Formoterol - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview

Formoterol is a bronchodilator used to prevent symptoms of respiratory conditions like asthma and chronic obstructive pulmonary disease (COPD). It relaxes the muscles of the air passages, thereby widening them and making breathing easier. It helps in relieving symptoms like shortness of breath, wheezing, breathing difficulties, chest tightness, and coughing. This drug is not recommended for patients below the age of five. The United States FDA (Food and Drugs Administration) approved Formoterol fumarate use on September 25, 2001. It is also marketed in combination formulations like Budesonide and Formoterol or Mometasone and Formoterol.

How Does Formoterol Work?

Formoterol is a long-acting beta-agonist (LABA). It has an extended duration of action of up to 12 hours compared to short-acting beta-agonists like Salbutamol which work for four to six hours. It works by relaxing the smooth muscles of the airway, causing bronchodilation. This helps to treat an exacerbation of asthma. However, LABAs are not recommended for the treatment of acute asthma.

Formoterol selectively binds to the beta2 adrenergic receptors in the bronchial smooth muscles. This leads to an activation of intracellular adenylyl cyclase, which in turn catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3&rdquo, 5”-adenosine monophosphate (cAMP). This activity results in bronchodilation.

What Are the Indications and Uses of Formoterol?

Formoterol is indicated for use for the below conditions:

1. In the treatment of asthma.

2. In the treatment of COPD.

3. Used in preventing exercise-induced breathing problems.

Asthma:

Formoterol is indicated for the treatment of asthma and the prevention of bronchospasm. It can only be used as a concomitant therapy along with a long-term asthma control medication like inhaled corticosteroids. Formoterol is indicated in adults and children older than five with reversible obstructive airway disease or nocturnal asthma symptoms.

LABAs, like Formoterol, can increase the risk of asthma-related deaths. Therefore, monotherapy without concomitant use of long-term asthma control medications like inhaled corticosteroids is not advisable. Also, in patients who have good control of asthma with low or medium-dose inhaled corticosteroids, Formoterol must not be used. After achieving good control, the patient must be monitored at regular intervals, and a step-down therapy must be opted for in which Formoterol use is discontinued.

Pediatric and Adolescent Patients:

Studies suggest an increased risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, in patients where separate long-term asthma control medications like inhaled corticosteroids and LABA are required, steps must be taken to ensure adherence with both components. Otherwise, a dose combination product containing both drugs can be used.

Exercise-Induced Bronchospasm (EIB):

Formoterol is used for acute cases of EIB. Therefore, it has to be used only when needed. The drug can be used in patients without asthma as a single therapy. However, it can only be used as an adjunct to an inhaled corticosteroid in asthmatic patients.

Chronic Obstructive Pulmonary Disease:

Formoterol is advised as a long-term twice-daily therapy to prevent bronchoconstriction in COPD patients with emphysema and chronic bronchitis.

Dosage and Administration:

• Formoterol capsules must be administered only through inhalation using an inhaler.

• The capsules must not be swallowed or ingested.

• The capsules must be stored in a blister and removed only before use.

• The contents of one 12 mcg capsule must be inhaled every 12 hours using an aerosolized inhaler.

• The patient should not exhale into the inhaler.

• The total daily dose must not exceed 24 mcg.

• Delivering larger or more frequent concentrations of the drug is not recommended.

• In case of symptoms between the doses, an inhaled short-acting beta agonist must be given for immediate relief.

• The therapeutic regimen must be re-evaluated if the normal dose fails to provide the usual response.

• Formoterol can be used in patients without persistent asthma to prevent exercise-induced bronchospasm. However, in patients with persistent asthma, it must be used concomitantly with a long-term asthma control medication like an inhaled corticosteroid.

• The dosage is one capsule of 12 mcg administered through an inhaler at least 15 minutes before exercise. It may protect for up to 12 hours.

• Additional doses must not be used in between the 12-hour dose. They may require a short-acting bronchodilator.

• In COPD patients, the recommended dosage is one 12 mcg capsule every 12 hours using the aerolizer inhaler. A total daily dose must not exceed 24 mcg.

• If the effective dosage regimen fails to provide a usual response, it indicates a destabilization of treatment, and an alternative therapeutic option must be considered.

Contraindications:

The following are the contraindications of Formoterol use:

• Due to the risk of asthma-related hospitalization and death, using Formoterol without the concomitant use of an inhaled corticosteroid (long-term asthma control medication) is contraindicated.

