Salmeterol

7 DRUG INTERACTIONS • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of cardiovascular effects. ( 7.1 ) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of salmeterol on vascular system. ( 7.2 ) • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 ) • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 )

7.1 Inhibitors of Cytochrome P450 3A4 Salmeterol is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur. In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and C max increased 1.4-fold).

Three (3) subjects were withdrawn due to beta 2 -agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants SEREVENT DISKUS 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.

7.3 Beta-adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of SEREVENT DISKUS with non–potassium-sparing diuretics.

8.1 Pregnancy Risk Summary The available data from published epidemiological studies and case reports with use of SEREVENT DISKUS in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Beta‑agonists may interfere with uterine contractility. There are clinical considerations in pregnant women with asthma (see Clinical Considerations) . Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta‑adrenoceptor stimulation at maternal doses approximately 50 times the maximum recommended human daily inhaled dose (MRHDID) on an AUC basis.

These adverse effects generally occurred at large multiples of the MRHDID when salmeterol was administered by the oral route to achieve high systemic exposures. No such effects occurred at an oral salmeterol dose approximately 20 times the MRHDID (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Severe asthma during pregnancy has been associated with maternal mortality, fetal mortality, or both. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor and Delivery: There are no adequate and well-controlled human studies that have evaluated the effects of SEREVENT DISKUS during labor and delivery.

Because of the potential for beta-agonist interference with uterine contractility, use of SEREVENT DISKUS during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Data Human Data: While available studies cannot definitively establish the absence of risk, published data from epidemiological studies and case reports have not established an association with SEREVENT DISKUS use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. The available studies have methodologic limitations, including retrospective data collection and inconsistent comparator…