Glycopyrrolate and formoterol

No formal drug interaction studies have been performed with BEVESPI AEROSPHERE. • Other adrenergic drugs may potentiate effect: Use with caution ( 5.3 , 7.1 ) • Xanthine derivatives, steroids, diuretics or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. ( 7.2 , 7.3 ) • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium sparing diuretics may worsen with concomitant beta 2 -agonists. ( 7.3 ) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system.

( 7.4 ) • Beta-blockers: Use with caution and only when medically necessary. ( 7.5 ) • Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administrations of BEVESPI AEROSPHERE with other anticholinergic-containing drugs. ( 7.6 )

7.1 Adrenergic Drugs If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol, a component of BEVESPI AEROSPHERE, may be potentiated [see Warnings and Precautions (5.3) ] .

7.2 Xanthine Derivatives, Steroids, or Diuretics Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of beta 2 adrenergic agonists such as formoterol, a component of BEVESPI AEROSPHERE.

7.3 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 2 -agonists, especially when the recommended dose of the beta 2 -agonist is exceeded. Approximately 17% of subjects were taking non-potassium sparing diuretics during the two 24-week placebo-controlled trials in subjects with COPD. The incidence of adverse events in subjects taking non-potassium-sparing diuretics was similar between BEVESPI AEROSPHERE and placebo treatment groups.

In addition, there was no evidence of a treatment effect on serum potassium with BEVESPI AEROSPHERE compared to placebo in subjects taking non-potassium sparing diuretics during the two 24-week trials. However, caution is advised in the coadministration of BEVESPI AEROSPHERE with non-potassium-sparing diuretics.

7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs BEVESPI AEROSPHERE, as with other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.

7.5 Beta-Blockers Beta-adrenergic receptor antagonists (beta-blockers) and BEVESPI AEROSPHERE may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta 2 -agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

7.6 Anticholinergics There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of BEVESPI AEROSPHERE with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions ( 5.7 , 5.8 ) and Adverse Reactions (6) ].

8.1 Pregnancy Risk Summary There are no adequate and well-controlled trials of BEVESPI AEROSPHERE or its individual components, glycopyrrolate and formoterol fumarate, in pregnant women to inform a drug-associated risk. In animal reproduction studies, glycopyrrolate alone, administered by the subcutaneous route in rats and rabbits, did not cause structural abnormalities or affect fetal survival at exposures approximately 2700 and 5400 times from the maximum recommended human daily inhalation dose (MRHDID), respectively. Glycopyrrolate had no effects on the physical, functional, and behavioral development of rat pups with exposures up to 2700 times the MRHDID.

Formoterol fumarate alone, administered by the oral route in rats and rabbits, caused structural abnormalities at 1500 and 61,000 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 structural abnormalities, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 350 times the MRHDID.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Labor or Delivery : There are no well-controlled human trials that have investigated the effects of BEVESPI AEROSPHERE on preterm labor or labor at term. Because beta 2 -agonists may potentially interfere with uterine contractility, BEVESPI AEROSPHERE should be used during labor only if the potential benefit justifies the potential risk.

Data Animal Data Glycopyrrolate In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 17, glycopyrrolate produced no structural abnormalities or effects on fetal survival; however, slight reductions of fetal body weight in the presence of maternal toxicity at the highest tested dose that was 2700 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 10,000 mcg/kg/day). Fetal body weights were unaffected with doses up to 270 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 1000 mcg/kg/day). Maternal toxicity was observed with doses 270 times…