Salmeterol

Salmeterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.

In clinical studies, inhaled corticosteroids and/or inhaled cromolyn sodium did not alter the safety profile of salmeterol oral inhalation when these drugs were administered concurrently.

The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 7,800(SRC), determined from a structure estimation method(2), indicates that salmeterol is expected to be immobile in soil(SRC). The estimated pKa of salmeterol is 11.2(3), indicating that this compound will primarily exist as a cation in the environment. Cations adsorb strongly to organic carbon and clay and do not volatilize from moist soil surfaces (SRC). Salmeterol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-15 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 7,800(SRC), determined from a structure estimation method(2), indicates that salmeterol is expected to adsorb to suspended solids and sediment(SRC). The estimated pKa of salmeterol is 11.2(3), indicating that this compound will primarily exist as a cation in the environment. Cations adsorb strongly to suspended solids and sediment and do not volatilize from the soil(4). According to a classification scheme(5), an estimated BCF of 7.0(SRC), from an estimated log Kow of 4.2(6) and a regression derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), salmeterol, which has an estimated vapor pressure of 1.9X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase salmeterol may be removed from the air by wet and dry deposition(SRC). Salmeterol does not contain chromophores that absorb light at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The most common adverse reactions of salmeterol (incidence ≥3%) in asthmatics include upper respiratory infection or inflammation, oral candidiasis, pharyngitis, bronchitis, dysphonia, headaches, cough, nausea, and vomiting. In patients with chronic obstructive pulmonary disease, the most common adverse effects include pneumonia, throat irritation, viral respiratory infections, oral candidiasis, dysphonia, headaches, and musculoskeletal pains.

There are reports of sympathomimetic syndrome with hyperlactatemia and metabolic acidosis after the intentional inhalation of salmeterol in a suicide attempt. Patients who overdose commonly present with heart palpitation, chest pain, hypophosphatemia, hypokalemia, lactic acidosis, ST-segment depression, and sinus tachycardia. Patients may also present with angina, hypotension, hypertension, dizziness, nausea, fatigue, malaise, insomnia, and muscle cramps. Overdose with salmeterol can lead to prolongation of the QT interval resulting in ventricular arrhythmias.

Salmeterol's long, lipophilic side chain binds to exosites near beta(2)-receptors in the lungs and on bronchiolar smooth muscle, allowing the active portion of the molecule to remain at the receptor site, continually binding and releasing. Beta(2)-receptor stimulation in the lung causes relaxation of bronchial smooth muscle, bronchodilation, and increased bronchial airflow.

Symptoms of overdose include angina (chest pain), dizziness, dry mouth, fatigue, flu-like symptoms, headache, heart irregularities, high or low blood pressure, high blood sugar, insomnia, muscle cramps, nausea, nervousness, rapid heartbeat, seizures, and tremor.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for salmeterol can be estimated to be 7,800(SRC). According to a classification scheme(2), this estimated Koc value suggests that salmeterol is expected to be immobile in soil. The estimated pKa of salmeterol is 11.2(3), indicating that this compound will primarily exist in cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ Data from a large placebo-controlled safety study that was stopped early suggest that salmeterol may be associated with rare serious asthma episodes or asthma-related deaths.Data from this study, called the Salmeterol Multi-center Asthma Research Trial (SMART), further suggest that the risk might be greater in African American patients. These results led to stopping the study prematurely. The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk. Given the similar basic mechanisms of action of beta2-agonists, it is possible that the findings seen in the SMART study may be consistent with a class effect. Findings similar to the SMART study findings were reported in a prior 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study. In the SNS study, the incidence of asthma-related death was numerically, though not statistically, greater in patients with asthma treated with salmeterol (42 ug twice daily) versus albuterol (180 ug 4 times daily) added to usual asthma therapy.

/SIGNS AND SYMPTOMS/ The expected signs and symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the adverse reactions ... e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. ... Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. Other signs of overdosage may include hypokalemia and hyperglycemia.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Salmeterol

DILI Negative

Oral; Respiratory (inhalation)

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 7.0 was calculated for salmeterol(SRC), using an estimated log Kow of 4.2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl salmeterol xinafoate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Salmeterol Xinafoate/

Anti-asthmatic /Xinafoate salt/

Bronchodilator

MEDICATION

Salmeterol ... /is/ indicated as bronchodilators for the treatment of bronchospasm associated with chronic obstructive airway disease, including bronchitis and pulmonary emphysema. ... /Included in US product labeling/

Use (kg; approx.) in Germany (2009): >10

For the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Oral Inhalation: Aerosol 21 ug (of salmeterol) per metered spray (from the actuator) Serevent ( with fluorochlorohydrocarbon propellants), (GlaxoSmithKline); Powder: 50 ug (of salmeterol) per inhalation Serevent Diskus, (GlaxoSmithKline). /Salmeterol xinafoate/

Oral Inhalation: Powder 50 ug (of salmeterol) with fluticasone propionate 100, 250, or 500 ug per inhalation- Advair (GlaxoSmithKline). /Salmeterol xinafoate combinations/

Structural analog of albuterol.

Information available in 2005 indicated that Salmeterol was used in the manufacture of pharmaceutical preparations in the following countries: Antigua & Barbuda, Aruba, Bahrain, Barbados, Chile, Croatia, Grenada, Guyana, India, Iran, Jamaica, Kuwait, Luxembourg, Netherlands Antilles, Oman, Qatar, Saint Lucia, Saint Vincent & The Grenadines, Slovenia, Turkey, Trinidad & Tobago, United Arab Emirates, Yugoslavia (1,2)

Information available in 2005 indicated that Salmeterol xinafoate was used in the manufacture of pharmaceutical preparations in the following countries: Algeria, Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Chile, Costa Rica, Czech Republic, Denmark, Dominican Republic, Ecuador, El Salvador, Finland, France, Germany, Greece, Guatemala, Honduras, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Luxembourg, Malaysia, Mexico, Netherlands, New Zealand, Nicaragua, Norway, Panama, Poland, Portugal, Romania, Russian Federation, Singapore, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Kingdom, United States (1,2) /Salmeterol xinafoate/