Arotide

A. Approved Indications

• Asthma (Maintenance Therapy):
  Indicated in patients aged 4 years and older for the long-term, maintenance treatment of asthma where use of both an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA) is appropriate, including:
• Moderate to severe persistent asthma not controlled with ICS alone.
• Patients with frequent symptoms and risk of exacerbations.
• Chronic Obstructive Pulmonary Disease (COPD):
  For maintenance treatment of airflow obstruction and reduction of exacerbations in patients with severe COPD (FEV₁ < 60% predicted), including chronic bronchitis and/or emphysema, and a history of exacerbations.

B. Off-Label or Clinically Accepted Uses

• Asthma-COPD Overlap Syndrome (ACOS):
  Management of chronic airway inflammation and bronchoconstriction in patients exhibiting features of both asthma and COPD.
• Exercise-Induced Bronchospasm:
  Prevention in patients who require both anti-inflammatory and bronchodilator therapy (not as monotherapy).

A. General Principles

• For inhalation only. Not to be used to relieve acute bronchospasm.
• Use consistently at the same times each day. Rinse mouth after use.

B. Adults and Adolescents (≥12 years)

• Asthma:
• DPI: 1 inhalation twice daily (morning and evening).
  Available strengths:
• 50 mcg Salmeterol + 100 mcg Fluticasone
• 50 mcg + 250 mcg
• 50 mcg + 500 mcg
• MDI: 2 puffs twice daily, equivalent strength to DPI formulations.
• COPD:
• Usual dose: 1 inhalation of 50 mcg + 500 mcg (DPI) twice daily.

C. Children (Aged 4–11 years)

• Asthma (MDI only):
• 50 mcg Salmeterol + 100 mcg Fluticasone: 2 puffs twice daily.
• DPI not recommended in children under 12 unless specifically advised.

D. Elderly

• No dosage adjustment necessary. Monitor for systemic corticosteroid effects.

E. Renal/Hepatic Impairment

• No specific dose adjustment required. Use with caution in severe hepatic impairment due to fluticasone metabolism.

F. Duration

• Chronic use: Long-term maintenance therapy. Evaluate response regularly.

Salmeterol is a long-acting beta-2 adrenergic agonist (LABA) that binds selectively to beta-2 receptors in bronchial smooth muscle, activating adenylate cyclase and increasing intracellular cyclic AMP. This cascade leads to bronchial smooth muscle relaxation and sustained bronchodilation for up to 12 hours. Fluticasone propionate is a potent inhaled corticosteroid that binds to glucocorticoid receptors in the airway epithelium. It suppresses the transcription of pro-inflammatory genes and promotes anti-inflammatory protein expression, thereby reducing airway hyperresponsiveness, mucus production, and edema. The combination provides both anti-inflammatory control and bronchodilation, reducing symptoms and preventing exacerbations in asthma and COPD.

• Absorption:
• Salmeterol: Rapid absorption via lungs; peak plasma levels in ~5–10 minutes.
• Fluticasone: Low oral bioavailability (<1%) due to extensive first-pass metabolism; systemic absorption primarily through lungs.
• Distribution:
• Both drugs are distributed predominantly to lung tissues; fluticasone has a high volume of distribution (~300 L).
• Metabolism:
• Salmeterol: Hepatic metabolism via CYP3A4 to inactive metabolites.
• Fluticasone: Also metabolized extensively by CYP3A4.
• Elimination:
• Salmeterol: Eliminated in feces (via biliary excretion); small amounts in urine.
• Fluticasone: Primarily excreted in feces; minimal renal elimination.
• Half-Life:
• Salmeterol: Approx. 5.5 hours
• Fluticasone: Approx. 7.8 hours
• Onset of Action:
• Salmeterol: Within 30–60 minutes
• Fluticasone: Gradual anti-inflammatory effect over several days

• Pregnancy:
• FDA Category C. Use only if clearly needed. Animal studies have shown adverse effects, but human data are limited.
• Monitor for fetal growth if used long-term during pregnancy.
• Lactation:
• Excretion of fluticasone into human milk is likely low due to poor oral bioavailability. Salmeterol data are limited.
• Use caution in breastfeeding mothers. Consider risk-benefit before prescribing.
• Note: Avoid high doses or prolonged use during pregnancy and lactation unless clinically indicated.

• Primary Class:
• Combination Inhaled Corticosteroid (ICS) + Long-Acting Beta-2 Agonist (LABA)
• Subclass:
• Respiratory maintenance therapy agent
• Anti-inflammatory + bronchodilator combination

• Hypersensitivity to salmeterol, fluticasone, or any component of the formulation
• Acute treatment of asthma or COPD exacerbations
• Primary treatment of status asthmaticus
• Known hypersensitivity to milk proteins (in DPI formulations containing lactose)

• Asthma-related Death (Black Box Warning):
  Increased risk with LABA monotherapy; must be used with ICS.
• Paradoxical Bronchospasm:
  Discontinue immediately if symptoms worsen after inhalation.
• Adrenal Suppression & Cushing’s Syndrome:
  Especially with high doses or prolonged use; taper gradually if discontinuing.
• Oral Candidiasis:
  Rinse mouth thoroughly after each use to prevent fungal infection.
• Pediatric Growth Suppression:
  Monitor growth in children receiving long-term corticosteroid therapy.
• Cardiovascular Caution:
  Use cautiously in patients with arrhythmias, hypertension, or ischemic heart disease.
• Monitoring Required:
  Regular evaluation of asthma/COPD control, lung function tests, and side effects.

A. Common (≥1%):

• Respiratory: Hoarseness, cough, sore throat, oral thrush (candidiasis)
• Cardiovascular: Palpitations, tachycardia
• Neurological: Headache, tremor, dizziness

B. Less Common:

• Muscle cramps
• Nausea
• Insomnia
• Increased risk of infections (e.g., pneumonia in COPD)

C. Serious or Rare:

• Paradoxical bronchospasm
• Anaphylaxis
• Adrenal suppression
• Growth retardation in children
• Hypokalemia (with high doses of beta-agonists)

• CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir):
  Increase plasma concentrations of both salmeterol and fluticasone, increasing systemic side effect risk.
• Beta-Blockers:
  May antagonize bronchodilatory effects of salmeterol.
• Diuretics (e.g., loop or thiazide):
  May potentiate hypokalemia when combined with beta-agonists.
• Other Sympathomimetics or Corticosteroids:
  May enhance cardiovascular and systemic corticosteroid effects.

• FDA Update:
  Reinforced black box warning requiring combination LABA + ICS use in asthma patients; LABA monotherapy not recommended.
• GINA Guidelines (2024):
  Emphasize low-dose ICS-formoterol as preferred reliever; however, fluticasone + salmeterol remains a strong maintenance option for moderate-to-severe persistent asthma.
• GOLD 2023 for COPD:
  Continues to recommend ICS + LABA in patients with high exacerbation risk and eosinophil count ≥300 cells/μL.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Humidity/Light: Protect from excessive humidity and direct sunlight.
• Handling:
• Do not freeze or expose inhaler canisters to heat.
• Shake well before use (for MDI).
• Discard after 30 days from opening (check specific product labeling).
• Dry Powder Inhalers (DPI):
• Keep dry and do not wash.
• Close cap tightly after each use.