Salmeterol Xinafoate

A. Approved Indications

• Asthma (Maintenance Therapy):
  Long-term, maintenance treatment of asthma in patients aged 4 years and older with persistent symptoms who require regular use of a long-acting bronchodilator.
• Chronic Obstructive Pulmonary Disease (COPD):
  Indicated for maintenance treatment of bronchospasm and prevention of exacerbations in adults with chronic bronchitis, emphysema, or mixed COPD.
• Exercise-Induced Bronchospasm (EIB):
  Prophylactic treatment of bronchospasm due to exercise in patients aged ≥4 years, when a long-acting bronchodilator is appropriate.

B. Off-Label or Clinically Accepted Uses

• Asthma-COPD Overlap Syndrome (ACOS):
  Used as part of combination therapy to maintain airway patency and reduce exacerbation risk in mixed respiratory disease.
• Nocturnal Asthma:
  Provides overnight bronchodilation to reduce nighttime symptoms.

Note: Salmeterol should not be used as monotherapy in asthma due to the increased risk of asthma-related death; it must always be combined with an inhaled corticosteroid.

A. Adults (≥18 years)

• Asthma:
• 50 mcg inhaled twice daily (morning and evening), via DPI (Diskus) or MDI (aerosol).
• Must be used in combination with an ICS.
• COPD:
• 50 mcg twice daily via DPI (Diskus); usually used alone or in combination with ICS depending on severity.
• Exercise-Induced Bronchospasm:
• 50 mcg 30 to 60 minutes before exercise; not to be used more than once every 12 hours.

B. Children (4–11 years)

• Asthma (with ICS):
• 50 mcg twice daily, with concurrent inhaled corticosteroid.

C. Elderly

• No dosage adjustment required; monitor for cardiovascular effects.

D. Special Populations

• Renal Impairment: No adjustment needed.
• Hepatic Impairment: Use with caution in severe hepatic dysfunction due to hepatic metabolism.

E. Duration

• For long-term maintenance therapy. Not for rescue use or acute bronchospasm.

F. Administration

• Inhalation only via DPI or MDI.
• Do not use more than every 12 hours.
• Shake well before use (for MDI).

Salmeterol Xinafoate is a long-acting beta-2 adrenergic receptor agonist (LABA) that selectively binds to beta-2 receptors located on bronchial smooth muscle. This activation stimulates adenylate cyclase, increasing intracellular cyclic AMP, which relaxes bronchial smooth muscle and results in prolonged bronchodilation lasting at least 12 hours. Salmeterol’s lipophilic side chain allows it to remain anchored within the receptor microenvironment, enabling sustained activity. It does not possess significant anti-inflammatory activity and must be used in conjunction with inhaled corticosteroids in asthma management to suppress airway inflammation and reduce mortality risk.

• Absorption:
  Rapidly absorbed after inhalation. Peak plasma concentration achieved within 5–10 minutes. Absolute bioavailability is low due to extensive first-pass metabolism.
• Distribution:
  Widely distributed in tissues. Plasma protein binding is approximately 96%.
• Metabolism:
  Extensively metabolized in the liver by CYP3A4 to inactive hydroxylated metabolites.
• Excretion:
  Excreted primarily via feces (as metabolites); small amount via urine.
• Half-Life:
  Approx. 5.5 hours after inhalation.
• Onset of Action:
  Within 30–60 minutes after inhalation.
• Duration of Action:
  Approximately 12 hours.

• Pregnancy:
• FDA Category C.
• Animal studies showed adverse fetal effects at high doses. No well-controlled human studies.
• Use only if potential benefit justifies potential fetal risk.
• Lactation:
• Unknown whether salmeterol is excreted in human milk.
• Due to systemic absorption being low, risk to the infant is considered minimal.
• Use with caution; consider alternative if nursing a premature or medically fragile infant.
• Caution: Avoid prolonged use or high doses in pregnancy unless clearly needed.

• Primary Class:
• Long-Acting Beta-2 Adrenergic Agonist (LABA)
• Subclass:
• Bronchodilator for maintenance therapy in obstructive airway diseases

• Known hypersensitivity to salmeterol or any component of the formulation
• Treatment of acute asthma symptoms or acute bronchospasm
• Use as monotherapy in asthma (without ICS)
• Severe milk protein allergy (for lactose-containing DPI formulations)

• Black Box Warning (Asthma-Related Death):
  Use of LABAs without an ICS increases the risk of asthma-related death. Never use salmeterol alone in asthma.
• Paradoxical Bronchospasm:
  May occur and can be life-threatening. Discontinue immediately if it occurs.
• Cardiovascular Effects:
  May cause palpitations, hypertension, arrhythmias. Use cautiously in patients with cardiovascular disease.
• Seizures or Thyrotoxicosis:
  Use with caution due to risk of exacerbation.
• Diabetes Mellitus:
  May cause transient increases in blood glucose levels.
• Use in Children:
  Long-term safety in pediatric use requires regular monitoring of growth and lung function.
• Regular Monitoring:
  Reassess therapy regularly to ensure optimal control and adherence.

A. Common (≥1%):

• Respiratory: Throat irritation, cough, hoarseness
• Neurological: Headache, dizziness, tremor
• Cardiovascular: Palpitations, tachycardia
• Musculoskeletal: Muscle cramps

B. Less Common:

• Nausea
• Anxiety
• Sleep disturbances
• Dry mouth

C. Serious and Rare:

• Paradoxical bronchospasm
• Hypersensitivity reactions (rash, urticaria, angioedema)
• QT interval prolongation
• Hypokalemia
• Asthma-related death (with monotherapy)

• CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir):
  May increase systemic exposure to salmeterol, enhancing risk of cardiovascular adverse effects.
• Beta-Blockers:
  May block bronchodilatory effect of salmeterol; avoid non-selective beta-blockers in asthmatics.
• Diuretics (loop or thiazide):
  May potentiate hypokalemia when used with beta-agonists.
• Monoamine Oxidase Inhibitors (MAOIs) / Tricyclic Antidepressants:
  May enhance cardiovascular effects of salmeterol.
• Alcohol:
  No known direct interaction, but may exacerbate cardiovascular side effects when used excessively.

• FDA Safety Updates:
  Reinforced warning against LABA monotherapy in asthma. LABAs must be prescribed with ICS.
• GINA Guidelines (2024):
  LABAs should not be used alone in asthma. Salmeterol must be combined with an ICS for safety and efficacy.
• GOLD Guidelines (2023):
  LABAs remain central to COPD therapy, especially in combination with LAMA or ICS in patients with frequent exacerbations.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Humidity: Protect from excessive moisture.
• Light: Store away from direct sunlight.
• Handling Precautions:
• Do not expose inhalers to heat or open flame.
• Do not freeze.
• For DPI: keep device dry; do not wash or take apart.
• For MDI: shake well before use and replace cap after each use.