RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Warnings and Precautions, Hypoglycemia (5.6) 06/2023

---

DRUG INTERACTIONS SECTION

Highlight: * Digitalis glycosides: Risk of bradycardia (7)

• Anticholinesterases: Prolongs neuromuscular blockade (7)
• Antihypertensive agents: Risk of rebound hypertension (7)
• Sympathomimetic drugs: Dose adjustment needed (7)
• Vasoconstrictive and positive inotropic effect substances: Avoid concomitant use (7)

7 DRUG INTERACTIONS

Concomitant use of esmolol hydrochloride injection with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate esmolol hydrochloride injection’s effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below.) Esmolol hydrochloride injection should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to:

• Digitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride injection leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride injection pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia.
• Anticholinesterases: Esmolol hydrochloride injection prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately prolonged clinical duration and recovery index of mivacurium.
• Antihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clonidine-, guanfacine-, or moxonidine-withdrawal rebound hypertension. If, during concomitant use of a beta blocker, antihypertensive therapy needs to be interrupted or discontinued, discontinue the beta blocker first, and the discontinuation should be gradual.
• Calcium channel antagonists: In patients with depressed myocardial function, use of esmolol hydrochloride injection with cardiodepressant calcium channel antagonists (e.g., verapamil) can lead to fatal cardiac arrests.
• Sympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of esmolol hydrochloride injection.
• Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use esmolol hydrochloride injection to control tachycardia in patients receiving drugs that are vasoconstrictive and have positive inotropic effects, such as epinephrine, norepinephrine, and dopamine.

---

ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (incidence >10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension (6)

To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reaction rates are based on use of esmolol hydrochloride injection in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important and common adverse effect has been hypotension [see Warnings and Precautions (5.1)]. Deaths have been reported in post-marketing experience occurring during complex clinical states where esmolol hydrochloride injection was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5)].

Table 3 Clinical Trial Adverse Reactions (Frequency ≥3%)

Clinical Trial Adverse Reactions (Frequency <3%)
Psychiatric Disorders

Confusional state and agitation (~2%)
Anxiety, depression and abnormal thinking (<1%)

Nervous System Disorders

Headache (~ 2%)

Paresthesia, syncope, speech disorder, and lightheadedness (<1%)

Convulsions (<1%), with one death

Vascular Disorders

Peripheral ischemia (~1%)

Pallor and flushing (<1%)

Gastrointestinal Disorders

Vomiting (~1%)
Dyspepsia, constipation, dry mouth, and abdominal discomfort (<1%)

Renal and Urinary Disorders

Urinary retention (<1%)

6.2 Post-Marketing Experience

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported in the post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.

Cardiac Disorders
Cardiac arrest, Coronary arteriospasm

Skin and Subcutaneous Tissue Disorders
Angioedema, Urticaria, Psoriasis

---