Tiotropium and Olodaterol (Inhalation)

The Stiolto Respimat inhaler, also known as tiotropium and olodaterol, is used to manage Chronic Obstructive Pulmonary Disease.

Overview

Tiotropium and olodaterol are used in combination to manage chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis. The combination of drugs is available only as an inhaler, which is sold in the United States under the brand name Stiolto Respimat. The two drugs are also available separately; tiotropium is sold as Spiriva, and olodaterol is marketed as Striverdi Respimat. However, using the two drugs in combination is now a widely preferred option for managing COPD because their complementary mechanisms of action can more effectively control the condition than either alone.

Using Stiolto Respimat has been correlated with, but not proven to cause, a variety of life-threatening conditions and a slightly increased risk of death, but the exact reasons why are not yet thoroughly understood; this is discussed in further detail in the "Warnings" section below.

Both tiotropium and olodaterol act as bronchodilators on their own, but with different mechanisms of action. Tiotropium is an anticholinergic, while olodaterol is a long-acting beta-adrenoreceptor agonist (LABA).

Anticholinergic drugs like tiotropium inhibit the effect of a neurotransmitter, acetylcholine, to act on the central and peripheral nervous system and cause muscles to constrict. Drugs targeting acetylcholine receptors can be either muscarinic or nicotinic, i.e. targeting either the muscarine or nicotine receptors that acetylcholine normally interacts with. Tiotropium is muscarinic.

There are five types of muscarinic receptors, labeled M1 to M5, each responsible for different actions in the body. Tiotropium binds primarily with the M3 receptor, which is found mostly in smooth muscle tissues, such as the lungs; quieting these receptors thus has the effect of relaxing the lungs. Many different anticholinergic drugs exist, and those occurring in plants have been used ever since ancient times to treat various conditions. Anticholinergics can be used to treat a wide variety of conditions because they can target any of the five types of acetylcholine receptors, each of which is found in different tissues of the body and serves different functions.

Olodaterol works by imitating the effect of the neurotransmitter epinephrine at its receptors in the lungs, called beta-2 adrenoreceptors, and stimulating them. This causes the lungs to relax by prompting the synthesis of a protein called cyclic-3',5' adenoine monophopshate (cAMP). Olodaterol almost fully stimulates the epinephrine receptors, bringing them to approximately 88 percent of their maximum excitation, and once bound to a receptor, it stays for almost a full day before being fully metabolized.

Tiotropium is also used to treat asthma and cystic fibrosis, but olodaterol is used only for Chronic Obstructive Pulmonary Disease. In fact, LABAs such as olodaterol is contraindicated in asthma patients following troubling findings during clinical trials, and these drugs may be very dangerous for them; more on this is detailed in the "Warnings" section below.

Tiotropium and olodaterol are both relatively new drugs; the former was first discovered in the early 1990s and approved for use only in 2004, while the latter was approved in the United States in 2014 (several European nations - the United Kingdom, Iceland, and Denmark - had approved it a year earlier). The inhaler containing the combination is sold by the German pharmaceutical company Boehringer Ingelheim; combined tiotropium and olodaterol currently remains under patent and is not yet available as a generic drug.

Since its ability to improve breathing could lead to stronger athletic performance, olodaterol is in fact listed by the World Anti-Doping Agency (WADA) as a banned substance to athletes competing in international sporting events such as the Olympics. Most beta-2 agonist drugs are prohibited for this reason, with the exception of small doses of salbutamol, formoterol, and salmeterol. Tiotropium is not banned by the WADA, but the combination of tiotropium and olodaterol is. Some local agencies may make exceptions to allow athletes with legitimate prescriptions to compete.

Chronic Obstructive Pulmonary Disease is estimated to be the fourth leading cause of death worldwide, killing at least three million people in 2004, and it, unfortunately, cannot be cured, only managed. Tiotropium and olodaterol represent some of the most recent developments to manage COPD, but they cannot reverse or improve the condition, only ward off its symptoms.

Conditions Treated

  • Chronic Obstructive Pulmonary Disease

Type of Medicine

  • Bronchodilator

Side Effects

The most common side effects of Stiolto Respimat is mild throat irritation including:

Throat irritation may subside as the patient adjusts to using the inhaler, but if a patient's throat becomes painfully irritated while using Stiotlo Respimat or if irritation persists for several days, they should seek advice from their doctor. Clinical trials indicate that approximately 12 percent of patients using tiotropium and olodaterol experience nasopharyngitis, an irritation of the upper respiratory tract.

Less common side effects include:

But these side effects usually don't require medical attention and subside quickly.

