Indications for: BREZTRI AEROSPHERE
Maintenance treatment of COPD.
Limitations of Use:
Not indicated for relief of acute bronchospasm or for treatment of asthma.
The approval was based on data from two multicenter, double-blind, phase 3 trials (Trial 1 and 2) that evaluated the efficacy and safety of Breztri Aerosphere in adults with moderate to very severe COPD who remained symptomatic while receiving 2 or more inhaled maintenance treatments for COPD for at least 6 weeks prior to screening.
Trial 1 (Clinicaltrials.gov Identifier: NCT02465567) included 8588 patients with a history of 1 or more moderate or severe exacerbations in the year prior to screening, post-bronchodilator FEV1/FVC ratio less than 0.7 and the post-bronchodilator FEV1 less than 65% predicted normal value. Patients were randomly assigned 1:1:1:1 to receive Breztri Aerosphere (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), budesonide, glycopyrrolate and formoterol fumarate [BGF MDI 160 mcg/18 mcg/9.6 mcg] (the BGF MDI 160 mcg/18 mcg/9.6 mcg dosing regimen is not approved), glycopyrrolate and formoterol fumarate [GFF MDI 18 mcg/9.6 mcg], or budesonide and formoterol fumarate [BFF MDI 320 mcg/9.6 mcg], all administered twice daily. The primary endpoint was the rate of moderate to severe COPD exacerbations.
Results showed that treatment with Breztri Aerosphere achieved a statistically significant reduction in the rate of moderate or severe COPD exacerbations over 52 weeks compared with GFF MDI (24% lower: rate ratio, 0.76; 95% CI, 0.69-0.83; P <.001) and BFF MDI (13% lower: rate ratio, 0.87; 95% CI, 0.79-0.95; P =.0027). Moreover, Breztri Aerosphere demonstrated an increase in on-treatment FEV1 AUC0-4 and trough FEV1 at week 24 compared with GFF MDI and BFF MDI.
Trial 2 (ClinicalTrials.gov Identifier: NCT02497001) included 1896 patients who were not required to have a history of moderate or severe exacerbations in the year prior to screening. Patients were randomly assigned 2:2:1:1 to receive Breztri Aerosphere (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), glycopyrrolate and formoterol fumarate [GFF MDI 18 mcg/9.6 mcg], budesonide and formoterol fumarate [BFF MDI 320 mcg/9.6 mcg], or open-label active comparator, all administered twice daily.
The primary endpoints were FEV1 area under the curve from 0-4 hours (FEV1 AUC0-4) at Week 24 for Breztri Aerosphere compared to BFF MDI and change from baseline in morning pre-dose trough FEV1 at Week 24 for Breztri Aerosphere compared to GFF MDI.
Results showed that Breztri Aerosphere demonstrated an increase in on-treatment FEV1 AUC0-4 at Week 24 relative to BFF MDI and an increase in mean change from baseline in morning pre-dose trough FEV1 at Week 24 compared with GFF MDI. The median time to onset on Day 1, defined as a 100 mL increase from baseline in FEV1, was within 5 minutes in subjects receiving Breztri Aerosphere 320 mcg/18 mcg/9.6 mcg. Treatment with Breztri Aerosphere 320 mcg/18 mcg/9.6 mcg reduced the annual rate of on-treatment moderate or severe COPD exacerbations compared with GFF MDI 18 mcg/9.6 mcg (rate ratio [95% CI]: 0.48 [0.37-0.64]), and compared with BFF MDI 320 mcg/9.6 mcg (rate ratio [95% CI]: 0.82 [0.58-1.17]).
Health-Related Quality of Life
In both trials, health-related quality of life was assessed using the St. George’s Respiratory Questionnaire (SGRQ) responder analysis which was defined as an improvement in SGRQ score from baseline of 4 or more.
In Trial 1, the on-treatment percentage of SGRQ responders at Week 24 was greater for subjects treated with Breztri Aerosphere 320 mcg/18 mcg/9.6 mcg (50%) compared with both GFF MDI 18 mcg/9.6 mcg (43%; odds ratio 1.4; 95% CI, 1.2-1.5) and BFF MDI 320 mcg/9.6 mcg (45%; odds ratio 1.2; 95% CI, 1.1-1.4). Similar differences between treatments were observed at Week 52.
