Budesonide and formoterol

In clinical studies, concurrent administration of SYMBICORT and other drugs, such as short-acting beta 2 -agonists, intranasal corticosteroids, and antihistamines/decongestants has not resulted in an increased frequency of adverse reactions. No formal drug interaction studies have been performed with SYMBICORT. • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. (7.1) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol 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 P4503A4 The main route of metabolism of corticosteroids, including budesonide, a component of SYMBICORT, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide.

Caution should be exercised when considering the coadministration of SYMBICORT with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.9) ] .

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants SYMBICORT should be administered with 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 formoterol, a component of SYMBICORT, on the vascular system may be potentiated by these agents. In clinical trials with SYMBICORT, a limited number of COPD and asthma patients received tricyclic antidepressants, and, therefore, no clinically meaningful conclusions on adverse events can be made.

7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers (including eye drops) may not only block the pulmonary effect of beta-agonists, such as formoterol, a component of SYMBICORT, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma 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 in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 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 SYMBICORT with non-potassium-sparing diuretics.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of SYMBICORT or one of its individual components, formoterol fumarate, in pregnant women; however studies are available for the other component budesonide. In animal reproduction studies, SYMBICORT, administered by the inhalation route, was teratogenic, embryocidal, and reduced fetal weights in rats at less than the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m 2 basis.

Budesonide alone, administered by the subcutaneous route, was teratogenic, embryocidal, and reduced fetal weights in rats and rabbits at less than the MRHDID, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women have not shown that inhaled budesonide alone increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. Formoterol fumarate alone, administered by the oral route, was teratogenic in rats and rabbits at 1600 and 65,000 times the MRHDID, respectively.

Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No teratogenic, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 375 times the MRHDID. The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. 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 Embryo/Fetal risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Labor or Delivery There are no well-controlled human studies that have investigated the effects of SYMBICORT during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of SYMBICORT during labor should be…