BREZTRI AEROSPHERE

Formoterol is an inhaled beta 2 -agonist used in the management of COPD and asthma that was first approved for use in the United States in 2001.

It acts on bronchial smooth muscle to dilate and relax airways, and is administered as a racemic mixture of its active (R;R).

• and inactive (S;S)-enantiomers.

A major clinical advantage of formoterol over other inhaled beta-agonists is its rapid onset of action (2-3 minutes), which is at least as fast as salbutamol, combined with a long duration of action (12 hours).

• for this reason, treatment guidelines for asthma recommend its use as both a reliever and maintenance medication.

It is available as a single-entity product 10, 16 and in several formulations in combination with both inhaled corticosteroids 13, 15 and long-acting muscarinic antagonists. 12, 11.

Formoterol is indicated in various formulations for the treatment of asthma and COPD.

For the treatment of

COPD, formoterol is available as a single-entity inhalation solution, 10 in combination with the long-acting muscarinic antagonists (LAMAs) aclidinium and glycopyrronium, 11 and in combination with the corticosteroid budesonide.

For the treatment of asthma, formoterol is available in combination with mometasone furoate for patients 5 years and older and with budesonide for patients 6 years and older.

Formoterol may also be used on an as-needed basis for prophylaxis against exercise-induced bronchospasm.

Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways.

It possesses both a rapid onset of action (approximately 2-3 minutes) 8 and a long duration of action (up to 12 hours).

The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death.

The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut).

Formoterol is rapidly absorbed into plasma following inhalation.

In healthy adults, formoterol T max ranged from 0.167-0.5 hours.

Following a single dose of 10 mcg, C max and AUC were 22 pmol/L and 81 pmol.h/L, respectively.

In asthmatic adult patients, T max ranged from 0.58-1.97 hours.

Following single-dose administration of 10 mcg, C max and AUC 0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C max and AUC 0-12h were 41 pmol/L and 226 pmol.h/L, respectively.

Absorption appears to be proportional to dose across standard dosing ranges. 13, 10.

Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. 10, 7 Minor pathways include sulfate conjugation of the parent drug and deformylation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized.

The major pathway of formoterol metabolism is a direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation following by glucuronidation at the phenolic hydroxyl group. 10, 7 In vitro studies of formoterol disposition indicate that O-demethylation of formoterol involves a number of cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) and glucuronidation involves a number of UDP-glucuronosyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), though specific roles for individual enzymes have not been elucidated.

Hover over products below to view reaction partners Formoterol O-demethylated formoterol (M1) O-demethylated formoterol (M1) glucuronide 2 O-demethylated formoterol (M1) glucuronide 1 Formoterol glucuronide 1 Formoterol glucuronide 2 Formoterol deformylated metabolite Deformylated formoterol metabolite sulfate conjugate Formoterol sulfate conjugate.

Elimination differs depending on the route and formulation administered.

Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively.

Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces.

Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively.

The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. 10, 16, 4 The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation.

Renal clearance of formoterol following inhalation is approximately 157 mL/min.

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The oral

LD in rats is 3130 mg/kg.

Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc.

Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis.

Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring.

Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate.

Use of a

LABA, including formoterol fumarate, without an inhaled corticosteroid is contraindicated in patients with asthma.

Formoterol fumarate is not indicated for the treatment of asthma.

The recommended dose of formoterol fumarate inhalation solution is one 20 mcg unit-dose vial administered twice daily (morning and evening) by nebulization.

A total daily dose greater than 40 mcg is not recommended.

Formoterol fumarate inhalation solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor.

The safety and efficacy of formoterol fumarate inhalation solution have been established in clinical trials when administered using the PARI-LC Plus ® nebulizer (with a facemask or mouthpiece) and the PRONEB ® Ultra compressor.

The safety and efficacy of formoterol fumarate inhalation solution delivered from non-compressor based nebulizer systems have not been established.

Formoterol fumarate inhalation solution should always be stored in the foil pouch, and only removed IMMEDIATELY BEFORE USE.

Contents of any partially used container should be discarded.

If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD.

Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered.

The drug compatibility (physical and chemical), efficacy, and safety of formoterol fumarate inhalation solution when mixed with other drugs in a nebulizer have not been established.

For oral inhalation only.

One 20 mcg/2 mL vial every 12 hours.

For use with a standard jet nebulizer (with a facemask or mouthpiece) connected to an air compressor.

Formoterol fumarate inhalation solution, 20 mcg/2mL is supplied as clear, colorless sterile solution for nebulization in 3 mL low-density polyethylene unit dose vials.

Each vial is overwrapped in a foil pouch and supplied in cartons as listed below.

Carton of 30 individually wrapped unit dose vials, NDC 42571-463-73 Carton of 60 individually wrapped unit dose vials, NDC 42571-463-62 Storage and Handling: Prior to dispensing to the patient: Store in a refrigerator, 2°C to 8°C (36°F to 46°F).

Protect pouch from light and heat.

After dispensing to the patient

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) and discard when drug expires or store at room temperature, 20°C to 25°C (68°F to 77°F) and discard if not used after 3 months.

Formoterol fumarate inhalation solution should only be administered via a standard jet nebulizer connected to an air compressor with an adequate airflow and equipped with a facemask or mouthpiece.

Vial should always be stored in the foil pouch, and only removed IMMEDIATELY before use.

Do not take by mouth.

Contents of any partially used container should be discarded.

Discard the container and top after use.

Keep out of the reach of children.

There are limited available data with formoterol fumarate inhalation solution use in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

Beta-agonists may interfere with uterine contractility.

In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately to 29,000 times the MRHD on a mg/m 2 or AUC basis.

These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures.

No effects were observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 300 times the MRHD.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Clinical Considerations Labor or delivery

There are no adequate and well-controlled human studies that have studied the effects of formoterol fumarate inhalation solution during labor and delivery.

Because of the potential for beta-agonists interference with uterine contractility, use of formoterol fumarate inhalation solution during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate did not cause malformations in either species.

However, for pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at an exposure approximately 50 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 1,500 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 6,000 mcg/kg and above).

In a pre.

• and post-natal development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth and neonatal mortality at an exposure approximately 1,500 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 6,000 mcg/kg and above).

However, no effects were observed in this study at an exposure approximately 50 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 200 mcg/kg).

In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both species.

Umbilical hernia, a malformation, was observed in rat fetuses at exposures approximately 730 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 3,000 mcg/kg/day and above).

Brachygnathia, a skeletal malformation, was observed in rat fetuses at an exposure approximately 3,600 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 15,000 mcg/kg/day).

In another study with rats, no teratogenic effects were observed with exposures up to approximately 300 times the MRHD (on a mcg/m 2 basis with a maternal inhalation dose of 1,200 mcg/kg/day).

Subcapsular cysts on the liver were observed in rabbit fetuses at an exposure approximately 29,000 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 60,000 mcg/kg/day).

No teratogenic effects were observed with exposures up to approximately 1,700 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 3,500 mcg/kg).

Formoterol fumarate inhalation solution is not indicated for use in children.

The safety and effectiveness of formoterol fumarate inhalation solution in pediatric patients have not been established.

The pharmacokinetics of formoterol fumarate has not been studied in pediatric patients.

Of the 586 subjects who received formoterol fumarate inhalation solution in clinical studies, 284 were 65 years and over, while were 75 years and over.

Of the 123 subjects who received formoterol fumarate inhalation solution in the 12-week safety and efficacy trial, 48 (39%) were 65 years of age or older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of formoterol fumarate inhalation solution has not been studied in elderly subjects.