Landiolol Hydrochloride: A Comprehensive Pharmacological and Clinical Review

1. Introduction to Landiolol Hydrochloride

Landiolol Hydrochloride is an ultra-short-acting, highly β1​-selective intravenous (IV) adrenergic antagonist. It is specifically formulated for the rapid control of heart rate in acute clinical settings where immediate and titratable β-blockade is imperative.[1] Its principal utility is in the management of supraventricular tachyarrhythmias (SVT), including atrial fibrillation and atrial flutter, particularly during the perioperative and postoperative periods, or in other critical care scenarios demanding short-term ventricular rate control.[2] The defining characteristics of Landiolol—its ultra-short duration of action and high β1​-selectivity—underpin its specialized therapeutic niche in acute care, distinguishing it from beta-blockers typically employed for chronic management.[1]

Landiolol Hydrochloride is classified as a beta-adrenergic receptor antagonist, commonly referred to as a beta-blocker, exhibiting pronounced selectivity for β1​-adrenergic receptors.[1] In the Vaughan Williams classification of antiarrhythmic drugs, it is categorized as a Class II agent.[7] The therapeutic importance of Landiolol is derived from its distinctive pharmacokinetic profile, characterized by an ultra-short elimination half-life that facilitates rapid onset and offset of action, and its pharmacodynamic properties, notably high β1​-selectivity, which leads to targeted cardiac effects with a potentially reduced incidence of systemic side effects. This combination offers considerable advantages over less selective or longer-acting beta-blockers in critical care and perioperative medicine, where precise and rapidly reversible hemodynamic control is often crucial.[1] The development of a drug with such a profile addresses the limitations of traditional beta-blockers, which often have longer half-lives and less selectivity, potentially leading to prolonged effects and undesirable side effects such as bronchospasm or sustained hypotension, especially in hemodynamically sensitive patients or during acute, transient tachyarrhythmias.

The development and regulatory approval of Landiolol have followed a phased global trajectory. It was first approved for medical use in Japan in 2002 under the brand name Onoact, primarily for the treatment of intraoperative tachyarrhythmias.[1] Its introduction into Western markets occurred significantly later. It received approval in Europe (e.g., as Rapibloc, marketed by Amomed Pharma GmbH) for indications including SVT and rapid ventricular rate control in atrial fibrillation and atrial flutter.[3] More recently, Landiolol gained approval in Canada in April 2024 [9] and in the United States on November 22/27, 2024, under the brand name Rapiblyk (marketed by AOP Orphan Pharmaceuticals GmbH) for similar indications.[5] The original developer of Landiolol is Ono Pharmaceutical [7], with companies such as AOP Orphan Pharmaceuticals GmbH and formerly Eagle Pharmaceuticals having played roles in its development and marketing in other regions.[5] The considerable time lag between its initial approval in Japan and its subsequent approvals in North America and Europe may reflect differing regulatory requirements, market priorities, or the need for additional region-specific clinical trials, as suggested by the FDA approval of Rapiblyk being based on five studies.[6] This gradual global rollout suggests a focused strategy on specific therapeutic niches where Landiolol's unique properties offer distinct advantages.

2. Chemical and Pharmaceutical Profile

A clear understanding of the chemical and pharmaceutical properties of Landiolol Hydrochloride is essential for its safe and effective use.

Nomenclature:

Landiolol Hydrochloride is identified by several names across different contexts:

• International Nonproprietary Name (INN): Landiolol.[1]
• **Chemical Name (IUPAC):**methyl 3-propoxy]phenyl]propanoate;hydrochloride.[15]
• Synonyms and Trade Names: Common synonyms include ONO 1101 hydrochloride and Landiolol HCl. It is marketed under various trade names globally, including Onoact (Japan), Rapibloc (Europe), and Rapiblyk (USA).[3]
• CAS Number: The Chemical Abstracts Service registry number for Landiolol hydrochloride is 144481-98-1.[7]

Chemical Structure:

Landiolol belongs to the chemical class of morpholines.15 Its structure is characterized by:

• SMILES Notation: CC1(OCC@HCOC(=O)CCC2=CC=C(C=C2)OCC@HO)C.Cl.[15]
• InChIKey: DLPGJHSONYLBKP-IKGOIYPNSA-N.[15] The molecule contains an ester linkage, which is critical for its rapid metabolism, and multiple chiral centers. Landiolol is specifically the pure S-enantiomer.[1] The selection of the S-enantiomer is a deliberate design choice, likely contributing to its high β1​-selectivity and potency, and potentially reducing off-target effects and hypotensive side effects that might be associated with a racemic mixture or a less pure enantiomeric form.[10] This structural feature, particularly the ester moiety, is directly responsible for its ultra-short half-life due to rapid hydrolysis by esterases in the blood and tissues.[1]

Physicochemical Properties:

Key physicochemical properties of Landiolol Hydrochloride are summarized in Table 1. It is typically a white to almost white powder.3 Its solubility in water is predicted to be 0.163 mg/mL.9

Table 1: Chemical and Physical Properties of Landiolol Hydrochloride

Property	Value	Reference(s)
IUPAC Name	methyl 3-propoxy]phenyl]propanoate;hydrochloride	15
Other Names/Synonyms	Landiolol, ONO 1101, Onoact, Rapibloc, Rapiblyk	1
CAS Number	144481-98-1 (for hydrochloride)	7
Molecular Formula	C25​H39​N3​O8​⋅HCl (Hydrochloride)	7
Molecular Weight	546.05 g/mol (Hydrochloride)	7
	509.60 g/mol (Base)	14
Appearance	White to almost white powder	3
Water Solubility (Predicted)	0.163 mg/mL	9
pKa (Strongest Basic)	15.05 (Predicted)	9
logP (Predicted)	0.95 (ALOGPS), -0.33 (ChemAxon)	9

Formulations and Presentations:

Landiolol Hydrochloride is available for intravenous administration as:

• A powder for solution for injection.[3]
• A concentrate for solution for injection.[15] For example, Rapibloc is supplied as a 300 mg powder for solution for infusion, which, upon reconstitution with 50 mL of a compatible diluent, yields a solution containing 6 mg/mL of landiolol hydrochloride.[3] Similarly, Rapiblyk is available as a lyophilized powder in single-dose vials containing 280 mg of landiolol (equivalent to 300 mg of landiolol hydrochloride).[6] These formulations are designed for administration in controlled hospital settings.