• It is also contraindicated in patients with hypersensitivity to Formoterol or its components.

What Are the Warnings and Precautions of Formoterol?

Asthma-Related Death:

Using Formoterol without an additional therapy like an inhaled corticosteroid can increase the risk of asthma-related death. Therefore, it must be used only as an additional therapy in patients who do not experience well-controlled asthma despite the use of inhaled corticosteroids. Once asthma control is achieved, the Formoterol dose must be gradually reduced and stopped if asthma is in good control.

Pediatric and Adolescent Patients:

There is an increased risk of asthma-related hospitalization in pediatric and adolescent patients using LABAs. Therefore, when the therapy has to be considered, a fixed-dose combination therapy containing both an inhaled corticosteroid and LABA must be considered.

Formoterol must not be used in the following cases:

• Patients with worsening or acutely deteriorating asthma.

• In conjunction with another long-acting beta2 agonist (LABA).

• Formoterol is not a substitute for inhaled corticosteroids; the dosage must not be reduced and must not be stopped if Formoterol usage is initiated.

• Patients taking short-acting beta2 agonists four times a day regularly must be instructed to stop them and use them only for symptomatic relief from acute asthma attacks when Formoterol is started.

Paradoxical Bronchospasm:

Formoterol may sometimes cause paradoxical bronchospasm, which can be life-threatening. When such an episode occurs, it is recommended to stop Formoterol and start with an alternative treatment.

Deterioration of Asthma:

In case of deteriorating asthma, which causes a decrease in the peak expiratory flow (PEF) or lung function, immediate medical attention must be sought. It is not recommended to increase the Formoterol dosage more than twice daily.

Use of Anti-inflammatory Agents:

No data suggests the anti-inflammatory effects of Formoterol. Therefore, patients on oral or inhaled corticosteroids must not stop them once they start feeling better after starting Formoterol. Any change in corticosteroid dosage must be done only after clinical evaluation.

Cardiovascular Effects:

Like other LABAs, Formoterol can also cause significant cardiovascular effects in some patients, such as an increase in pulse rate and blood pressure. If such effects occur, the drug must be discontinued. Also, ECG (electrocardiogram) changes like flattening of the T wave, depression of ST segment, and prolongation of QTc interval can occur. Therefore, Formoterol must be used with caution in patients with cardiovascular disorders like hypertension, cardiac arrhythmia, and coronary insufficiency.

Immediate Hypersensitivity Reactions:

Immediate hypersensitivity reactions, like anaphylactic reactions, rash, urticaria, angioedema, and bronchospasm, can occur in a few patients.

Do Not Exceed the Recommended Dosage:

Use of Formoterol higher than the recommended dosage is associated with an increased risk of exacerbation of asthma attacks. It can also cause death due to cardiac arrest. Hypoxia and unexpected and severe acute asthmatic attack lead to cardiac arrest.

Precautions:

General:

• Formoterol must not be used to treat acute asthmatic attacks.

• Despite regular twice-daily use of Formoterol, the physician must also prescribe a short-acting beta2 adrenergic agonist to manage symptoms of acute asthmatic attacks.

• Patients must also be warned about deteriorating asthma with an increased dosage of short-acting beta2 adrenergic agonists.

• Formoterol must be used cautiously in patients with cardiovascular disorders, convulsive disorders, and thyrotoxicosis and who are unusually responsive to sympathomimetic amines.

• Administration of a related beta2 agonist, Albuterol administered intravenously, was found to aggravate pre-existing diabetic mellitus and ketoacidosis.

• Beta agonist medications can produce transient hypokalemia resulting in cardiovascular effects due to intracellular shunting.

• Long-term studies showed no significant changes in blood glucose and serum potassium with Formoterol use.

• Formoterol contains trace amounts of lactose. In patients with severe milk protein allergies, allergic reactions were noted.

• Formoterol capsules must only be used in an inhaler and should not be chewed.

• The capsules must be removed from the blister only before use.

For Patients:

What Is Asthma, and How Is It Treated?

Asthma is when the airways narrow, swell, and produce extra mucus. This results in breathing difficulties, wheezing, and coughing. In some patients, an asthma attack can be life-threatening. In some people, the symptoms flare up due to exercise, and exposure to allergens, chemical fumes, gasses, and dust. Asthma cannot be cured completely, but the symptoms can be managed.

