Salmeterol precautions

List of precautions
General Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Use in labor and delivery Nursing mothers Pediatric use Geriatric use
 * Use with spacer/other devices
 * Cardiovascular/other effects
 * Metabolic effects

Use with spacer/other devices
The safety and effectiveness of salmeterol when used with a spacer or other devices have not been adequately studied. Return to top

Cardiovascular/other effects
No effect on the cardiovascular system is usually seen after the administration of inhaled salmeterol in recommended doses, but the cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood pressure, heart rate, excitement) can occur after use of salmeterol and may require discontinuation of the drug. Salmeterol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. As has been described with other beta-adrenergic agonist bronchodilators, clinically significant changes in systolic and/or diastolic blood pressure, pulse rate, and ECGs have been seen infrequently in individual patients in controlled clinical studies with salmeterol. Return to top

Metabolic effects
Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. No effects on glucose have been seen with salmeterol at recommended doses. Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen rarely during clinical studies with long-term administration of salmeterol at recommended doses. Return to top

Carcinogenesis
In an 18-month oral carcinogenicity study in CD-mice, salmeterol xinafoate at oral doses of 1.4 mg/kg and above (approximately 9 times the maximum recommended daily inhalation dose in adults based on comparison of the areas under the plasma concentration versus time curves [AUCs]) caused dose-related increases in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and cysts in the ovaries. The incidence of leiomyosarcomas was not statistically significant. No tumors were seen at 0.2 mg/kg (comparable to the maximum recommended human daily inhalation dose in adults based on comparison of the AUCs). In a 24-month inhalation and oral carcinogenicity study in Sprague Dawley rats, salmeterol caused dose-related increases in the incidence of mesovarian leiomyomas and ovarian cysts at inhalation and oral doses of 0.68 mg/kg/day and above (approximately 55 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis). No tumors were seen at 0.21 mg/kg/day (approximately 15 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Return to top

Mutagenesis
Salmeterol xinafoate produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. Return to top

Impairment of fertility
No effects on fertility were identified in male and female rats treated orally with salmeterol xinafoate at doses up to 2 mg/kg (approximately 160 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis). Return to top

Pregnancy
Pregnancy Category C No teratogenic effects occurred in the rat at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended human daily inhalation dose in adults on a mg/m2 basis). In pregnant Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 20 times the maximum recommended human daily inhalation dose in adults based on the comparison of the AUCs), salmeterol xinafoate exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation; these included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No significant effects occurred at an oral dose of 0.6 mg/kg (approximately 10 times the maximum recommended human daily inhalation dose in adults based on comparison of the AUCs). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at oral doses of 10 mg/kg (approximately 1,600 times the maximum recommended human daily inhalation dose on a mg/m2 basis). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to use in humans. There are no adequate and well-controlled studies with salmeterol in pregnant women. Salmeterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Return to top

Use in labor and delivery
There are no well-controlled human studies that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of salmeterol for prevention of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Return to top

Nursing mothers
Plasma levels of salmeterol after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in milk. However, since there is no experience with use of salmeterol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when salmeterol xinafoate is administered to a nursing woman. Return to top

Pediatric use
The safety and effectiveness of salmeterol in children younger than 12 years of age have not been established. Return to top

Geriatric use
No apparent differences in the efficacy and safety of salmeterol were observed when geriatric patients were compared with younger patients in asthma and COPD clinical trials. As with other beta2-agonists, however, special caution should be observed when using salmeterol in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug. Based on available data, no adjustment of salmeterol dosage in geriatric patients is warranted. Return to top