Arformoterol

Arformoterol is an asthmatic agent/ Broncho dilating agent belonging to the pharmacological class of Long-acting Beta 2 adrenergic receptor agonists. Arformoterol is approved for the treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Arformoterol is found to have Pulmonary bioavailability of 21-37% and Total systemic bioavailability of 46%. The Arformoterol protein binding was found to be Moderate about 61-64%. Arformoterol is fully metabolized upon oral administration and the glucuronic acid pathway was found to be a major pathway for drug metabolism. Arformoterol was found to achieve total elimination of 63% after the oral route of administration.

The common side effects associated with Arformoterol include nervousness, weakness, dizziness, dry mouth, trouble sleeping (insomnia), leg cramps, fever, nasal congestion, or hoarseness or deepened voice,etc

Arformoterol is available in the form of mainly oral inhalation, and nebulizer only.

Arformoterol was first approved in the U.S in 2006. It is available in the U.S, European Union, India, Canada., etc.

Arformoterol belonging to the pharmacological class of Long-Acting Beta 2 Adrenergic Receptor Agonist, acts as an Anti-asthmatic/Bronchodilator therapeutic agent. Arformoterol 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.

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

Arformoterol has an onset of action of 1-3 hours (mean peak achieved), and the duration of action exceed more than 12 hours.Arformoterol achieved Tmax -0.5 hours and Cmax- 4.3 pg/mL during inhalation therapy.

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 Arformoterol 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.

8. After using clean the nebulizer (see manufacturer’s instructions).

Rotacaps:

1. Hold the rotahaler vertically
2. Remove the rotacap from the bottle and place it in the rotacap hole such that it’s transparent end is facing downward.
3. Rotate the base while holding the mouth piece 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 the breath for 10 seconds and breathe out.
8. Now dispose off the empty capsule by opening the rotahaler.

Arformoterol can be used in the treatment of:

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

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

Arformoterol is approved for use in the following clinical indications:

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

Arformoterol administration dose is 15 mcg along with other drug combinations which is inhaled twice daily.

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

It is available in 15mcg/2ml.

Mainly Inhalation dosage form is available, such as nebulizers, rotacaps.

Arformoterol should be used in the treatment 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.

Arformoterol 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
• In Diabetes Mellitus, as may lead to Ketoacidosis
• In pregnancy as 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 Arformoterol 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:

Arformoterol 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, Arformoterol should not be used. The use of short-acting beta 2 agonists should be considered in this situation.

While starting the administration of Arformoterol, 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 Arformoterol 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 Arformoterol or increased usage of Arformoterol 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. Arformoterol should be withdrawn, and other alternate therapy must be considered.

• Paradoxical bronchospasm:

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

• Cardiovascular events:

Arformoterol 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:

Arformoterol 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 Arformoterol 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 Arformoterol as it may worsen dizziness if present.

Arformoterol 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 Arformoterol in the pregnant women. Arformoterol has shown to be teratogenic in animals. Arformoterol has caused neonatal mortality and developmental delays in rats. The animal reproduction studies are not always predictive of human response.Therefore Arformoterol Should be used during pregnancy, only if the potential benefits outweigh the risks to the fetus. Arformoterol has been shown to have teratogenic effects in rats based upon findings of omphalocele also called as umbilical hernia, a malformation that occurs at oral doses which is equal to or greater than 370 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Increased pup loss at birth and decreased pup weights were observed in the rats at oral doses equal to or greater than 1100 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Delays in the development were evident with an oral dose of 2400 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Arformoterol has shown to have teratogenic effects in rabbits based upon findings of malpositioned right kidney, a malformation, at oral doses equal to or greater than 8400 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Malformations including bulbous aorta,brachydactyly,and liver cysts were observed at oral doses equal to or greater than 22,000 times the maximum recommended daily inhalation dose (MRDID). Lobular dysgenesis of the lung, malformations including adactyly, and interventricular septal defect were observed at an oral dose of about 43,000 times the maximum recommended daily inhalation dose (MRDID). Embryolethality was observed at an oral dose of 43,000 times the maximum recommended daily inhalation dose in adults (MRDID). No teratogenic findings were found in rabbits with oral doses which is equal to or less than 4900 times adult exposure at the maximum recommended daily inhalation dose(MRDID).

No known interactions with food are noted.

The adverse reactions related to Arformoterol 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
• Weakness
• Bronchitis
• Fever
• Muscle Tremors

Rare

• Paroxysmal Supraventricular Tachycardia
• Atrial Flutter
• Abnormal Heart Rhythm
• Chronic Heart Failure
• Acute Cerebral Infarction
• Low Blood Pressure
• An Infection Around A Tooth
• 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
• 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 Arformoterol are briefly summarized here:

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

• Beta-blockers or Sympathomimetics: Arformoterol 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 Arformoterol, such as Hypokalemia and ECG changes.