Prevention and long-term control are the keys to stopping an asthma attack before it starts. Treatment involves tracking and avoiding the triggers and checking the breathing pattern to know if the medications are helping to keep the symptoms under control. Medications include long-term asthma control medications like inhaled corticosteroids, leukotriene modifiers, combination inhalers (containing Formoterol), and Theophylline. Quick relief medications include short-acting beta-agonists, anticholinergic agents, and corticosteroids. The therapy must be flexible and changed according to the symptoms.

Patient Information:

• Patients must read the medication guide with each new prescription and refill.

• Patients must be informed about asthma-related deaths and hospitalizations in pediatric and adolescent patients using long-acting beta2 adrenergic agonists (LABAs) like Formoterol.

• They must be instructed to continue using their long-term asthma control medication, and adding Formoterol to the therapy is not a substitute.

• Formoterol is not used to treat acute asthma symptoms, and an inhaled short-acting beta2 agonist must be prescribed for such symptoms.

• They must not inhale more than one capsule at a time, and the maximum dose per day is two capsules.

• The dosage of inhaled corticosteroids must not be changed even if the patient feels better after the therapy with both medications.

• Formoterol, used for the prevention of EIB during exercise, must take the dose 15 minutes prior and should not take an additional dose till the next 12 hours.

• Patients must be informed about the adverse effects like palpitations, tremors, chest pain, nervousness, and rapid heart rate.

• They must not use Formoterol with a spacer and should never exhale into the device.

• The inhaler must never be washed and should be kept dry. Also, a new inhaler that comes with a refill must be used.

• Women should contact the doctor if they get pregnant during the therapy or are nursing.

• The capsules must be used immediately after removing them from the blister and must be pierced only once.

• The patients must be aware of how to use the inhaler.

For Doctors:

Drug Interactions:

1. In case of the use of additional adrenergic drugs through any route, they must be used cautiously as the predictable sympathetic effects of Formoterol may be potentiated.

2. Hypokalemic effects of adrenergic agonists may be potentiated if they are used concomitantly with steroids, diuretics, or xanthine derivatives.

3. Caution is advised during the co-administration of beta-agonists with non-potassium-sparing diuretics like a loop or Thiazide diuretics.

4. Formoterol must be used with caution in patients on monoamine oxidase inhibitors, tricyclic antidepressants, and those which prolong the QTc interval. These drugs can potentiate the action of adrenergic agonists on the cardiovascular system. Drugs that prolong the QTc interval can also cause ventricular arrhythmia.

5. Beta-blockers and Formoterol can inhibit the actions of each other when administered concomitantly. Apart from blocking the therapeutic effects of Formoterol, beta blockers can produce severe bronchospasm in asthmatic patients. In cases like prophylaxis after myocardial infarction, where beta-blockers must be used, they must be used with extreme caution.

Use in Specific Populations:

Gender:

The pharmacokinetics of Formoterol does not differ among males and females.

Hepatic and Renal Impairment:

The pharmacokinetics of Formoterol have not been studied in geriatric patients. However, limited data is available on pediatric patients.

In a clinical study conducted in pediatric patients between five to 12 years of age who were administered 12 mcg to 24 mcg twice daily for 12 weeks, about 6 and 6.5 % to 9 % dose was recovered in the urine unchanged as conjugated Formoterol, respectively.

Geriatric and Pediatric Patients:

Formoterol pharmacokinetics have not been studied in patients with hepatic and renal impairment.

Overdosage:

The overdose signs and symptoms were mainly due to excessive beta-adrenergic stimulation. The symptoms of overdosage include:

• Angina.

• Hypotension or hypertension.

• Tachycardia.

• Arrhythmia.

• Nervousness.

• Headache.

• Tremor.

• Muscle cramps.

• Seizures.

• Dry mouth.

• Dizziness.

• Palpitation.

• Nausea.

• Fatigue.

• Hypokalemia.

• Hyperglycemia.

• Insomnia.

• Metabolic acidosis.

• Cardiac arrest and death.

Overdosage treatment includes discontinuation of Formoterol and initiation of supportive therapy. In addition, cardiac monitoring is recommended in cases of overdosage.

Description:

Formoterol is available in capsule form for oral inhalation. It is a dry powder formulation to be used with an aerolizer inhaler. Each clear and hard gelatin capsule contains a dry powder containing 12 mcg of Formoterol and 25 mcg lactose as a carrier.

