Rapiblyk Drug Information

is indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia including atrial fibrillation and atrial flutter, and pediatric patients with supraventricular tachycardia. RAPIBLYK is a beta adrenergic blocker indicated for the short-term reduction of ventricular rate in: adults with supraventricular tachycardia including atrial fibrillation and atrial flutter, and pediatric patients with supraventricular tachycardia.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the 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 safety of RAPIBLYK was evaluated in 19 placebo-controlled clinical trials involving 1,761 adult patients (in a variety of clinical in-patient settings) with supraventricular tachycardia or at high risk for supraventricular tachycardia. The most common adverse reaction is hypotension, which occurred in 9.9% of patients receiving RAPIBLYK vs. 1% in those receiving placebo.

In a single-arm, unblinded clinical trial in 60 pediatric patients who received RAPIBLYK, the most common adverse reaction was hypotension, which occurred in 10% of patients aged birth to <18 years receiving RAPIBLYK. Hypotension was also the most common adverse reaction leading to treatment discontinuation.

Negative Inotropes and Chronotropes

Avoid concomitant use of RAPIBLYK with negative inotropes and medications that slow heart rate or cardiac conduction. Beta-blockers, like RAPIBLYK, can cause depression of myocardial contractility and increase the risk of bradycardia or heart block. Concomitant use of RAPIBLYK with negative inotropes or chronotropes may augment these effects .

Sympathomimetics, Positive Inotropes and Vasoconstrictors Beta adrenergic agonists will antagonize the effects

of RAPIBLYK and may attenuate the heart rate lowering effects of RAPIBLYK. Positive inotropes and vasoconstrictors may attenuate the heart rate and blood pressure lowering effects of RAPIBLYK.

Catecholamine Depleting Drugs Observe patients treated with

RAPIBLYK plus a catecholamine depletor (e.g., reserpine, monoamine oxidase inhibitors) for hypotension or marked bradycardia, which may cause vertigo, syncope, or postural hypotension. Catecholamine depleting drugs may have an additive effect when given with beta-blockers, which may increase the risk of hypotension or marked bradycardia related vertigo, syncope, or postural hypotension .

Pregnancy Risk Summary The available published data on RAPIBLYK use in pregnant women are insufficient to inform a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Landiolol exposure was limited to a single injection at the time of Cesarean delivery in a small clinical trial. Neonatal bradycardia, hypoglycemia, and respiratory depression have been observed with use of beta-blockers in pregnancy near the time of delivery (see Clinical Considerations). Administration of landiolol to pregnant rats showed distribution of landiolol to the placenta and the fetus.

In animal reproduction studies, no embryo-fetal toxicity was observed in rats or rabbits during the period of organogenesis at landiolol exposure in rats approximately 2.7 times human exposure at the maximum recommended human dose (MRHD) (see Data). The 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 Fetal/Neonatal Adverse Reactions Landiolol crosses the placenta in rats. Neonates born to mothers who are receiving landiolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Monitor neonates exposed to landiolol during pregnancy and labor for hypotension, hypoglycemia, bradycardia, and respiratory depression and manage accordingly.

Data Animal Data Landiolol HCl was administered intravenously to pregnant rats (25, 50, or 100 mg/kg/day from gestation day 7 to 17) and rabbits (25, 50, or 100 mg/kg/day from gestation day 8 to 18). No adverse embryo-fetal effects were observed in rats at the landiolol HCl dose of 25 mg/kg/day, resulting in systemic landiolol exposure (AUC) of approximately 2.7-times the exposure at the MRHD. In rabbits, no adverse embryo-fetal effects were detected at the landiolol HCl dose of 100 mg/kg/day; the resulting systemic landiolol exposure (AUC) at this dose level was not determined. In a prenatal and postnatal development study in rats, landiolol HCl was administered intravenously at 25, 50, or 100 mg/kg/day from gestation day 17 to postpartum/lactation day 20. A decrease in the viability index for the offspring on postpartum day 4 was observed for the high dose group. No effect on pre/post-natal development was observed at 50 mg/kg dose, which represents landiolol exposures approximately 5.4 times the human exposure at the MRHD.

Pediatric Use The safety and effectiveness of RAPIBLYK for the short-term reduction of ventricular rate in supraventricular tachycardia have been established in pediatric patients. Use of RAPIBLYK is supported by evidence from adequate and well-controlled studies in adults, with additional pharmacokinetic, pharmacodynamic and safety data from a descriptive single-arm, unblinded study that enrolled 60 pediatric patients from birth to <18 years of age. In this study, treatment with RAPIBLYK resulted in a >20% reduction in ventricular rate from baseline in patients with atrioventricular reentrant tachycardia (6/7, 85.7%), focal atrial tachycardia (4/8, 50%), junctional ectopic tachycardia (3/12, 25%), and in inappropriate sinus tachycardia (10/30, 33.3%).

Severe sinus bradycardia Sick sinus syndrome Heart block greater than first degree

Decompensated heart failure Cardiogenic shock Pulmonary hypertension Known hypersensitivity to landiolol

Signs and Symptoms of Overdose Overdoses of

RAPIBLYK injection can cause adverse cardiac and central nervous system effects. These adverse effects may precipitate severe signs, symptoms, sequelae, and complications such as severe cardiac and respiratory failure, including shock and coma, and may be fatal. Continuous monitoring of the patient is required.

Cardiac adverse effects include bradycardia, atrioventricular block (1-, 2-, 3-degree), junctional rhythms, intraventricular conduction delays, decreased cardiac contractility, hypotension, cardiac failure (including cardiogenic shock), cardiac arrest/asystole, and pulseless electrical activity. Central nervous system adverse effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma. In addition, bronchospasm, hyperkalemia, and hypoglycemia (especially in pediatric patients) may occur.

Treatment Recommendations

Because of its approximately 4-minute elimination half-life, the first step in the management of toxicity should be to discontinue RAPIBLYK infusion. Then, based on the observed clinical effects, consider the following general measures: Bradycardia Consider intravenous administration of atropine or another anticholinergic drug or cardiac pacing. Cardiac Failure Consider intravenous administration of a diuretic or digitalis glycoside.

In shock resulting from inadequate cardiac contractility, consider intravenous administration of dopamine, dobutamine, isoproterenol, milrinone or inamrinone. Symptomatic Hypotension Consider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine. Bronchospasm Consider intravenous administration of a beta agonist or a theophylline derivative.