Olodaterol

Olodaterol a Bronchodilating agent belonging to the pharmacological class of Ultra Long-Acting Beta 2 Adrenergic Receptor Agonist (LABA).

Olodaterol is approved for treating COPD (Chronic Obstructive Pulmonary Disease), Chronic Bronchitis, and Emphysema.

Olodaterol is absorbed and it reaches maximum plasma concentration in 10 to 20 minutes with maximum bioavailability of 30%.The volume of distribution of Olodaterol is high as 1110 litres.Olodaterol is essentially metabolized by direct glucuronidation and O-demethylation at the methoxy moiety followed by conjugation. Out of the six metabolites which were found, only the unconjugated demethylation product has been found to bind to beta2-receptors. After intravenous administration of [14C]-labeled Olodaterol, 38% of the radioactive dose was eliminated in the urine and 53% was eliminated in the feces.

The common side effects associated with Olodaterol include nasal congestion, sneezing, sore throat, pain or burning micturation, back pain or rash, joint pain, cough, shortness of breath, chest discomfort, diarrhea, and dizziness.

Olodaterol is available in the form of an Inhalation Therapy.

Olodaterol is available in U.S., Canada, U.K, E.U., Turkey, and Thailand

Olodaterol belonging to the pharmacological class Ultra Long-Acting Beta 2 Adrenergic Receptor Agonist acts bronchodilating therapeutic agent (LABA).

Olodaterol acts via agonistic action on beta 2 adrenergic receptor which in turn stimulates adenyl cyclase following the conversion of ATP to cAMP. This in turn causes an increase in cAMP and leads to the relaxation of the smooth muscles in the airways.

Olodaterol causes bronchial smooth muscle relaxation, which is helpful in relieving the patient from COPD, Emphysema, or Chronic Bronchitis.

Olodaterol has an onset of action of 5 minutes, and the duration of action lasts up to more than 12 hours, approximately 24 hours. Olodaterol maximum concentration Cmax were found to be 112% (84%–151%) (mild impairment) and 99% (73% -135%) (moderate impairment)

Olodaterol can be used to treat:

• Chronic bronchitis
• Emphysema
• Maintain airflow obstruction in patients suffering from Chronic Obstructive Pulmonary Disease.

Olodaterol is approved for use in the following clinical indications:

• COPD (Chronic Obstructive Pulmonary Disease)
• Chronic Bronchitis
• Emphysema

It is recommended that Olodaterol should be inhaled twice at the same time of the day with not more than two inhalations every 24 hours

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

2.7mcg equivalent to 2.5mcg

Powdered Inhalation

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 high glycemic index and saturated and trans fat food needs to be restricted.

The dietary restriction should be individualized as per patient requirements

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

Olodaterol may be contraindicated in the following as per the following conditions:

• Olodaterol is not indicated in the treatment of Asthma as a monotherapy(can be used along with inhaled corticosteroids).

• Olodaterol has been contraindicated the patients with a history of Hypersensitivity towards Olodaterol or any ingredient of the medication.

• Deterioration of Asthmatic Condition, including death:

There might be a deterioration of the asthma condition over a period of time. The increased usage of Olodaterol 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:

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

While starting the administration of Olodaterol, 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 Olodaterol 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 Olodaterol or increased usage of Olodaterol 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 skin, difficulties in breathing or swallowing, rashes, Olodaterol should be withdrawn, and other alternate therapy must be considered.

• Paradoxical bronchospasm:

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

• Cardiovascular events:

Olodaterol 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:

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

Olodaterol or the components of the drug medication have not been known to be excreted in milk.

Yet 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 is no well-known, established data on Olodaterol use in pregnant women.

Olodaterol was not found teratogenic in rats at inhalation doses approximately 2,731 times the maximum recommended human daily inhalation dose set by MHRD on an AUC basis (at a rat maternal inhalation dose of 1,054 mcg/kg/day). The Placental transfer of Olodaterol drug was observed in pregnant rats.

Olodaterol has shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHD in adults on an AUC basis (at a rabbit maternal inhalation dose of 2,489 mcg/kg/day). Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. No significant effects occurred at an inhalation dose approximately 1,353 times the MRHD in adults on an AUC basis (at a rabbit maternal inhalation dose of 974 mcg/kg/day).

Yet 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.

No known interactions with food is noted.