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

The common side effects of Arformoterol include the following:

• Swelling of arms or legs
• Insomnia
• Diarrhea
• Nausea
• Vomiting
• Cramps
• Dry mouth
• Nervousness
• Headache
• Dizziness
• Tiredness
• Lack of energy
• Flu symptoms

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

• Breastfeeding Warning of Arformoterol

Arformoterol 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 Arformoterol of  in pregnant women. Arformoterol has been shown to be teratogenic in animals. Arformoterol has caused neonatal mortality and developmental delays in rats. Animal reproduction studies are not always predictive of human response. Therefore Arformoterol Should be used during pregnancy, only if the potential benefits outweigh the risks to the fetus. Arformoterol has been shown to have teratogenic effects in rats based upon findings of omphalocele also called umbilical hernia, a malformation that occurs at oral doses which is equal to or greater than 370 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Increased pup loss at birth and decreased pup weights were observed in the rats at oral doses equal to or greater than 1100 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Delays in the development were evident with an oral dose of 2400 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Arformoterol has shown to have teratogenic effects in rabbits based upon findings of malpositioned right kidney, a malformation, at oral doses equal to or greater than 8400 times adult exposure at the maximum recommended daily inhalation dose (MRDID). Malformations including the bulbous aorta, brachydactyly, and liver cysts were observed at oral doses equal to or greater than 22,000 times the maximum recommended daily inhalation dose (MRDID). Embryolethality has been observed at an oral dose of 43,000 times the maximum recommended daily inhalation dose in adults (MRDID). No teratogenic findings were found in rabbits with oral doses which is equal to or less than 4900 times adult exposure at the maximum recommended daily inhalation dose(MRDID).

• Labor and Delivery

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

• Nursing Mothers

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

• Pediatric Use

Arformoterol is approved for use in the long-term maintenance treatment of bronchoconstriction associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. The safety and efficacy of Arformoterol in pediatric patients have not been established.

• Geriatric Use

Out of the 873 patients who received Arformoterol in two placebo-controlled clinical studies in adults with COPD (Chronic Obstructive Pulmonary Disease), 391 were 65 years of age or older while 96 were 75 years of age or older. There were found to be no overall differences in safety or effectiveness between these subjects and younger subjects. Among subjects aged 65 years and older, 129 received Arformoterol at the recommended dose of 15 mcg twice a day, while the remainder received higher doses.

Pharmacodynamics

Arformoterol is the active (R, R)-enantiomer of formoterol, which is a selective long-acting β2-adrenergic receptor agonist that has two-fold greater potency than racemic formoterol.

Arformoterol 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.

Pharmacokinetics

The pharmacokinetics of Arformoterol 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 of up to 96 mcg.

• Absorption

In COPD patients who were administered with 5 mcg Arformoterol every 12 hours for 14 days, the mean steady-state peak (R, R)-formoterol plasma concentration i.e.Cmax, and systemic exposure i.e. AUC0-12h were found to be 4.3 pg/mL and 34.5 pg•hr/mL, respectively. The median steady-state peak (R, R)-formoterol plasma concentration-time i.e.tmax was observed approximately one-half hour after drug administration. In a crossover study in patients with COPD, when Arformoterol 15 mcg and 12 and 24 mcg formoterol fumarate inhalation powder was administered twice a day for 2 weeks, the accumulation index was approximately 2.5 based on the plasma (R, R)-formoterol concentrations in all three treatments. At steady state, geometric means of systemic exposure i.e.AUC0-12h) to (R, R)-formoterol following 15 mcg of Arformoterol and 12 mcg of formoterol fumarate inhalation powder were 39.33 pg•hr/mL and 33.93 pg•hr/mL, respectively while the geometric means of the Cmax were 4.30 pg/mL and 4.75 pg/mL, respectively. In a study in patients with asthma, treatment with Arformoterol 50 mcg with pre-and post-treatment with activated charcoal resulted in a geometric mean decrease in (R, R)-formoterol AUC0-6h by 27% and Cmax by 23% as compared to treatment with Arformoterol which is 50 mcg alone. This suggests that a substantial portion of systemic drug exposure is due to pulmonary absorption.

• Distribution

The binding of Arformoterol to human plasma proteins in-vitro was found to be 52-65% at various concentrations of 0.25, 0.5, and 1.0 ng/mL of radiolabeled Arformoterol. The concentrations of Arformoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of multiple doses of 50 mcg Arformoterol.

• Metabolism

Arformoterol is primarily metabolized by direct conjugation i.e.glucuronidation and secondarily by O-demethylation. At least five human uridine diphosphate glucuronosyltransferase (UGT) isozymes catalyze Arformoterol glucuronidation in-vitro. Two cytochrome P450 isozymes i.e.CYP2D6 and secondarily CYP2C19, catalyze the O-demethylation of arformoterol. Direct conjugation of Arformoterol with glucuronic acid was the major metabolic pathway. Most of the drug-related material in the plasma and urine was in the form of glucuronide or sulfate conjugates of Arformoterol. 17 % of the dose of Arformoterol of O-Demethylation and conjugates of the O-desmethyl metabolite were recovered in urine and feces.

• Elimination

After the administration of a single oral dose of radiolabeled Arformoterol to 8 healthy male subjects, 63% of the total radioactive dose of Arformoterol was recovered in urine and 11% of it in the feces within 48 hours. A total of 89% of the total radioactive dose of Arformoterol was recovered within 14 days of the administration, with 67% in the urine and 22% in the feces. Around 1% of the dose was recovered as unchanged Arformoterol in urine over 14 days.

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6. TITCK Product Information: Airbir (arformoterol tartrate/budesonide) capsule with powder for inhalation

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