In Trial 2, the on-treatment percentage of SGRQ responders at Week 24 was greater for subjects treated with Breztri Aerosphere 320 mcg/18 mcg/9.6 mcg (50%) compared with both GFF MDI 18 mcg/9.6 mcg (44%; odds ratio 1.3; 95% CI, 1.0-1.6) and BFF MDI 320 mcg/9.6 mcg (43%; odds ratio 1.3; 95% CI, 1.0-1.7).
2 inhalations twice daily (in the AM + PM). Max 2 inhalations twice daily. Rinse mouth after each use.
BREZTRI AEROSPHERE Warnings/Precautions:
LABA as monotherapy (without ICS) for asthma can increase risk of asthma-related events. Do not initiate in acutely deteriorating COPD. Not for relief of acute symptoms. Prescribe a short-acting inhaled β2-agonist for acute symptoms; monitor for increased need. Do not exceed recommended dose. Monitor for signs/symptoms of pneumonia. Immunosuppressed. Tuberculosis. Systemic infections. Ocular herpes simplex. If exposed to chickenpox or measles, consider immune globulin prophylaxis or antiviral treatment. Monitor for adrenal insufficiency when transferring from systemic steroids. May need supplemental systemic corticosteroids during periods of stress or a severe COPD exacerbation. May unmask previously suppressed allergic conditions. Reevaluate periodically. Monitor for hypercorticism and HPA axis suppression (if occurs, discontinue gradually), IOP, glaucoma, or cataracts. Discontinue immediately and treat if paradoxical bronchospasms or hypersensitivity reactions occur; use alternative therapy. Cardiovascular disorders (eg, coronary insufficiency, cardiac arrhythmias, hypertension). Assess for bone mineral density if risk factors exist (eg, prolonged immobilization, osteoporosis, postmenopausal, advanced age, others). Urinary retention. Narrow-angle glaucoma. Prostatic hyperplasia. Bladder-neck obstruction. Hyperresponsiveness to sympathomimetics. Convulsive disorders. Thyrotoxicosis. Diabetes. Ketoacidosis. Hypokalemia. Hyperglycemia. Severe hepatic impairment: monitor. Severe renal impairment or ESRD requiring dialysis. Pregnancy. Labor & delivery. Nursing mothers.
BREZTRI AEROSPHERE Classification:
Corticosteroid + anticholinergic + long-acting beta-2 agonist (LABA).
BREZTRI AEROSPHERE Interactions:
Not for use with other drugs containing LABAs. Caution with concomitant strong CYP3A4 inhibitors (eg, long-term ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin). Extreme caution with MAOIs, tricyclics, or drugs known to prolong QTc interval. Increased risk of reduction in bone mineral density with anticonvulsants, oral corticosteroids. Caution with concomitant other adrenergic drugs; may potentiate sympathetic effects. Concomitant xanthine derivatives, steroids, or diuretics may potentiate hypokalemia. Caution with non-K+-sparing diuretics. Antagonized by β-blockers; if needed, use cardioselective agents if no acceptable alternatives. Additive effects with concomitant other anticholinergic-containing drugs; avoid.
Upper RTI, pneumonia, back pain, oral candidiasis, influenza, muscle spasm, UTI, cough, sinusitis, diarrhea; paradoxical bronchospasm, hypersensitivity reactions, cardiovascular effects.
Budesonide: Budesonide was excreted in urine and feces in the form of metabolites. Only negligible amounts of unchanged budesonide have been detected in the urine. The effective half-life of budesonide in subjects with COPD derived via population pharmacokinetic analysis was ~5 hours.
Glycopyrrolate: After IV administration of a 0.2 mg radiolabeled glycopyrronium, 85% of dose recovered was recovered in urine 48 hours post-dose and some of radioactivity was also recovered in bile. The effective half-life of glycopyrronium in subjects with COPD derived via population pharmacokinetics analysis was ~15 hours.
Formoterol Fumarate: The excretion of formoterol was studied in 6 healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the drug related radioactivity of formoterol was excreted in the urine while 24% was eliminated in the feces. The effective half-life of formoterol in subjects with COPD derived via population pharmacokinetics analysis was ~10 hours.
Generic Drug Availability:
Inhalation aerosol—10.7g (120 inh)