Formoterol

Formoterol is an asthmatic agent/ Bronchodilating agent belonging to the pharmacological class of Long-acting Beta 2 adrenergic receptor agonists

Formoterol is approved for the treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Formoterol is said to achieve 43% of the pulmonary bioavailability of the delivered dose while systemic bioavailability is 60% of the delivered dose. The volume of distribution for Formoterol was found to be 4L/kg. Formoterol is metabolized by glucuronidation of the parent drug. In eliminating about 60% of the unchanged parent drug in the oral administration and 10% in inhalation, the administration was excreted in the urine.

The common side effects of Formoterol usage are headache, dizziness, dry mouth, tremors, tiredness, and muscle cramps.

Formoterol is available as rotacaps, nebulizers, and inhalation powders.

Formoterol was initially marketed in the U.S, European Union, India, Canada, Turkey, and Germany.

Formoterol belonging to the pharmacological class of Long-Acting Beta 2 Adrenergic Receptor Agonist, acts as an Anti-asthmatic/Bronchodilator therapeutic agent. Formoterol acts via a series of pathways causing increasing cAMP, thereby deactivating myosin light chain kinase and activating myosin light chain phosphate leading to smooth muscle relaxation in the bronchioles. Increased intracellular cyclic AMP levels lead relaxation of smooth muscles in the bronchioles and cause the inhibition of the release of pro-inflammatory mediators from cells, especially from mast cell mediators such as histamines and leukotriene.

Formoterol hence is used for the treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Formoterol has an onset of action of 2-3 minutes (mean peak achieved), and the duration of action exceeds longer than 12 hours.

Formoterol achieved Tmax -0.167 to 0.5 hours and Cmax- 22 pmol/L 10 mg during inhalation therapy.

Rotacaps:

1. Hold the rotahaler vertically
2. Remove the rotacap from the bottle and place it in the rotacap hole such that its transparent end is facing downward.
3. Rotate the base while holding the mouthpiece firmly.
4. Breathe out fully
5. Now place the Rotahaler between the teeth.
6. Tightly close the lips around the haler and breathe in rapidly and deeply.
7. Now hold your breath for 10 seconds and breathe out.
8. Now dispose of the empty capsule by opening the rotahaler.

Turbuhaler:

• Load dose by holding the inhaler in an upright position and turning the greenish-blue grip as far as it will go in one direction and then turn it as far as it will go in the other direction.
• Prior to first use, this procedure should be done twice; with subsequent dosing, perform this procedure once.
• Clicking sound means the inhaler is loaded with dose and ready for use.
• Exhale fully. Do not exhale into the mouthpiece of the inhaler.
• Place mouthpiece between teeth and close lips over the mouthpiece. Inhale deeply and forcefully.
• Do not exhale through the inhaler. If the Turbuhaler is dropped, shaken, or breathed into after it is loaded, the dose will be lost and a new dose will need to be loaded.
• Clean the outside of the mouthpiece once weekly with a dry tissue.
• Avoid getting the inhaler wet.
• Discard the device after 0 displays in the dose window.

Ready to use vial:

A ready-to-use vial should be used right away.

1. The foil pouch is opened by tearing on the rough edge along the seam of the pouch. The ready-to-use vial of Formoterol is removed.

2. The top of the ready-to-use vial is carefully twisted and opened and used right away

3. All of the medicine from the ready-to-use vial is squeezed into the nebulizer medicine cup.

4. The nebulizer reservoir is connected to the mouthpiece or face mask

5. The nebulizer is connected to the compressor

6. Place the mouthpiece in your mouth by sitting in an upright position and turn on the compressor

7. Now Breathe as deeply, and evenly as possible until no more mist is formed in the nebulizer reservoir. It will take about 5 -10 minutes for each treatment.

Formoterol can be used in the treatment of:

• Bronchospasm
• Emphysema
• Bronchial Asthma
• Chronic Obstructive Pulmonary Disease
• Exercised Induced Bronchospasm

Formoterol can help to relax bronchial smooth muscle leading to Bronchodilation and improving the patient's respiration.