The adverse reactions related to Olodaterol can be categorized as

• Common

 Sneezing

 Sore throat

 Unusual tiredness or weakness

 Body aches or pain

 Chills

 Headache

 Loss of voice

 Runny or stuffy nose

 Cough

 Difficulty in breathing

 Ear congestion

 Fever

• Less Common

 Lower back or side pain

 Skin rash

 Tightness in the chest

 Bladder pain

 Difficult, burning, or painful urination

 Frequent urge to urinate

 Bloody or cloudy urine

 Chest pain

 Cough-producing mucus

• Rare

 Loss of appetite

 Weight loss

 Cough that does not go away or gets worse

 Hoarseness

 Coughing up blood

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

• Monoamine Oxidase Inhibitors or Anti-Depressants: Patients should be monitored closely, or an alternate therapy must be considered while using Olodaterol as it might lead to some cardiovascular events in patients such as prolongation of QT-wave, cardiac arrhythmias, etc.
• Beta-blockers or Sympathomimetics: Olodaterol 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 Olodaterol, such as Hypokalemia and ECG changes.
• Xanthine and Steroids: The use of Xanthines and Steroids along with Olodaterol might lead to Hypokalemia. Therefore caution is advised during concomitant use.

The common side effects of Olodaterol include the following cold symptoms such as:

• Nasal congestion,
• Sneezing.
• Sore throat.
• Pain or burning when you urinate.
• Back pain or rash.
• Joint pain.
• Cough.
• Shortness of breath.
• Chest discomfort.
• Diarrhea
• Dizziness.

The use of Olodaterol should be prudent in the following group of special populations:

Pregnancy

• Pregnancy Category C

There is no well-known, established data on Olodaterol use in pregnant women.

Olodaterol was not found teratogenic in rats at inhalation doses of approximately 2,731 times the maximum recommended human daily inhalation dose set by MRHD on an AUC basis (at a rat maternal inhalation dose of 1,054 mcg/kg/day). The Placental transfer of Olodaterol drug was observed in pregnant rats.

Olodaterol has shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHD in adults on an AUC basis (at a rabbit maternal inhalation dose of 2,489 mcg/kg/day). Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. No significant effects occurred at an inhalation dose approximately 1,353 times the MRHD in adults on an AUC basis (at a rabbit maternal inhalation dose of 974 mcg/kg/day).

Yet 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.

• Labor and Delivery

For Olodaterol use on preterm labor or labor at term, there were found to be no adequate and well-controlled human studies. Because there is a potential for beta-agonist interference with uterine contractility, the use of Olodaterol during labor should be restricted and should be used if only in whom the benefits clearly outweigh the risks.

• Breastfeeding Mothers

Olodaterol or the components of the drug medication have not been known to be excreted in milk.

Yet 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.

• Pediatric Use

In pediatric patients, the safety and effectiveness of Olodaterol have not been established. Yet, Olodaterol is not indicated for use in children.

• Geriatric Use

Based on available data, no adjustment of Olodaterol dosage in geriatric patients is warranted. Of the 876 patients who received Olodaterol at the recommended dose of 5 mcg once daily in the clinical studies from the pooled 1-year database, 485 were less than or equal to 65 years of age, and 391 (44.6%) were greater than 65 years of age.

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

An increase in pulse rate, systolic blood pressure, and QTc interval was found in COPD patients after administering single doses of 40 times, the 75 mcg dose associated the expected 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 Olodaterol overdose, cardiac arrest and even death may be associated.

Treatment of overdosage consists of:

• Withdrawing of Olodaterol 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

Olodaterol is found to be a potent agonist of the human beta2-adrenergic receptor and is highly selective for this receptor, which is commonly expressed on adipose tissue and cardiac, smooth muscle. Olodaterol binds to the receptor causing smooth muscle relaxation in the lungs and causing bronchodilation. It has shown the potential of reversing active bronchoconstriction.

Pharmacokinetics

Olodaterol has shown linear pharmacokinetics. After repeating once-daily inhalation, a steady-state of Olodaterol plasma concentrations was achieved after 8 days. The extent of exposure was found to be increased up to 1.8-fold when compared to one single dosage.

• Absorption

Olodaterol reaches maximum plasma concentrations within 10 to 20 minutes following Olodaterol inhalation. In the healthy volunteers, the absolute bioavailability of Olodaterol after inhalation was approximately 30%, whereas the absolute bioavailability was below 1% when Olodaterol was given as an oral solution.

• Distribution

The volume of distribution is found to be high i.e., 1110 L, suggesting extensive distribution into tissue. In vitro binding of Olodaterol to the human plasma proteins is not dependent on the concentration and is found to be approximately around 60%.

• Metabolism

Olodaterol is essentially metabolized by direct glucuronidation and O-demethylation at the methoxy moiety followed by conjugation. Out of the six metabolites which were found, only the unconjugated demethylation product has been found to bind to beta2-receptors. This unconjugated demethylation product, however, is not been detectable in the plasma after chronic inhalation of the recommended dose of Olodaterol. The Cytochrome P450 isozymes such as CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are also involved in the O-demethylation of Olodaterol, while the uridine diphosphate glycosyltransferase isoforms UGT2B7, UGT1A1, have been identified to be involved in the formation of metabolized product Olodaterol glucuronides.

• Elimination

The Total clearance of Olodaterol in healthy volunteers was found to be 872 mL/min, and renal clearance was found to be 173 mL/min. The terminal half-life following intravenous administration of Oldaterol was found to be 22 hours. After intravenous administration of [14C]-labeled Olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in the feces. The amount of unchanged Olodaterol which was recovered in the urine after intravenous administration was found to be 19%. Following the oral administration of Olodaterol , only 9% of Olodaterol and/or its metabolites was recovered in the urine, while the major portion recovered in feces was about 84%. More than 90% of the dose was excreted within 5 and 6 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged Olodaterol in urine within the dosing interval in healthy volunteers at steady-state accounted for 5% to 7% of the dose.

There are some clinical studies of drug olodaterol mentioned below:

• Rabe KF, Chalmers JD, et.al. Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD: a Post Hoc Analysis of the TONADO(®) Trials. AdvTher. 2021 Jan;38(1):579-593.
• Singh D, Wedzicha JA, et.al. Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials. Respir Res. 2020 Sep 17;21(1):240.
• Andreas S, Bothner U, et.al. No Influence on Cardiac Arrhythmia or Heart Rate from Long-Term Treatment with Tiotropium/Olodaterol versus Monocomponents by Holter ECG Analysis in Patients with Moderate-to-Very-Severe COPD. Int J Chron Obstruct Pulmon Dis. 2020 Aug 10;15:1945-1953.
• Andreas S, McGarvey L, et.al. Absence of Adverse Effects of Tiotropium/Olodaterol Compared with the Monocomponents on Long-Term Heart Rate and Blood Pressure in Patients with Moderate-to-Very-Severe COPD. Int J Chron Obstruct Pulmon Dis. 2020 Aug 10;15:1935-1944.
• Wedzicha JA, Buhl R, et.al. Tiotropium/Olodaterol Decreases Exacerbation Rates Compared with Tiotropium in a Range of Patients with COPD: Pooled Analysis of the TONADO(®)/DYNAGITO(®) Trials. AdvTher. 2020 Oct;37(10):4266-4279.
• Buhl R, de la Hoz A, et.al. Efficacy of Tiotropium/Olodaterol Compared with Tiotropium as a First-Line Maintenance Treatment in Patients with COPD Who Are Naïve to LAMA, LABA and ICS: Pooled Analysis of Four Clinical Trials. AdvTher. 2020 Oct;37(10):4175-4189.

1) https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203108s006lbl.pdf

2) https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203108Orig1s000ClinPharmR.pdf

3) https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_203108.pdf

4) https://go.drugbank.com/drugs/DB09080

5) https://pubchem.ncbi.nlm.nih.gov/compound/Olodaterol

6) McGarvey L, Koch A, Sachs P, et al. 48-week administration of olodaterol QD via Respimat® vs placebo and formoterol BID in patients with COPD: Pooled safety analysis. EurRespir J. 2013;42(Suppl 57):749s–P3633.

7) Bouyssou T, Hoenke C, Rudolf K, et al. Discovery of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med ChemLett. 2010;20(4):1410–1414.

8) Maltais F, Kirsten A, Hamilton A, De Sousa D, Wang F, Decramer M. Evaluation of the effects of olodaterol on exercise endurance in patients with COPD: results from two 6-week studies; Abstract 748A presented at CHEST; Chicago, IL, USA. October 26–31, 2013.

9) Derom E, Westerman J, Grönke L, et al. The 24-hour lung function profile of once-daily tiotropium and olodaterol fixed-dose combination compared with placebo and monotherapies in chronic obstructive pulmonary disease (VIVACITO); Abstract D44 presented at American Thoracic Society; San Diego, CA, USA. May 16–21, 2014.

10) Lange P, Aumann J-L, Derom E, et al. The 24-h FEV1 time profile of olodaterol QD delivered via Respimat® in COPD: results from two 6-week studies. EurRespir J. 2013;42(Suppl 57):982s–4635.