Active Ingredient:

Formoterol Fumarate.

Chemical Name:

(±)-2-hydroxy-5-[(1RS)-1-hydroxy-2­ [(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl] formanilide fumarate dihydrate.

Molecular Formula:

(C19H24N2O4)2•C4H4O4•2H2O.

Molecular Weight:

840.9.

Physical Properties:

Formoterol fumarate is a white to yellowish crystalline powder. It is freely soluble in glacial acetic avoid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and insoluble in acetone, diethyl ether, and ethyl acetate.

The aerolizer inhaler is a plastic device that is used for inhaling Formoterol. The amount of drug delivered to the patient depends upon factors like inspiratory time and inspiratory flow rate. To use the delivery system, a Formoterol capsule is placed in the well of the inhaler, pierced by pressing and releasing the buttons on the side of the inhaler. The Formoterol formulation is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece.

Clinical Pharmacology:

Mechanism of Action:

Formoterol is a long-acting selective beta2 agonist. The inhaled drug acts locally in the lung as a bronchodilator. The pharmacological effects of Formoterol are due to the stimulation of intracellular adenylyl cyclase, an enzyme that catalyzes the conversion of ATP (adenosine triphosphate) to cyclic AMP (cyclic 3’, 5’- adenosine monophosphate). Increased cAMP levels relax the bronchial smooth muscles and inhibit the release of mediators of immediate hypersensitivity like mast cells.

Pharmacokinetics:

Absorption:

After inhalation of a single 120 mcg dose by 12 healthy subjects, Formoterol was rapidly absorbed into the plasma within five minutes of dosing. The maximum drug concentration was 92 pg/mL (picograms per milliliter). COPD patients who received 12 or 24 mcg Formoterol for 12 weeks had mean plasma concentrations ranging from 4 to 8.8 pg/mL and 8 to 17.3 pg/mL, respectively, at ten minutes, two and six hours post inhalation. As with many drugs, it was observed that most inhaled Formoterol delivered was swallowed and absorbed into the gastrointestinal tract.

Distribution:

The percentage of Formoterol that bound to human plasma proteins was 61 to 64 % in vitro at concentrations between 0.1 to 100 ng/mL. Binding to human serum albumin was 31 to 38 % at concentrations of 5 to 500 ng/ml. Formoterol concentrations used to assess plasma protein binding were greater than those achieved in plasma following inhalation of a single 120 mcg dose.

Metabolism:

Formoterol is metabolized primarily by direct glucuronidation at either the aliphatic or phenolic hydroxyl group, and O-demethylation is followed by glucuronide conjugation at phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of Formoterol followed by deformylation. The most important pathway involves direct conjugation at the phenolic hydroxyl group. The second important pathway involves o-demethylation followed by conjugation at the phenolic 2’-hydroxyl group.

Four cytochromes of P450 enzymes, namely CYP2D6, CYP2C19, CYP2C9, and CYP2A6, are involved in the O-demethylation of Formoterol. However, it did not inhibit CYP450 enzymes at therapeutically relevant concentrations.

Excretion:

The primary route of excretion of Formoterol is through urine and feces. Based on plasma concentration studies, following inhalation of a single 120 mcg dose, it was noted that the mean terminal half-life was ten hours.

Drug Abuse and Dependence:

There is no clinical data regarding drug abuse of Formoterol and dependence.

How Is Formoterol Supplied?

Formoterol is supplied as aluminum blister-packaged 12 mcg clear gelatin capsules. The capsules have “CG” printed on one end and “FXF” printed on the other. It is supplied along with an aerolizer and a medication guide.

It is available in two unit doses:

1. Unit dose-blister pack (Box of 12, with strips of 6).

2. Unit dose-blister pack (Box of 60, with strips of 6).

• Formoterol capsules must be used with an aerolizer inhaler. The inhaler must not be used for other capsules.

• Before dispensing, the medicine must be stored in a refrigerator at 2 degrees 8 degrees Celsius.

• After dispensing to the patient, it must be stored at 20 to 25 degrees Celsius.

• The medicine must be protected from heat and moisture.

• Capsules must always be stored in the blister and removed before use.

• Formoterol and the aerolizer must be discarded at the “ by use” date and a new one must be used as per the prescription.

• The medicine must be kept out of reach of children.