Formoterol is approved for use in the following indications:

• Bronchospasm
• Emphysema
• Bronchial Asthma
• Chronic Obstructive Pulmonary Disease
• Exercised Induced Bronchospasm

Formoterol administration dose is 6mcg and 12mcg along with other drug combinations which are inhaled twice daily.

Pediatric Patients ≥6 years and Adolescents Patients ≤16 years:

• Oral inhalation: 12 mcg every 12 hours;

• Maximum daily dose: 24 mcg/day.

Adult patients≥17 years:

• Oral inhalation: 12 mcg every 12 hours; in severe cases,

• 24 mcg every 12 hours may be necessary;

Maximum daily dose: 48 mcg/day.

The duration and dosage of treatment should be as per the clinical judgment of the treating physician.

Formoterol is available in 6mcg, 12mcg, 20mcg/2ml.

Mainly Inhalation dosage form is available, such as Capsule Powdered Inhalations, and Turbuhalers.

Formoterol should be used in the treatment of bronchospasm,bronchial  asthma ,emphysema,COPD,exercised induced bronchospasm along with appropriate dietary restrictions:

• To maintain good respiratory health, smoking cessation is a must.

• Diet containing refined and high energy-dense foods, red and processed meat, added sugar, salt, preservatives, low antioxidants and vitamins, low fiber, food with a high glycemic index, and saturated and trans fat food needs to be restricted.

The dietary restriction should be individualized as per patient requirements.

Formoterol may be contraindicated in the following:

Hypersensitive to Sympathomimetic amines:

• Hypersensitive to any components of the medication
• Paradoxical bronchospasm
• Patients with Pheochromocytoma, as sympathomimetic amines, cause increased heart rate and blood pressure.
• Used with caution in Hyperthyroidism patients
• Diabetes Mellitus, as may lead to Ketoacidosis
• In pregnancy, it may cause fetal tachycardia and cardiac issues in the pregnant woman, and therefore the drug should be withdrawn in case of prolonged tocolysis.
• Monoamine Oxidase Inhibitors/Antidepressants

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Deterioration of Asthmatic Condition, including death:

There might be a deterioration of the asthma condition over a period of time. The increased usage of Formoterol is a noted marker for the destabilization of the condition. Therefore a re-evaluation of the patient's condition should be considered, and the usage of anti-inflammatory agents such as corticosteroids should be considered. Serious asthma-related events, including deaths, have been reported in clinical trials.

• Deterioration of the acute and severe conditions of COPD:

Formoterol should not be administered in the conditions of acute and severe COPD, as it might lead to a life-threatening condition.

In the acute symptoms of bronchospasm, Formoterol should not be used. The use of short-acting beta 2 agonists should be considered in this situation.

While starting the administration of Formoterol, the patients must be advised to withdraw the regular usage of short-acting beta 2 agonists and to only use it for symptomatic relief from acute respiratory symptoms.

During the episodes of the deterioration of the COPD condition, the use of Formoterol must be withdrawn, and a re-evaluation of the patient's condition must be considered. The markers for the deterioration of the condition include an increased dose of Formoterol or increased usage of Formoterol or less effectiveness of the short-acting beta 2 agonists.

• Hypersensitivity events:

In the rare events of Hypersensitivity such as swelling of tongue, lips, and face, urticaria of the skin, difficulty in breathing or swallowing, rashes. Formoterol should be withdrawn, and other alternate therapy must be considered.

• Paradoxical bronchospasm:

Paradoxical bronchospasm might be a life-threatening condition; therefore, Formoterol should be immediately withdrawn during such a condition.

• Cardiovascular events:

Formoterol has the potential of causing Myocardial Ischemia, Cardiac Arrest, changes in the ECG curve such as flattening of the T segment, prolongation of Q-Tc segment, and ST-segment depression has been found to be associated with the beta 2 adrenergic agonist.

• Hypokalemia:

Formoterol causes a decrease in potassium levels which potentially produces adverse cardiac events.

• Xanthine, Steroids, and Diuretics:

In acute asthma conditions, the use of Xanthine, Steroids, and Diuretics should be avoided or closely monitored as it may lead to hypoxia,

• Diabetes Mellitus:

During Formoterol usage, a patient with Diabetes Mellitus condition might suffer from hyperglycemia and will be unable to compensate in the condition of ketoacidosis

Avoid drinking alcohol, while taking Formoterol as it may worsen dizziness if present.

