Budesonide - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Serious asthma-related events: Long-acting beta2-adrenergic agonists as monotherapy increase the risk. • Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or COPD or to treat acute symptoms. • Use with additional long-acting beta 2 -agonist: Do not use in combination because of risk of overdose. • Localized infections: Candida albicans infection of the mouth and throat may occur.

Monitor patients periodically for signs of adverse effects on the oral cavity.

Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. • Pneumonia: Increased risk in patients with COPD.

Monitor patients for signs and symptoms of pneumonia and other potential lung infections. • Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients. • Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids.

Taper patients slowly from systemic corticosteroids if transferring to budesonide and formoterol fumarate dihydrate. • Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue budesonide and formoterol fumarate dihydrate slowly. • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects.

Exercise caution when used with budesonide and formoterol fumarate dihydrate. • Paradoxical bronchospasm: Discontinue budesonide and formoterol fumarate dihydrate and institute alternative therapy if paradoxical bronchospasm occurs. • Patients with cardiovascular or central nervous system disorders: Use with caution because of beta-adrenergic stimulation. • Decreases in bone mineral density: Assess bone mineral density initially and periodically thereafter. • Effects on growth: Monitor growth of pediatric patients. • Glaucoma and cataracts: Close monitoring is warranted. • Metabolic effects: Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. ( 5.16 , 5.18 ) • Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations and Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART) ].

Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients.

These findings are considered a class effect of LABA.

When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone (see Serious Asthma-Related Events with ICS/LABA ).

Serious Asthma-Related Events with ICS/LABA Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared to ICS alone in patients with asthma.

Three trials included adult and adolescent patients aged ≥12 years: one trial compared budesonide/formoterol (budesonide and formoterol fumarate dihydrate) to budesonide [see Clinical Studies ] ; one trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder; and one trial compared mometasone furoate/formoterol to mometasone furoate.

The fourth trial included pediatric patients 4 to 11 years of age and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder.

The primary safety endpoint for all four trials was serious asthma-related events (hospitalizations, intubations and death).

A blinded adjudication committee determined whether events were asthma-related.

The three adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk of 2.7.

Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone.

A meta-analysis of the three adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1).

These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

Meta-analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older ICS/LABA (N = 17,537) Randomized patients who had taken at least 1 dose of study drug.

Planned treatment used for analysis.

ICS (N = 17,552) ICS/LABA vs ICS Hazard ratio (95% CI) Estimated using a Cox proportional hazards model of time to first event with baseline hazards stratified by each of the 3 trials.