Some uncommon side effects include:

For serious side effects, the most common were exacerbations of COPD and pneumonia. These can develop as a result of irritation from inhaling particulates, even when the particulates are medicine to relax the respiratory system, and may emerge either suddenly or piecemeal. New or worsening symptoms of COPD, including wheezing, shortness of breath, or other breathing problems can develop, and demand immediate medical attention. Inhalers that distribute the medicine as a fine mist rather than an aerosolized spray are available for some other drugs, though not tiotropium and olodaterol at this time of writing, and could provide relief for patients prone to irritation from the current inhalers.

Tiotropium and olodaterol can raise patients' blood sugar; it interacts with a protein, glucagon, that is essentially the opposite to insulin, working to raise blood sugar as part of digestion. Patients should be closely monitored for symptoms of high blood sugar, including confusion, sleepiness, frequent urination, flushing, and fast or shallow breathing. Unexpected changes in blood sugar can be especially dangerous for patients with diabetes. Diabetic patients can safely use tiotropium and olodaterol, but they must closely monitor their blood sugar and understand how the drug affects it.

Tiotropium and olodaterol can also lower patients' potassium levels. Potassium is important for facilitating nerve signals, and in fact, for the normal function of all living cells. Therefore, significant potassium deficiencies can be very dangerous. Minor potassium deficiencies often present no symptoms, but more serious cases often include muscle cramps, tiredness, and weakness. In the most severe cases, potassium deficiency (hypokalemia) can result in cardiac arrest. Potassium deficiency can usually be treated with simple dietary changes or daily vitamin supplements.

Tiotropium and a related anticholinergic drug, ipratropium, had in the past been thought to raise the risk of heart attacks or other cardiovascular problems, but further research has indicated that this is not the case, and virtually all physicians agree that the drugs do not pose a significant risk to the cardiovascular system.

Dosage

Patients using tiotropium and olodaterol together as Stiolto Respimat should take only two inhalations each day. The two inhalations should be taken together in quick succession. Patients should try to use their inhaler at approximately the same time each day.

The Stiolto Respimat inhaler can be used without regard to food. The only inhaler of the drugs currently available dispenses two and a half micrograms of each medicine with each puff. Each puff releases approximately four grams of the solution in total, the remaining amount being composed of benzalkonium chloride and edetate disodium.

Tiotropium and olodaterol should replace other drugs used daily for the long-term management of COPD. Many patients may have been using a short-acting beta-2 agonist to manage symptoms. They should stop using it for daily maintenance when they begin using the tiotropium and olodaterol inhaler, and use their short-acting inhaler only as needed for relief of acute symptoms. Combining olodaterol with another beta-2 agonist for a long period of time could result in an overdose.

If a patient misses his or her dose, they should take it as soon as they remember, unless it is nearly time for the next dose. Patients should never exceed more than two inhalations per 24 hours.

The inhaler may not deliver the correct dose on the first use, or if it has not been used for more than three days. Before using the inhaler for the first time, or after at least twenty-one days of dormancy, patients should spray it into the air three times to prime it. If the inhaler has not been used in at least three days, but less than twenty-one, it should only need one spray to prime it before use.

Interactions

Drugs containing tiotropium should not be taken alongside other anticholinergic drugs, such as aclidinium, eluxadoline, glycopyrrolate, ipratropium, levosulpiride, oxatomide, and umeclidinium, in order to avoid excessive attenuation of acteylcholine. Likewise, drugs containing olodaterol should not be used with other long-acting beta-2 agonists, such as iobenguange and linezolid.

LABAs such as olodaterol should not be used alongside other sympathomimetic drugs (those that imitate neurotransmitters) because serious cardiovascular side effects and even death have been documented due to overdoses on sympathomimetic drugs. Many drugs are sympathomimetic, including several drugs of abuse such as cocaine and MDMA, but also some common prescription drugs for ADHD (amphetamine, pemoline, and Ritalin), antidepressants (maprotiline), and a handful of widely used over-the-counter drugs such as pseudoephedrine (Sudafed) and oxymetazoline (Afrin nasal spray).

Beta blockers, used to treat high blood pressure and other heart conditions, should not be taken with Stiolto Respimat because they are known to diminish the effectiveness of beta-2 agonists.

Anticholinergic drugs such as tiotropium should not be taken with supplemental glucagon, a hormone naturally created by the pancreas that regulates blood sugar alongside insulin. Mixing glucagon and anticholinergics can result in a dangerous spike in blood sugar and serious gastrointestinal side effects.

Anticholinergic drugs should not be used with potassium citrate because this significantly increases the likelihood of developing an ulcer.

The antipsychotic drug loxapine should not be used alongside tiotropium and olodaterol because the combination is known to raise the likelihood of the patient experiencing acute bronchospasm episodes.

Warnings

Tiotropium and olodaterol should never be used by asthma patients. Long-acting beta-2 agonist drugs such as olodaterol are known to be correlated with an increased risk of asthma-related death. A placebo-controlled longitudinal study with a very large sample size (the SMART 2006 study) showed that patients who added another LABA drug called salmeterol to their usual asthma-control regimen were significantly more likely to die during the course of the reporting. The exact mechanism behind this correlation is not yet understood.

