Landiolol

FDA Drug Information • Also known as: Rapiblyk

Brand Names: Rapiblyk
Route: INTRAVENOUS
Dosage Form: INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION RAPIBLYK (landiolol) for injection is a beta-1 adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 4 minutes). Landiolol is: [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholine-4-carbonylamino)ethylamino]propoxy]phenyl]propionate and has the following structure: The active pharmaceutical ingredient is the hydrochloride salt of landiolol, which has the empirical formula C 25 H 39 N 3 O 8 ∙ HCl and a molecular weight of 546.06 g/mol. It has two chiral centers and is used as pure S,S-enantiomer. Landiolol HCl is a white crystalline powder. It is a relatively hydrophilic compound, which is very soluble in water. RAPIBLYK is supplied as a single presentation of 280 mg landiolol (equivalent to 300 mg landiolol HCl) as a white to almost white sterile lyophilized powder for intravenous injection in a 50 mL vial. Inactive ingredients include 300 mg of mannitol and sodium hydroxide as needed to adjust pH. StructuralFormula

What Is Landiolol Used For?

1 INDICATIONS AND USAGE RAPIBLYK is indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia including atrial fibrillation and atrial flutter. 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. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Administer as an intravenous infusion in a monitored setting. ( 2.1 ) Titrate according to ventricular rate. ( 2.1 ) If normal cardiac function, start at 9 mcg/kg/min; adjust dose in 10-minute intervals as needed in increments of 9 mcg/kg/min to a maximum of 36 mcg/kg/min. ( 2.1 ) If impaired cardiac function, start at 1 mcg/kg/min; adjust dose in 15-minute intervals as needed in increments of 1 mcg/kg/min to a maximum of 36 mcg/kg/min. ( 2.1 ). 2.1 Recommended Dosage Administer RAPIBLYK as a continuous intravenous infusion, titrating as needed for heart rate control. There are limited data beyond 24 hours of use. Table 1: Dosing Normal cardiac function Impaired cardiac function Starting dose 9 mcg/kg/min 1 mcg/kg/min Titration interval 10 min 15 min Titration step 9 mcg/kg/min 1 mcg/kg/min Maximum dose 36 mcg/kg/min 36 mcg/kg/min 9 mcg/kg/min landiolol is equivalent to 9.6 mcg/kg/min landiolol hydrochloride. 2.2 Transitioning from RAPIBLYK Injection Therapy to Alternative Medications When transitioning to alternative medications consider the pharmacodynamics of the medication to which the patient is being transitioned and monitor clinical response. If switched to an oral beta-blocker, the dosage of RAPIBLYK can be reduced as follows: Ten minutes after administration of the oral beta-blocker, reduce the infusion rate of RAPIBLYK by 50%. If satisfactory control is maintained for at least one hour, discontinue RAPIBLYK. 2.3 Instructions for Preparation Use appropriate aseptic technique for reconstitution. Reconstitute each 280 mg vial of RAPIBLYK with 50 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Gently swirl to dissolve contents. Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be a clear, colorless solution. Use immediately. The reconstituted RAPIBLYK solution storage conditions are described in Table 2. Discard unused portion. Table 2: Reconstituted RAPIBLYK Solution Storage and Use Conditions Diluent used to Prepare Solution Reconstituted RAPIBLYK Solution Storage and Use Conditions 50 mL of 0.9% Sodium Chloride Injection, USP Use within 4 hours at room temperature (25°C, 77°F) 50 mL of 5% Dextrose Injection, USP Use within 48 hours at room temperature (25°C, 77°F) 2.4 Administration Following reconstitution, the product contains 280 mg landiolol/50 mL = 5.6 mg/mL. The infusion rate can be calculated as: Infusion rate (mL/hour) = target dose (mcg/kg/min) × body weight (kg) / 93

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The most common adverse reaction (9.9%) is hypotension ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AOP Orphan Pharmaceuticals at [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Landiolol injection was studied in 19 placebo-controlled clinical trials involving 1,761 patients (in a variety of clinical in-patient settings) with supraventricular tachycardia or at high risk for supraventricular tachycardia. The most important and common adverse reaction is hypotension, which occurred in 9.9% of patients receiving RAPIBLYK vs. 1% in those receiving placebo [see Warnings and Precautions ( 5.1 )] .

Drug Interactions

7 DRUG INTERACTIONS Negative Inotropes and Chronotropes: Avoid ( 7.1 ) Sympathomimetics, Positive Inotropes and Vasoconstrictors: Avoid ( 7.2 ) Catecholamine Depleting Drugs: Monitor blood pressure and heart rate ( 7.3 ). 7.1 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 [see Warnings and Precautions ( 5.2 )( 5.3 )] . 7.2 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. 7.3 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 [see Warnings and Precautions ( 5.1 )] .

Contraindications

4 CONTRAINDICATIONS RAPIBLYK is contraindicated in patients with: Severe sinus bradycardia, sick sinus syndrome, heart block greater than first degree [see Warnings and Precautions ( 5.2 )] . Decompensated heart failure [see Warnings and Precautions ( 5.3 )] . Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest. Pulmonary hypertension: May precipitate cardiorespiratory decompensation. Hypersensitivity reactions, including anaphylaxis, to landiolol or any of the inactive ingredients 5.3 Severe sinus bradycardia ( 4 ) Sick sinus syndrome ( 4 ) Heart block greater than first degree ( 4 ) Decompensated heart failure ( 4 ) Cardiogenic shock ( 4 ) Pulmonary hypertension ( 4 ) Known hypersensitivity to landiolol ( 4 )

Pregnancy and Breastfeeding

8.1 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...

Overdosage

10 OVERDOSAGE 10.1 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 children) may occur. 10.2 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied RAPIBLYK is supplied as a white to almost white, preservative-free, lyophilized powder in single dose vials containing 280 mg landiolol for injection (equivalent to 300 mg landiolol HCl). Each vial is supplied in a carton NDC 84381-110-01 16.2 Storage Store unreconstituted product at 20°C to 25°C (68ºF to 77ºF) [see USP Controlled Room Temperature], with excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Manufactured for: AOP Orphan Pharmaceuticals GmbH Leopold-Ungar-Platz 2 1190 Vienna Austria Part number/ 16.1 How Supplied RAPIBLYK is supplied as a white to almost white, preservative-free, lyophilized powder in single dose vials containing 280 mg landiolol for injection (equivalent to 300 mg landiolol HCl). Each vial is supplied in a carton NDC 84381-110-01

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.