Formoterol or the components of the drug medication has not been known to be excreted in milk but a decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

Pregnancy Category C

There are found to be no known adequate and well-controlled studies of Formoterol in pregnant women. Formoterol has shown to be teratogenic in animals. Formoterol has caused neonatal mortality and developmental delays in rats. The animal reproduction studies are not always predictive of human response. Therefore Formoterol should be used during pregnancy, only if the potential benefits outweigh the risks to the fetus.

Formoterol has shown delayed ossification in the fetus, stillbirth, decreased weight, umbilical hernia in doses greater than the Maximum Recommended Daily Inhalation Dose in rats and rabbits.

When given to rats throughout organogenesis, oral doses of 0.2 mg/kg which is approximately 40 times the maximum recommended daily inhalation dose in humans and above caused a delay in the ossification of the fetus, and doses of 6 mg/kg which is approximately 1200 times the maximum recommended daily inhalation dose in humans and caused a decrease in fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg.

No known interactions with food are noted.

The adverse reactions related to Formoterol can be categorized as :

Common

• Backache
• Leg Cramps
• Flu-Like Symptoms
• Pain
• Trouble Breathing
• Fluid Retention
• Diarrhea
• Skin Rash
• Chest Pain
• Sinusitis

Less Common

• Hyperkalemia
• Leukocytosis
• Lung Congestion
• Headache
• Vomiting
• Nervousness
• Generalized Weakness
• Bronchitis
• Fever
• Muscle Tremors

Rare

• Paroxysmal Supraventricular Tachycardia
• Atrial Flutter
• Abnormal Heart Rhythm
• Chronic Heart Failure
• Acute Cerebral Infarction
• Low Blood Pressure
• Gastritis
• Kidney Stones
• Inflammation Of The Bladder
• Hematuria
• Neck Stiffness
• An Abscess
• Diminished Movement
• Visible Water Retention
• High Blood Sugar
• Crystalluria
• Shingles
• Herpes Simplex Infection
• Breast Tumor
• Low Blood Sugar
• Excessive Fat In The Blood
• Gout
• Excess Body Acid
• Dehydration
• Hypokalemia
• Paralysis
• Glaucoma
• High Blood Pressure
• Heart Attack
• Atrioventricular Block

The clinically relevant drug interactions of Formoterol are briefly summarized here:

• Monoamine Oxidase Inhibitors or Anti-Depressants: Patients should be monitored closely, or an alternate therapy must be considered while using Formoterol as it might lead to some cardiovascular events in patients such as prolongation of QT-wave, cardiac arrhythmias, etc.

• Beta-blockers or Sympathomimetics: Formoterol should not be concomitantly administered with the beta-blockers as it might worsen the patient's respiratory condition. In the condition of myocardial infarction use of cardioselective beta-blockers should be considered with caution.

• Diuretics: The use of loop diuretics and thiazide diuretics might worsen the condition of the patient under the treatment of Formoterol, such as Hypokalemia and ECG changes.

• Xanthine and Steroids: The use of Xanthines and Steroids along with Formoterol might lead to Hypokalemia. Therefore caution is advised during concomitant use.

• Halogenated Hydrocarbons: There is found to be an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.

The common side effects of Formoterol includes the following:

• Swelling of arms or legs
• Difficulty falling asleep or staying asleep
• Pain, especially back pain
• Diarrhea
• Nausea
• Vomiting
• Cramps
• Dry mouth
• Nervousness
• Headache
• Dizziness
• Tiredness
• Lack of energy
• Flu symptoms

The use of the molecule Formoterol should be prudent in the following group of special populations

• Breastfeeding Warning of Formoterol

Formoterol or the components of the drug medication has not been known to be excreted in milk but a decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

• Pregnancy warning

Pregnancy Category C

There are found to be no known adequate and well-controlled studies of Formoterol in pregnant women. Formoterol has been shown to be teratogenic in animals. Formoterol has caused neonatal mortality and developmental delays in rats. Animal reproduction studies are not always predictive of human response. Therefore Formoterol should be used during pregnancy, only if the potential benefits outweigh the risks to the fetus.

Formoterol has shown delayed ossification in the fetus, stillbirth, decreased weight, and umbilical hernia in doses greater than the Maximum Recommended Daily Inhalation Dose in rats and rabbits.

When given to rats throughout organogenesis, oral doses of 0.2 mg/kg which is approximately 40 times the maximum recommended daily inhalation dose in humans and above caused a delay in the ossification of the fetus, and doses of 6 mg/kg which is approximately 1200 times the maximum recommended daily inhalation dose in humans and caused a decrease in fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg.

• Labor and Delivery

There are no known human studies that have investigated the effects of Formoterol on preterm labor. Beta-agonists may potentially interfere with uterine contractility, therefore Formoterol should be used during labor and delivery only if the potential benefits outweigh the risks.

• Nursing Mothers

In reproductive studies in rats, Formoterol was found to be excreted in the milk. But it is not known whether Formoterol is excreted in human milk. As a lot of drugs are excreted in human milk, caution should be exercised when Formoterol is administered to a nursing woman.

• Pediatric Use

Asthma

Available data from controlled clinical trials suggested that LABA can increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require the addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be administered to ensure adherence with both drugs.

Exercise-Induced Bronchospasm

Out of a total of 25 pediatric patients, only 4-11 years of age, were studied in two well-controlled single-dose clinical trials. The safety and effectiveness of Formoterol in pediatric patients less than 5 years of age have not been established

• Geriatric Use

Out of the total number of patients who received Formoterol in adolescent and adult chronic dosing asthma clinical trials, 318 were aged 65 years or older and 39 were aged 75 years and older. Out of the 811 patients who received Formoterol in two pivotal multiple-dose controlled clinical studies in patients with COPD, 395 (48.7%) were of 65 years age or older while 62 (7.6%) were of 75 years age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. A slightly higher frequency of chest infection was reported in the 39 asthma patients 75 years of age and older.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Formoterol.

• An increase in pulse rate, systolic blood pressure, and QTc interval was found in COPD patients. Signs and symptoms for e.g., nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, angina, hypertension or hypotension, tachycardia, hypokalemia, hyperglycemia, metabolic acidosis with heart rate up to 200 bpm, arrhythmias, nausea, dizziness, fatigue, malaise, and insomnia. With all inhaled sympathomimetic medications along with Formoterol overdose, cardiac arrest and even death may be associated.

Treatment of overdosage consists of:

• Withdrawing of Formoterol together with institution of appropriate symptomatic and supportive therapy.
• The use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.
• Monitoring heart rate is recommended in cases of overdosage

Pharmacodynamics

Formoterol works locally in the lungs as a bronchodilator, relaxing the smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) 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.

Pharmacokinetics

The pharmacokinetics of Formoterol has been investigated in elderly subjects, really and hepatically impaired subjects, healthy subjects, and COPD patients followed by the nebulization of the recommended therapeutic dose up to 96 mcg.

• Absorption

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 has rapidly been absorbed into plasma following inhalation. In healthy adults, formoterol T_max ranged from 0.167 to 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 to 1.97 hours. Following single-dose administration of 10mcg, 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.

• Distribution

The binding of formoterol to human plasma proteins in vitro was 61%-64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31%-38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose.

• Metabolism

Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. Minor pathways include sulfate conjugation of the parent drug and deformation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized. The major pathway of formoterol metabolism is direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation followed by glucuronidation at the phenolic hydroxyl group.

In vitro studies of formoterol, disposition indicates 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.

• Elimination

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 were eliminated in the urine and feces, respectively. Another study that 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.

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10. FDA Approved Drug Products: Perforomist® inhalation solution
11. FDA Approved Drug Products: Bevespi Aerosphere inhalation aerosol
12. FDA Approved Drug Products: Duaklir® Pressair® inhalation powder
13. FDA Approved Drug Products: Dulera® inhalation aerosol
14. FDA Approved Drug Products: Foradil® Aerolizer inhalation powder
15. FDA Approved Drug Products: Symbicort (budesonide/formoterol fumarate) inhalation aerosol
16. Health Canada Product Monograph: Oxeze (formoterol) dry powder inhaler
17. CaymanChem: Formoterol MSDS
18. Global Initiative for Asthma: 2019 Guidelines Pocket Guide

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