A more recent double-blind trial examining patients of all ages (pediatric, adolescent, and adult) using salmaterol with a corticosteroid (fluticasone) revealed no such correlation, and in fact, found that those taking salmaterol had fewer asthma attacks. As of 2017, no study has examined the correlation of LABA drugs and likelihood of death in COPD patients, only asthma. However, due to the statistical significance of the correlation found in the first study, LABA drugs such as olodaterol are not recommended for patients suffering from asthma.

Inhaling particulates, even those containing medicine for the respiratory system, can sometimes paradoxically trigger an acute exacerbation of COPD symptoms. Patients should always carry a rescue inhaler, and seek medical attention immediately if they experience difficulty breathing after using tiotropium and olodaterol.

Patients should not use Stiolto Respimat if they have ever experienced a hypersensitive reaction to tiotropium, olodaterol, atropine or ipratropium (other anticholinergic drugs similar to tiotropium), or either of the other components of the formulation (benzalkonium chloride and edetate disodium). Allergic reactions to tiotropium or olodaterol, while uncommon, could occur, Patients should seek immediate medical attention if they begin to experience any symptoms of anaphylaxis, including swelling of the lips, face, or tongue, hives, or extreme difficulty breathing.

Patients who have experienced a dangerous reaction to other sympathomimetic drugs imitating the neurotransmitter epinephrine may experience a similar reaction with olodaterol, but documentation of cross-sensitivity is limited.

Tiotropium and olodaterol can cause watery eyes, blurry vision or pupil dilation if it touches a patient's eyes. Care should be taken so that any aerosolized medicine does not touch the eyes. If tiotropium and olodaterol touch a patient's eyes, they should wash them with plenty of water as soon as possible.

If a patient has been using a short-acting beta-2 agonist drug to manage their COPD, they should stop its regular use when beginning to take tiotropium and olodaterol, and use it only to relieve acute symptoms.

Tiotropium and olodaterol have not been tested in patients younger than eighteen years old; patients this age should not use this drug.

Patients with moderate to severe kidney dysfunction (a creatinine clearance of less than 60 milliliters per minute) should use Stiolto Respimat with caution, and be monitored closely because they are more likely to have adverse reactions to anticholinergics such as tiotropium.

Beta-2 agonists should be used with caution by patients with a variety of medical conditions because by stimulating neural receptors and changing the behavior of muscle tissue, these drugs can cause profound changes to the body. Heart patients need to be mindful of their blood pressure and heart rate, and diabetes patients should note that beta-2 agonists can increase blood glucose.

Since tiotropium and olodaterol can, in rare cases, cause dizziness or blurred vision, patients should refrain from driving or operating machinery until they understand how the drugs affect them.

Storage

Tiotropium and olodaterol inhalers should be stored at room temperature (approximately 59 to 77 degrees Fahrenheit, or 15 to 25 Celsius) in a closed container. It should be protected from heat and direct sunlight. It should also be protected from moisture, and thus not stored in a bathroom that becomes steamy during bathing. Inhalers should never be frozen.

Tiotropium and olodaterol inhalers should always be kept out of reach of children, especially those who might confuse them with a fast-acting asthma inhaler such as albuterol.

Inhalers expire relatively quickly and should be disposed of three months after their first use whether finished or not. Like all medicine, tiotropium and olodaterol inhalers should be properly disposed of in a designated drug drop-off point such as at a police or fire station to prevent trace amounts of the drug from entering the ecosystem or food supply.

Summary

For patients suffering from COPD, tiotropium and olodaterol can reduce the frequency of acute exacerbations by working two ways to relax the lungs and respiratory tract. It should never be used to treat sudden symptoms and patients should always carry a rescue inhaler for these situations.

The most serious complications associated with tiotropium and olodaterol are the unintentional triggering of a bronchospasm with the aerosolized medication and the potential risk for asthma patients suggested by clinical trials. Hopefully, more research in the near future can shed light on the correlation between LABA drugs such as olodaterol and the increased risk of death for asthma patients noted in the first clinical trial. Patients prone to bronchospasm during inhalation may find relief with different types of inhalers; some are able to distribute medicine as a fine mist, rather than an aerosolized spray, and are intended for patients with limited mobility or difficulty using the regular inhalers. These mist inhalers may be available for tiotropium and olodaterol soon.

Tiotropium and olodaterol remain relatively new to the market and represent some of the most recent advances in COPD management. By reducing the frequency of acute symptoms, the combination of drugs can significantly improve COPD patients' quality of life.

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Last Reviewed:
January 31, 2018
Last Updated:
April 05, 2018
Content Source: