 1,600 times the MRHDID (on a mg/m basis at a maternal oral dose of 10 mg/kg/day).

Salmeterol crossed the placenta following oral administration to mice and rats.

Labor And Delivery

There are no well-controlled human trials that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of Serehal during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Plasma levels of salmeterol after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. Since there are no data from controlled trials on the use of Serehal by nursing mothers, caution should be exercised when Serehal is administered to a nursing woman.

Pediatric Use

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs.

The safety and efficacy of Serehal in adolescents (aged 12 years and older) have been established based on adequate and well-controlled trials conducted in adults and adolescents. A large 28-week placebo-controlled US trial comparing salmeterol (SEREVENT Inhalation Aerosol) and placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol. Post-hoc analyses in pediatric patients aged 12 to 18 years were also performed. Pediatric patients accounted for approximately 12% of patients in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The safety and efficacy of Serehal have been evaluated in over 2,500 patients aged 4 to 11 years with asthma, 346 of whom were administered Serehal for 1 year. Based on available data, no adjustment of dosage of Serehal in pediatric patients is warranted for either asthma or EIB.

In 2 randomized, double-blind, controlled clinical trials of 12 weeks' duration, Serehal 50 mcg was administered to 211 pediatric patients with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of Serehal was demonstrated over the 12-week treatment period with respect to peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV₁). Serehal was effective in demographic subgroups (gender and age) of the population.

In 2 randomized studies in children aged 4 to 11 years with asthma and EIB, a single 50- mcg dose of Serehal 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 patients.

Geriatric Use

Of the total number of adult and adolescent subjects with asthma who received Serehal in chronic dosing clinical trials, 209 were aged 65 years and older. Of the total number of subjects with COPD who received Serehal in chronic dosing clinical trials, 167 were aged 65 years and older and 45 were aged 75 years and older. No apparent differences in the safety of Serehal were observed when geriatric subjects were compared with younger subjects in clinical trials. As with other beta₂-agonists, however, special caution should be observed when using Serehal in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by betaagonists. Data from the trials in subjects with COPD suggested a greater effect on FEV₁ of Serehal in subjects younger than 65 years, as compared with subjects aged 65 years and older. However, based on available data, no adjustment of dosage of Serehal in geriatric patients is warranted.

Hepatic Impairment

Formal pharmacokinetic studies using Serehal have not been conducted in patients with hepatic impairment. Since salmeterol is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (> 1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000) including isolated reports. Common and uncommon events were generally determined from clinical trial data. The incidence on placebo was not taken into account. Very rare events are generally determined from post-marketing spontaneous data.

The following frequencies are estimated at the standard dose of 50mcg twice daily. Frequencies at the higher dose of 100mcg twice daily have also been taken to account where appropriate.

The pharmacological side effects of β₂-agonist treatment, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and to reduce with regular therapy. Tremor and tachycardia occur more commonly when administered at doses higher than 50mcg twice daily.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

LABA, including salmeterol, the active ingredient in Serehal, 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 Serehal 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 Serehal With ≥ 3 Incidence and More Common Than Placebo in Adult and Adolescent Subjects With Asthma

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 Serehal 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 Serehal 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 Serehal 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 Serehal 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

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 Serehal 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 Serehal With ≥ 3% Incidence in US Controlled Clinical Trials in Subjeci ts With Chronic Obstructive Pulmonary Disease^a

Additional Adverse Reactions

Other adverse reactions occurring in the group receiving Serehal 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.

Symptoms and signs

The signs and symptoms of salmeterol overdosage are those typical of excessive β_2-adrenergic stimulation including dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. Additionally, hypokalaemia can occur and therefore serum potassium levels should be monitored. Potassium replacement should be considered.

Treatment

If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

The expected signs and symptoms with overdosage of Serehal are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with Serehal can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias.

As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of Serehal.

Treatment consists of discontinuation of Serehal 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 SEREVENT

DISKUS. Cardiac monitoring is recommended in cases of overdosage.

Pharmacotherapeutic Group: Selective β₂-adrenoreceptor agonists.

ATC Code: R03AC12

Salmeterol is a selective long-acting (usually 12 hours) β₂-adrenoceptor agonist with a long side-chain which binds to the exo-site of the receptor.

These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilatation, lasting for at least 12 hours, than recommended doses of conventional short-acting β₂-agonists. In vitro tests have shown that salmeterol is a potent and long-lasting inhibitor of the release from the human lung of mast cell mediators, such as histamine, leukotrienes and prostaglandin D2. In man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids, which should not be stopped or reduced when Serehal Accuhaler is prescribed.

Salmeterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function, and quality of life. Salmeterol acts as a β₂-agonist on the reversible component of the disease. In vitro salmeterol has also been shown to increase cilial beat frequency of human bronchial epithelial cells, and also reduce a ciliotoxic effect of Pseudomonas toxin on the bronchial epithelium of patients with cystic fibrosis.

Asthma Clinical Trials

The Salmeterol Multi-centre Asthma Research Trial (SMART)

SMART was a multi-centre, randomised, double-blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50μg twice daily) and 13,179 patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if >12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences.

Key findings from SMART: primary endpoint

(Risk in bold is statistically significant at the 95% level.)

Key findings from SMART by inhaled steroid use at baseline: secondary endpoints

(*=could not be calculated because of no events in placebo group. Risk in bold is statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all-cause death or life-threatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population.

COPD clinical trials

TORCH study

TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500mcg bd, salmeterol Diskus 50mcg bd, fluticasone propionate (FP) Diskus 500mcg bd or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (pre-bronchodilator) FEV1 <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all cause mortality at 3 years for Seretide vs Placebo.

1. Non significant P value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status

There was a trend towards improved survival in subjects treated with Seretide compared with placebo over 3 years however this did not achieve the statistical significance level p≤0.05. The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for Seretide.

The mean number of moderate to severe exacerbations per year was significantly reduced with Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.

Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for Seretide compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was 1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.

The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for Seretide (Hazard ratio for Seretide vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for Seretide. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

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 Serehal 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 Serehal 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 Serehal has not been established. In 29 subjects who experienced worsening of asthma while receiving Serehal 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 Serehal was approximately 4 inhalations/day. Twentyfour percent (24%) of subjects using Serehal 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 Serehal concurrently with a theophylline product had adverse event rates similar to those in 302 subjects receiving Serehal without theophylline. Based on the available data, the concomitant administration of methylxanthines with Serehal 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.

Salmeterol acts locally in the lung, therefore plasma levels are not predictive of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma because of the very low plasma concentrations at therapeutic doses (approximately 200 pg/ml or less) achieved after inhaled dosing.

After regular dosing with salmeterol xinafoate, xinafoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 ng/ml. These concentrations are up to 1000-fold lower than steady state levels observed in toxicity studies. These concentrations in long term regular dosing (more than 12 months) in patients with airways obstruction, have been shown to produce no ill effects.

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.