3. Mechanism of Action

Landiolol Hydrochloride exerts its therapeutic effects through selective blockade of β1​-adrenergic receptors.

Detailed Elucidation of Beta-Adrenergic Blockade:

Landiolol is a potent and highly selective β1​-adrenergic receptor antagonist.1 It competitively inhibits the binding of endogenous catecholamines, such as adrenaline (epinephrine) and noradrenaline (norepinephrine), to β1​-receptors. These receptors are predominantly located in cardiac tissue, and their stimulation by catecholamines leads to increased heart rate, myocardial contractility, and atrioventricular (AV) conduction velocity.1 By blocking these receptors, Landiolol effectively attenuates the sympathetic nervous system's drive on the heart.1 At a cellular level, β1​-receptor blockade by Landiolol interferes with the Gs protein-coupled signaling pathway. This prevents the activation of adenylyl cyclase, thereby reducing the intracellular conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Lower cAMP levels lead to decreased activation of protein kinase A (PKA). PKA normally phosphorylates various intracellular proteins, including L-type calcium channels and proteins involved in calcium handling by the sarcoplasmic reticulum (e.g., phospholamban). Consequently, Landiolol's action results in reduced calcium influx into cardiac myocytes during the plateau phase of the action potential and altered intracellular calcium cycling.8 This ultimately translates into its negative chronotropic, dromotropic, and, to a lesser extent, inotropic effects.

High β1​-Selectivity and its Clinical Implications:

A hallmark of Landiolol is its exceptionally high selectivity for β1​-receptors over β2​-receptors. The selectivity ratio for β1​ versus β2​ blockade is reported to be 255:1.1 This is substantially higher than that of other commonly used intravenous beta-blockers such as esmolol (selectivity ratio approximately 33:1) and metoprolol.1 This high degree of selectivity has several important clinical implications:

1. Reduced Risk of Bronchoconstriction: β2​-adrenergic receptors are predominantly located in the smooth muscle of the bronchi. Blockade of these receptors can lead to bronchoconstriction, which is a significant concern in patients with reactive airway diseases such as asthma or chronic obstructive pulmonary disease (COPD). Landiolol's high β1​-selectivity minimizes its interaction with β2​-receptors, thereby reducing the risk of inducing or exacerbating bronchospasm. While caution is still advised in these patients, Landiolol is generally considered a safer option when beta-blockade is necessary.[1]
2. Minimized Peripheral Vasoconstriction and Metabolic Disturbances: β2​-receptors are also involved in mediating vasodilation in certain vascular beds and play a role in metabolic processes, including glycogenolysis and gluconeogenesis. Non-selective beta-blockers or those with less β1​-selectivity can cause peripheral vasoconstriction and may impair glucose metabolism, potentially masking symptoms of hypoglycemia. Landiolol's focused action on β1​-receptors is associated with less impact on blood pressure and a lower likelihood of these peripheral and metabolic side effects.[1]
3. Preservation of β2​-Mediated Coronary Vasodilation: Pharmacological stimulation of β2​-receptors contributes to coronary vasodilation. A highly cardio-selective β1​-blocker like Landiolol reduces myocardial oxygen demand (by decreasing heart rate and contractility) while potentially allowing for β2​-receptor-mediated coronary exercise hyperemia, which could be beneficial in maintaining coronary blood flow.[1]

The pronounced β1​-selectivity is a cornerstone of Landiolol's favorable therapeutic index in specific clinical scenarios, allowing for targeted cardiac effects while minimizing unwanted systemic actions.

Molecular Targets:

The primary molecular target of Landiolol is the β1​-adrenergic receptor, encoded by the ADRB1 gene.7

Effects on Cardiac Electrophysiology and Contractility:

Landiolol's interaction with β1​-receptors leads to distinct effects on cardiac function:

• Negative Chronotropic Effect: It significantly reduces heart rate by decreasing the spontaneous depolarization rate (automaticity) of the sinoatrial (SA) node, the heart's primary pacemaker.[1]
• Negative Dromotropic Effect: It slows electrical conduction velocity through the atrioventricular (AV) node and prolongs the AV nodal refractory period. This action is crucial for controlling ventricular response rates in atrial tachyarrhythmias like atrial fibrillation and flutter.[1]
• Negative Inotropic Effect: Landiolol decreases myocardial contractility.[8] However, it is consistently described as having a "limited negative inotropic potential" relative to its potent negative chronotropic effects.[1] This characteristic suggests that Landiolol can effectively reduce heart rate with a proportionally smaller depression of cardiac pump function, which is particularly advantageous in patients with compromised ventricular function. Landiolol does not possess membrane-stabilizing activity (MSA) or intrinsic sympathomimetic activity (ISA) in vitro, which are properties found in some other beta-blockers that can modify their overall pharmacodynamic profile.[1]

The pharmacological profile of Landiolol, characterized by high β1​-selectivity and a more pronounced effect on heart rate and AV conduction than on myocardial contractility, makes it a valuable agent for acute rate control, especially in patients where preserving cardiac output is a priority. Furthermore, unlike some beta-blockers such as esmolol, Landiolol does not appear to significantly induce the re-expression of β-receptors. This may reduce the likelihood of developing drug tolerance during prolonged infusions and potentially mitigate rebound tachycardia upon abrupt discontinuation [1], enhancing its safety and predictability in clinical use.

4. Pharmacokinetics (PK)

The pharmacokinetic profile of Landiolol Hydrochloride is central to its utility as an ultra-short-acting intravenous agent, characterized by rapid onset, predictable metabolism, and swift elimination.

Table 2: Key Pharmacokinetic Parameters of Landiolol Hydrochloride

Parameter	Value	Reference(s)
Route of Administration	Intravenous (bolus and/or continuous infusion)	3
Onset of Action	Immediate with bolus; 2-5 min with loading dose infusion; 10-20 min with standard continuous infusion	1
Time to Steady State	Approx. 15 min (continuous infusion); 2-5 min (with loading dose)	17
Volume of Distribution (Vd)	0.3 - 0.4 L/kg	17
Protein Binding	<10% (dose-dependent)	17
Primary Metabolic Pathway	Ester hydrolysis by plasma pseudocholinesterases and liver carboxylesterases	1
Key Metabolites	M1 (carboxylic acid, inactive), M2 (further oxidized M1, inactive)	1
Elimination Half-life (t1/2​)	Approx. 3-4 minutes (mean); Range 2.3-4.52 minutes	1
Total Body Clearance	57 - 66.1 mL/kg/min	17
Primary Route of Excretion	Urine (primarily as metabolites M1 and M2)	17

Absorption (Intravenous Administration Context):

Being an intravenously administered drug, Landiolol achieves complete bioavailability. Upon IV administration, either as a continuous infusion or an initial bolus followed by continuous infusion, it rapidly enters systemic circulation.3 Steady-state blood concentrations are typically reached within approximately 15 minutes of initiating a continuous infusion. This can be expedited to 2-5 minutes if a loading dose regimen is employed.17 Peak plasma concentrations (Cmax) of Landiolol are dose-dependent. For instance, a single 100 mcg/kg bolus in healthy volunteers resulted in a mean Cmax of 0.294 mcg/mL.16

Distribution:

Landiolol exhibits a relatively small volume of distribution (Vd), approximately 0.3-0.4 L/kg.17 This suggests that its distribution is largely confined to the plasma and extracellular fluid compartments, rather than extensive tissue penetration. Plasma protein binding of Landiolol is low, reported to be less than 10%, and is dose-dependent.17 The low protein binding means a higher fraction of the drug is free and pharmacologically active, potentially contributing to its rapid onset of action and clearance.

Metabolism:

The metabolism of Landiolol is rapid and extensive, which is the primary determinant of its ultra-short half-life. It is primarily metabolized in the plasma by pseudocholinesterases and in the liver by carboxylesterases via hydrolysis of its ester moiety.1 This enzymatic degradation is a key feature of its pharmacological design.

The hydrolysis of the ester linkage yields a ketal component (which is further broken down into glycerol and acetone) and a carboxylic acid metabolite, designated M1. Metabolite M1 subsequently undergoes beta-oxidation to form metabolite M2, a substituted benzoic acid.1 Crucially, both M1 and M2 metabolites possess negligible β-blocking activity, estimated to be 1/200th or less than that of the parent compound Landiolol.1 This ensures that the therapeutic effect is primarily due to the parent drug and terminates rapidly upon its metabolism.

In vitro studies have indicated that Landiolol and its metabolites do not significantly inhibit the metabolic activity of major cytochrome P450 (CYP450) enzymes.1 This characteristic suggests a low potential for CYP450-mediated drug-drug interactions, a significant advantage in critically ill or perioperative patients who are often receiving multiple medications. The primary reliance on esterases for metabolism distinguishes Landiolol from many other cardiovascular drugs that are substrates or modulators of the CYP450 system.

Elimination:

The elimination of Landiolol and its metabolites is predominantly via the kidneys into the urine.17 Approximately 75% of an administered dose is excreted in the urine within 4 hours (with 54.4% as M1 and 11.5% as M2). Greater than 99% of the dose and its major metabolites are excreted within 24 hours.17

Landiolol is characterized by an ultra-short elimination half-life (t1/2​), consistently reported to be in the range of 3 to 4.5 minutes across various studies and patient populations.1 This rapid elimination is dosage-independent.16 The total body clearance of Landiolol is high, with values reported around 57 mL/kg/min at steady state and 66.1 mL/kg/min after a bolus dose.17

The entire pharmacokinetic profile—rapid hydrolysis by ubiquitous esterases, low protein binding, small Vd, high clearance, and swift urinary excretion of inactive metabolites—indicates a drug intentionally designed for rapid inactivation and removal. This ensures minimal risk of drug accumulation, even with continuous infusions (within recommended durations), and a highly predictable offset of action upon discontinuation, facilitating rapid recovery from any potential dose-related adverse effects.

Linearity and Dose-Proportionality:

Landiolol exhibits a linear pharmacokinetic-pharmacodynamic relationship across its recommended dosage range.17 Studies have confirmed that maximum blood concentrations and the area under the concentration-time curve (AUC) increase in a dose-dependent manner.16 This linearity simplifies dosing and titration, making its effects predictable and manageable in clinical practice.

5. Pharmacodynamics (PD)

The pharmacodynamic profile of Landiolol Hydrochloride is characterized by its rapid, selective, and titratable effects on the cardiovascular system.

Onset and Offset of Action (Ultra-Rapid):

Landiolol demonstrates an ultra-rapid onset of action. Following intravenous administration, a decrease in heart rate can be observed almost immediately, particularly with a bolus dose, or within 2-4 minutes when a loading dose infusion is used. Steady-state effects, such as heart rate reduction, are typically established within 10-20 minutes of initiating a continuous infusion.1

Equally important is its rapid offset of action. Due to its ultra-short elimination half-life, the pharmacological effects of Landiolol diminish quickly upon discontinuation of the infusion. Heart rate typically returns to baseline levels within 30 minutes after the infusion is stopped.1 This rapid on/off kinetic profile is a defining feature of Landiolol, allowing for precise titration to achieve the desired therapeutic effect and enabling swift reversal of its actions if necessary, such as in the event of excessive bradycardia or hypotension.

Dose-Response Relationships:

Landiolol exhibits a predictable and linear pharmacokinetic-pharmacodynamic relationship.17 The extent of heart rate reduction is dose-dependent; increasing the infusion rate leads to a greater decrease in heart rate, allowing clinicians to titrate the drug to the desired physiological endpoint.16 This predictability is crucial for managing acute tachyarrhythmias effectively while minimizing the risk of adverse hemodynamic consequences.

Effects on Heart Rate, Blood Pressure, and Myocardial Contractility:

• Heart Rate: Landiolol exerts a potent negative chronotropic effect, leading to a significant and rapid decrease in heart rate. This is its primary therapeutic action and the main objective of its use in tachyarrhythmias.[1]
• Blood Pressure: Landiolol is generally described as having a less pronounced negative effect on blood pressure compared to other beta-blockers, particularly at doses effective for heart rate control.[1] This relative cardiovascular stability is attributed to its high β1​-selectivity and limited negative inotropic effects. However, hypotension remains the most frequently observed adverse drug reaction, underscoring the need for continuous blood pressure monitoring during its administration.[3]
• Myocardial Contractility: Landiolol possesses limited negative inotropic potential.[1] This means that while it can reduce the force of myocardial contraction to some extent, this effect is less significant compared to its impact on heart rate. This characteristic is particularly beneficial in patients with compromised cardiac function where excessive depression of contractility could be detrimental.

The pharmacodynamic profile of Landiolol is thus optimized for effective and rapid heart rate control with a potentially wider safety margin concerning hemodynamic depression (blood pressure and contractility) compared to less selective or more negatively inotropic beta-blockers. The ability to fine-tune the therapeutic effect through precise titration, facilitated by its rapid onset and offset, is a key advantage in acute care settings.

6. Therapeutic Indications and Clinical Use

Landiolol Hydrochloride is indicated for specific acute cardiovascular conditions where rapid and short-term control of ventricular rate is necessary.

Approved Indications:

The primary approved indications for Landiolol Hydrochloride across various regulatory regions (including Japan, Europe, USA, and Canada) generally encompass:

• Supraventricular Tachycardia (SVT): For the short-term reduction of ventricular rate in adult patients.[1]
• Atrial Fibrillation and Atrial Flutter: For the rapid control of ventricular rate in patients during perioperative (intraoperative, postoperative) periods, or in other circumstances where short-term control of ventricular rate with a short-acting agent is desirable.[3] It is also used for the prevention of postoperative atrial fibrillation (POAF) in certain settings, such as after cardiac surgery.[18]
• Non-compensatory Sinus Tachycardia: In situations where, in the physician's judgment, the rapid heart rate requires specific intervention and is not a physiological response to a condition like hypovolemia or fever.[3]

These indications consistently reflect Landiolol's utility in the acute management of rapid heart rhythms where prompt, titratable, and temporary rate control is the therapeutic goal.

Context of Use:

Landiolol Hydrochloride is exclusively used in settings where continuous monitoring and the ability to manage acute cardiovascular changes are available:

• Critical Care Settings: Intensive care units (ICUs), cardiac critical care units (CCCUs).[2]
• Perioperative Management: Intraoperatively and postoperatively, particularly following cardiac surgery, to manage or prevent tachyarrhythmias.[3]
• Emergency Departments: For acute stabilization of patients with relevant tachyarrhythmias.[6] It is explicitly stated that Landiolol is intended for short-term use and is not suitable for chronic management of arrhythmias.[3] Administration must be performed by, or under the supervision of, healthcare professionals appropriately trained in its use and in the management of its potential adverse effects, within a monitored environment.[3]

The focus on acuity and precise control is a direct consequence of Landiolol's pharmacokinetic and pharmacodynamic properties. Its ultra-short action and high selectivity make it ideal for dynamic clinical situations where longer-acting beta-blockers might be less appropriate due to their prolonged effects and potential for sustained hemodynamic compromise if the patient's condition changes or side effects occur. Beyond treating established tachyarrhythmias, evidence from studies like the PASCAL trial [19] and meta-analyses [18] supports a role for Landiolol in the prevention of postoperative atrial fibrillation. This prophylactic use, potentially leveraging its anti-inflammatory and anti-ischemic effects in addition to rate control, could significantly improve surgical outcomes and reduce healthcare costs associated with POAF.

7. Posology and Method of Administration

The administration of Landiolol Hydrochloride requires careful attention to dosing, titration, and method of delivery to ensure efficacy and safety.

Table 3: Recommended Dosing Regimens for Landiolol Hydrochloride in Approved Indications

Indication	Optional Loading Dose (mcg/kg/min for 1 min)	Initial Infusion Rate (mcg/kg/min)	Titration Steps/Frequency	Max Maintenance Dose (mcg/kg/min)	Max Daily Dose (mg/kg/day)	Special Considerations (e.g., Cardiac Dysfunction)	Reference(s)
SVT, Atrial Fibrillation/Flutter (Rate Control)	100	10 - 40	Adjust based on response and tolerance; may increase stepwise	Up to 80 (limited time)	57.6	Start at lower end (e.g., 1 mcg/kg/min), titrate cautiously up to 10 mcg/kg/min or higher if tolerated, under close hemodynamic monitoring.	3
Non-compensatory Sinus Tachycardia	100	10 - 40	Adjust based on response and tolerance; may increase stepwise	Up to 80 (limited time)	57.6	Similar caution as above if cardiac dysfunction present.	3

Recommended Dosing Regimens:

The dosing of Landiolol Hydrochloride must be individualized and carefully titrated according to the patient's heart rate response and hemodynamic status.3

• Initial Infusion: For most adult patients, the infusion is typically initiated at a rate of 10-40 mcg/kg/min. This generally establishes a heart rate-lowering effect within 10-20 minutes.[3]
• Optional Loading Dose: If a more rapid onset of action (within 2-4 minutes) is desired, an optional loading dose of 100 mcg/kg/min can be administered for 1 minute, immediately followed by a continuous infusion, usually starting at 10-40 mcg/kg/min.[3]
• Maintenance Dose and Titration: The maintenance infusion rate can be adjusted based on the therapeutic response. If needed, and if the patient's cardiovascular status permits, the dose can be increased, potentially up to 80 mcg/kg/min for a limited duration. However, the maximum recommended total daily dose should not be exceeded.[3]
• Maximum Recommended Daily Dose: The maximum recommended daily dose is 57.6 mg/kg/day, which corresponds to an infusion of 40 mcg/kg/min for 24 hours. Experience with infusion durations beyond 24 hours at doses greater than 10 mcg/kg/min is limited.[3]
• Patients with Cardiac Dysfunction: In patients with impaired cardiac function (e.g., LVEF <40%, NYHA Class III-IV), lower starting doses, such as 1 mcg/kg/min, are recommended. The dose should then be increased stepwise (e.g., up to 10 mcg/kg/min or higher if tolerated) under close and continuous hemodynamic monitoring, particularly blood pressure.[4]

The precision required in dosing reflects Landiolol's potency and its ultra-short half-life. Small adjustments in the infusion rate can rapidly alter plasma concentrations and, consequently, the pharmacodynamic effect. This necessitates weight-based dosing and vigilant monitoring.

Titration Guidelines:

Titration is a critical aspect of Landiolol therapy. The infusion rate should be adjusted to achieve the desired ventricular rate while maintaining hemodynamic stability. If adverse reactions such as hypotension or excessive bradycardia occur, the infusion rate should be reduced, or the infusion discontinued. Once the patient's condition has stabilized, the infusion may be restarted at a lower dose.3

Method of Intravenous Administration:

Landiolol Hydrochloride must be reconstituted prior to administration. For example, a 300 mg vial of Rapibloc is typically reconstituted with 50 mL of a compatible solution (e.g., 0.9% Sodium Chloride, 5% Dextrose, Ringer’s solution, Ringer-lactate solution) to achieve a final concentration of 6 mg/mL.3 The reconstituted solution should be clear and colorless and used immediately after opening.

The infusion should be administered intravenously via a central line or a large peripheral vein to minimize the risk of infusion site reactions.3 It is generally recommended not to administer Landiolol through the same intravenous line as other medicinal products unless compatibility has been definitively established.3 The use of an infusion pump is necessary to ensure accurate and controlled delivery.

The requirement for administration in a monitored setting by qualified healthcare professionals underscores its status as a specialized critical care medication. The potential for rapid hemodynamic shifts necessitates continuous ECG and blood pressure monitoring, which are standard in ICU or perioperative environments.

Transitioning to Alternative Antiarrhythmic Agents:

Once adequate ventricular rate control is achieved and the patient's clinical status is stable, a transition to an alternative, longer-acting antiarrhythmic agent (e.g., an oral beta-blocker or calcium channel blocker) may be considered. A common approach involves reducing the Landiolol infusion rate by 50% within the first hour after the administration of the first dose of the alternative oral agent. If satisfactory rate control is maintained for at least one hour after the second dose of the alternative medication, the Landiolol infusion can typically be discontinued.17 The specific labeling of the chosen alternative agent should be carefully consulted for appropriate dosing.

8. Clinical Efficacy and Safety

The clinical utility of Landiolol Hydrochloride is supported by data from various clinical trials and meta-analyses, highlighting its efficacy in controlling heart rate and its safety profile in specific patient populations.

Table 4: Summary of Key Clinical Trials Investigating Landiolol Hydrochloride

Trial Name/Identifier (if available)	Study Phase	Patient Population (Indication, Key Characteristics)	No. of Patients	Landiolol Dosage Regimen	Comparator(s)	Primary Endpoint(s)	Key Efficacy Results (Quantitative)	Key Safety Findings (Major ADRs, Discontinuation Rates)	Reference(s)
PASCAL Trial	RCT	Patients undergoing CABG surgery	140	Perioperative infusion (details not fully specified in snippets)	Placebo	Occurrence of POAF up to 1 week postoperatively	POAF: 10% (Landiolol) vs. 34.3% (Placebo), p=0.0006. Lower postoperative HR, lower inflammatory/ischemic parameters.	No hypotension or bradycardia reported in Landiolol group. Lower medical costs.	19
FDA Approval Basis (Rapiblyk)	Multiple RCTs (5)	Adults with SVT including atrial fibrillation and atrial flutter	317 (Landiolol)	Infused doses ranged from 9.3 to 74.6 mcg/kg/min	Placebo	Heart rate reduction	Heart rate decrease in 40-90% (Landiolol) vs. 0-11% (Placebo) within ~10 minutes. Definition: >20% HR decrease or HR <100 bpm or intermittent cessation of arrhythmia.	ADRs: 9.9% (Landiolol) vs. 1% (Placebo). Main ADR: Hypotension.	5
Nagai et al. (2013)	RCT	Tachycardia and cardiac dysfunction (LVEF 25–50%)	200	Titrated 1-10 mcg/kg/min for 2h, then continued for 1-2 days (mean 6.3-6.7 mcg/kg/min)	Digoxin	HR control	More profound HR decrease and higher rate of HR control with Landiolol vs. Digoxin.	Comparable adverse event rate to digoxin. Blood pressure statistically lower with Landiolol during initial 2h infusion. Landiolol discontinued in 3/200 patients.	4
Propensity Score-Matched Study (ICU)	Observational	Critically ill ICU patients with tachycardia (HR ≥100 bpm)	438 (matched)	Standard ICU dosing	Esmolol	Heart rate control, hemodynamic response, LOS	Landiolol reduced HR by an additional 4.7 bpm vs. Esmolol (p=0.007). Higher minimal ScvO2, lower maximal PCO2 gap with Landiolol. Shorter hospital and ICU LOS with Landiolol.	Comparable proportion able to stabilize vasopressors in first 24h. Norepinephrine doses and lactate levels similar.	20

Summary of Key Clinical Trial Findings:

• Postoperative Atrial Fibrillation (POAF) Prevention: The PASCAL trial, a randomized controlled study in patients undergoing coronary artery bypass grafting (CABG), demonstrated that perioperative administration of Landiolol significantly reduced the incidence of POAF compared to placebo (10% vs. 34.3%, p=0.0006). Patients receiving Landiolol also exhibited lower postoperative heart rates and reduced inflammatory and ischemic parameters, along with lower medical costs.[19]
• Basis for FDA Approval (Rapiblyk): The FDA approval of Rapiblyk for SVT, including atrial fibrillation and atrial flutter, was supported by data from five randomized, double-blind, placebo-controlled studies. These trials showed that Landiolol, at infused doses ranging from 9.3 to 74.6 mcg/kg/min, achieved a significant heart rate decrease (defined as >20% reduction, or HR <100 bpm, or intermittent arrhythmia cessation) in 40-90% of treated patients within approximately 10 minutes, compared to 0-11% in placebo-treated patients.[5]
• Use in Cardiac Dysfunction: Clinical studies have explored Landiolol's use in patients with heart failure (NYHA Class III-IV, LVEF 25-50%). In a randomized trial by Nagai et al., Landiolol (titrated 1-10 mcg/kg/min) was more effective than digoxin in achieving heart rate control in patients with tachycardia and cardiac dysfunction, with comparable tolerance despite a transiently lower blood pressure during the initial infusion.[4] Retrospective studies have also supported its use in this population, showing effective heart rate reduction with limited impact on blood pressure and, in some instances, an improvement in LVEF.[4]

Evidence from Meta-Analyses:

A meta-analysis focusing on the prevention of POAF after cardiac surgery found that Landiolol administration was significantly associated with a decreased risk of developing AF (Risk Ratio = 0.33, 95% CI: 0.23-0.48) without an associated increase in the risk of major complications (Risk Ratio = 0.79, 95% CI: 0.43-1.45) compared to control groups.18 This higher level of evidence reinforces the prophylactic utility of Landiolol in this setting.

Comparative Efficacy and Safety:

• Versus Esmolol: A retrospective, propensity score-matched observational study involving critically ill ICU patients with tachycardia (HR $\geq$100 bpm) suggested that Landiolol provided superior heart rate control compared to esmolol. Landiolol reduced heart rate by an additional 4.7 bpm (p=0.007) over 72 hours of infusion, while maintaining a comparable proportion of patients able to stabilize vasopressor doses within the first 24 hours. The Landiolol group also exhibited higher minimal central venous oxygen saturation (ScvO2) and a lower maximal PCO2 gap, potentially indicating less impact on cardiac output. Furthermore, patients in the Landiolol group experienced shorter hospital and ICU lengths of stay.[20] Landiolol's greater β1​-selectivity (255:1 vs. esmolol's ~33:1) may contribute to these observed differences.[1]
• Versus Digoxin: As mentioned previously, in patients with tachycardia and cardiac dysfunction, Landiolol demonstrated more profound heart rate decrease and a higher rate of heart rate control compared to digoxin, with comparable overall tolerance.[4]

These comparative data suggest that Landiolol may offer advantages over other short-acting beta-blockers like esmolol in specific critical care scenarios, particularly regarding the extent of heart rate reduction and potentially a more favorable hemodynamic profile.

Impact on Patient Outcomes:

The clinical use of Landiolol has been associated with several positive patient outcomes:

• Effective and rapid control of ventricular heart rate in SVT, atrial fibrillation, and atrial flutter [[16], [4], [6], [11].
• Conversion to sinus rhythm in a proportion of patients with paroxysmal SVT.[16]
• Significant reduction in the incidence of POAF following cardiac surgery.[18]
• Potential for reduced medical costs associated with the prevention of POAF.[19]

The ability to use Landiolol cautiously in patients with some degree of cardiac dysfunction represents an important clinical advantage, as tachyarrhythmias in this population can significantly worsen hemodynamics, and traditional beta-blockers might be poorly tolerated due to more pronounced negative inotropic effects. The economic benefit observed in POAF prevention further strengthens the rationale for its use in appropriate surgical settings.

9. Use in Special Populations

The use of Landiolol Hydrochloride in specific patient populations requires careful consideration of potential pharmacokinetic and pharmacodynamic alterations.

Elderly Patients (≥ 65 years):

No specific dose adjustment is mandated for elderly patients.17 However, clinical experience and safety data suggest that serious adverse events such as shock, cardiac arrest, and AV block, when they occur, have been reported predominantly in elderly patients or those with significant comorbidities.3 This implies that while the drug's intrinsic pharmacology may not necessitate a different dosing schedule based on age alone, the higher prevalence of underlying cardiovascular disease and reduced physiological reserve in the elderly warrants increased vigilance and potentially more cautious dose titration.

Patients with Renal Impairment:

Formal dose adjustments are not considered necessary for patients with renal impairment.17 Landiolol itself is rapidly metabolized by esterases, independent of renal function. However, its main metabolite, M1, is excreted via the kidneys and could theoretically accumulate in patients with significant renal dysfunction. Although M1 has negligible beta-blocking activity (1/200th or less of the parent drug), caution is advised, particularly with prolonged infusions or in severe renal failure.17 The clinical significance of M1 accumulation appears low due to its inactivity, but monitoring for any unexpected adverse effects might be prudent in this population.

Patients with Hepatic Impairment:

Data on the use of Landiolol in patients with hepatic impairment are limited. Due to the liver's role in producing some esterases involved in Landiolol metabolism, careful dosing, starting with the lowest recommended dose, is advised for patients with any degree of hepatic impairment. Studies in patients with mild to moderate hepatic impairment have shown a reduction in the volume of distribution and a 40% increase in Landiolol plasma levels, although the elimination half-life and overall elimination were not significantly different from healthy adults.17 These findings suggest that reduced initial doses and careful, hemodynamically guided titration are important in this group.

Patients with Cardiac Dysfunction (e.g., Heart Failure, LVEF <40%):

Landiolol can be used in patients with cardiac dysfunction, but lower starting doses (e.g., 1 mcg/kg/min) and gradual, stepwise dose increases under close hemodynamic monitoring (especially blood pressure) are recommended.4 This cautious approach is necessary to balance the benefits of heart rate control against the potential risk of exacerbating heart failure due to Landiolol's negative inotropic effects, even though these are considered limited compared to other beta-blockers. The ultra-short action of Landiolol is an advantage in this setting, allowing for rapid withdrawal if cardiac function deteriorates.

Paediatric Population (0-18 years):

The safety and efficacy of Landiolol in the paediatric population have not been fully established in all regulatory regions, and the European Medicines Agency (EMA) had previously deferred the obligation to submit results of studies with Rapibloc in children.17 However, emerging data are promising. Limited published literature has reported successful heart rate control in some paediatric cases with doses ranging from 1.0 to 10.0 mcg/kg/min, with an instance of bradycardia observed at the higher end of this dose range.17

More substantially, the LANDI-PED study, a European prospective, multicentre clinical trial, investigated Landiolol for managing SVT in paediatric patients. The study found Landiolol to be effective in treating SVTs across diverse etiologies and in children of all ages. It was well-tolerated, with no new safety concerns identified, and its pharmacokinetic characteristics in children were consistent with those observed in adults, supporting the use of similar dosage regimens.11 These findings suggest a growing evidence base for Landiolol's potential utility in paediatric critical care and cardiology, addressing an unmet need for rapidly titratable rate control agents in children.

10. Contraindications, Warnings, and Precautions

The use of Landiolol Hydrochloride is subject to specific contraindications, warnings, and precautions to ensure patient safety.

Absolute Contraindications:

Landiolol Hydrochloride should not be used in patients with the following conditions 3:

• Known hypersensitivity to Landiolol Hydrochloride or any of its excipients.
• Severe bradycardia (heart rate less than 50 beats per minute).
• Sick sinus syndrome (unless a functioning pacemaker is present).
• Severe atrioventricular (AV) nodal conductance disorders, specifically second- or third-degree AV block (unless a functioning pacemaker is present).
• Cardiogenic shock.
• Severe hypotension.
• Decompensated heart failure, unless the heart failure is considered to be secondary to the tachyarrhythmia being treated.
• Pulmonary hypertension.
• Untreated phaeochromocytoma.
• Acute asthmatic attack or severe bronchospastic disease.
• Severe, uncorrectable metabolic acidosis. These contraindications are largely consistent with those for other beta-blockers and reflect situations where the pharmacological effects of Landiolol could be detrimental.

Detailed Warnings:

• Hypotension: This is the most frequently reported adverse effect. Blood pressure must be continuously monitored during Landiolol administration. If hypotension occurs, it can usually be managed by administering IV fluids, reducing the Landiolol dose, or discontinuing the infusion. Patients who are hemodynamically compromised or hypovolemic are at increased risk.[3]
• Bradycardia: Significant bradycardia can occur. Continuous heart rate monitoring is essential. If clinically significant bradycardia develops, the dose should be reduced or the infusion stopped.[5]
• Cardiac Failure: Landiolol can depress myocardial contractility and may precipitate or worsen heart failure. If signs of impending cardiac failure develop, Landiolol should be discontinued.[5]
• Reactive Airway Disease: While Landiolol has high β1​-selectivity, beta-blockers should generally be avoided in patients with bronchospastic diseases. If Landiolol is deemed necessary, it must be used with extreme caution, starting at the lowest possible effective dose, and with readiness to manage bronchospasm (e.g., by stopping the infusion and administering a β2​-agonist).[3]
• Diabetes Mellitus and Hypoglycemia: Beta-blockers can mask the tachycardic symptoms of hypoglycemia. Landiolol may increase the risk of severe or prolonged hypoglycemia, especially in patients with diabetes, those who are fasting, or children.[3]
• Infusion Site Reactions: Reactions such as pain, swelling, and erythema can occur. Infusion into small veins or through butterfly catheters should be avoided. If a local reaction develops, an alternative infusion site should be used.[6]
• Abrupt Discontinuation: Although one study noted a lack of withdrawal tachycardia with Landiolol after a 24-hour infusion [17], standard warnings for beta-blockers regarding abrupt discontinuation in patients with coronary artery disease (CAD) apply. Such discontinuation can lead to severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias. Patients, especially those with CAD, should be observed for signs of myocardial ischemia upon discontinuation.[6] The differing perspectives on withdrawal phenomena may stem from variations in study populations or a precautionary stance adopted by regulatory agencies based on class effects.
• Hyperkalemia: Landiolol can cause increases in serum potassium, particularly in patients with risk factors such as renal impairment.[6]

Precautions for Use:

• Pre-excitation Syndromes (e.g., Wolff-Parkinson-White Syndrome): In patients with pre-excitation syndromes and concomitant atrial fibrillation, beta-blockers should be avoided due to the risk of increased conduction through an accessory pathway, potentially leading to ventricular fibrillation.[17]
• First-Degree Heart Block: Use with caution, as beta-blockers can prolong AV conduction time.[17]
• Prinzmetal's Angina: Beta-blockers may increase the frequency and duration of anginal attacks. Non-selective beta-blockers should not be used, and β1​-selective blockers like Landiolol should be used with utmost care.[17]
• Phaeochromocytoma: Landiolol should only be used in patients with phaeochromocytoma after adequate α-receptor blockade has been established to prevent a paradoxical hypertensive crisis.[3]
• Peripheral Circulatory Disorders (e.g., Raynaud’s disease): Use with great caution as beta-blockers may aggravate these conditions.[17]
• Anaphylactic Reactions: Patients receiving beta-blockers may exhibit increased sensitivity to allergens and an augmented severity of anaphylactic reactions. They may also be unresponsive to standard doses of epinephrine used to treat such reactions.[17]
• Hyperthyroidism: Beta-blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade might precipitate a thyroid storm; therefore, patients should be monitored for signs of thyrotoxicosis when Landiolol therapy is withdrawn.[6]
• Metabolic Acidosis: Beta-blockers have been reported to cause hyperkalemic renal tubular acidosis. Acidosis, in general, may be associated with reduced cardiac contractility.[6]

It is important to recognize that while high β1​-selectivity mitigates certain risks (e.g., bronchospasm), many warnings and contraindications are class effects applicable to most beta-blockers. The fundamental cardiovascular effects of Landiolol necessitate these cautions.

11. Adverse Drug Reactions (ADRs)

The adverse drug reaction profile of Landiolol Hydrochloride is primarily characterized by extensions of its pharmacological effects on the cardiovascular system.

• Common Adverse Effects (Incidence $\geq$1% to <10%):
• Hypotension: This is the most frequently reported ADR, occurring in approximately 8.5% to 9.9% of patients in controlled studies. It is generally dose-dependent and rapidly reversible upon dose reduction or discontinuation of the infusion, often with fluid administration.[3]
• Bradycardia: A decrease in heart rate below clinically desired levels is another common effect, reported in approximately 0.5% to 2.1% of patients.[3]
• Blood pressure decreased: This is a general term also noted as common.[3] The predictability of these ADRs, stemming directly from Landiolol's beta-blocking mechanism, combined with its short half-life, allows for effective management primarily through infusion rate adjustment.
• Uncommon Adverse Effects (Incidence $\geq$0.1% to <1%): A range of less frequent ADRs has been reported, including: pneumonia, hyponatremia, cerebral ischemia, headache, cardiac arrest, sinus arrest, tachycardia (paradoxical or rebound), hypertension (paradoxical), pulmonary edema, vomiting, nausea, and liver disorder. Various laboratory abnormalities such as ECG ST-segment depression and changes in cardiac index have also been noted.3
• Rare Adverse Effects (Incidence <0.1%): More serious or diverse rare ADRs include: mediastinitis, thrombocytopenia, hyperglycemia, cerebral infarction, seizure, myocardial infarction, ventricular tachycardia, atrial fibrillation (new onset/worsening), low cardiac output syndrome, various forms of AV block and bundle branch block, shock, hot flush, asthma, respiratory distress, bronchospasm, dyspnea, hypoxia, abdominal discomfort, erythema, muscle spasms, renal failure, pyrexia, chills, and chest discomfort.3 The low frequency of bronchospasm, despite being a potential concern with beta-blockers, supports the clinical benefit of Landiolol's high β1​-selectivity, especially when used cautiously in patients with reactive airway disease.3
• Management of Adverse Reactions: The primary management strategy for ADRs like hypotension and bradycardia is to reduce the Landiolol infusion rate or temporarily discontinue the infusion. Due to its ultra-short half-life, these effects typically resolve quickly. Supportive medical management, such as intravenous fluids for hypotension or atropine for severe bradycardia, may be administered if necessary.3

12. Drug Interactions

Landiolol Hydrochloride can interact with other medications, primarily through pharmacodynamic mechanisms, given its limited involvement in CYP450 metabolism.

Table 5: Clinically Significant Drug Interactions with Landiolol Hydrochloride

Interacting Drug/Class	Potential Effect	Mechanism of Interaction (PK/PD)	Clinical Recommendation/Management	Reference(s)
Calcium Channel Blockers (Verapamil, Diltiazem)	Excessive cardiac suppression (bradycardia, hypotension, AV block), decreased contractility	PD: Additive negative chronotropic, dromotropic, and inotropic effects.	Concomitant use not recommended in patients with AV conduction abnormalities. Titrate with caution, close hemodynamic monitoring.	17
Class I Antiarrhythmics, Amiodarone, Digitalis Glycosides	Excessive cardiac suppression, AV conduction abnormalities, bradycardia	PD: Additive negative chronotropic and dromotropic effects.	Titrate with caution, close hemodynamic monitoring.	17
Inhalation Anaesthetics	Increased hypotensive effect	PD: Additive vasodilatory/cardiodepressant effects.	Titrate Landiolol cautiously.	17
Suxamethonium (Succinylcholine)	Prolonged neuromuscular blockade by suxamethonium; increased Landiolol Cmax (~20%)	PK: Competition for plasma esterases, slowing metabolism of both drugs.	Monitor for prolonged neuromuscular blockade. Be aware of potential for slightly higher Landiolol levels.	17
Other Esterase Substrates, Cholinesterase Inhibitors (e.g., Neostigmine)	Intensified heart rate lowering, prolonged Landiolol action	PK/PD: Potential for slowed Landiolol metabolism (esterase substrates) or enhanced cholinergic effects (cholinesterase inhibitors).	Titrate Landiolol with caution.	17
Insulin, Oral Antidiabetic Drugs	Altered blood glucose control; masking of hypoglycemic tachycardia	PD: Beta-blockade can interfere with glucose regulation and mask adrenergic symptoms of hypoglycemia.	Monitor blood glucose levels closely.	3
Catecholamine-Depleting Agents (e.g., Reserpine), Clonidine, Dexmedetomidine	Additive hypotension and/or bradycardia; risk of rebound hypertension with clonidine withdrawal	PD: Additive sympatholytic effects.	Monitor closely for hypotension and bradycardia. Manage clonidine withdrawal carefully if Landiolol is co-administered.	17
Sympathomimetic Agents (with β-agonist activity)	Counteraction of Landiolol's effects	PD: Opposing effects on β-receptors.	Dose adjustment of either agent may be necessary.	17
NSAIDs	Decreased hypotensive effect of beta-blockers	PD: NSAIDs can cause sodium and water retention and inhibit prostaglandin synthesis, potentially antagonizing antihypertensive effects.	Monitor blood pressure.	17
Heparin (IV)	Decreased Landiolol plasma levels (~50% in one study of cardiac surgery patients)	PK: Mechanism unclear, possibly related to heparin-induced BP changes and altered Landiolol circulation time.	Clinical significance on heart rate control was not apparent in the cited observation, but potential for altered Landiolol exposure exists.	17

Clinically Significant Interactions with Other Cardiovascular Drugs:

Landiolol's primary interactions are pharmacodynamic, involving additive effects with other drugs that modulate cardiac function.

• Calcium Channel Blockers (Non-dihydropyridine type, e.g., verapamil, diltiazem): Co-administration can lead to an increased risk of excessive cardiac suppression, including severe bradycardia, AV block, and depressed myocardial contractility. This combination is generally not recommended, especially in patients with pre-existing AV conduction abnormalities.[17]
• Other Antiarrhythmic Agents (e.g., Class I agents like quinidine or procainamide, Class III agents like amiodarone) and Digitalis Glycosides: These drugs can also depress cardiac conduction and contractility. When used with Landiolol, careful titration and close hemodynamic monitoring are essential to avoid excessive bradycardia or AV block.[17]
• Catecholamine-Depleting Drugs (e.g., reserpine) and Other Sympatholytic Agents (e.g., clonidine, dexmedetomidine): These agents can have additive effects with Landiolol, leading to profound hypotension and/or bradycardia. Abrupt withdrawal of clonidine in patients receiving beta-blockers can precipitate rebound hypertension.[17]

Interactions with Anaesthetic Agents:

Given Landiolol's frequent use in the perioperative setting, interactions with anaesthetic agents are of particular importance.

• Inhalation Anaesthetics: Many volatile anaesthetics have cardiodepressant and vasodilatory properties. Concomitant use with Landiolol may enhance hypotensive effects. Careful titration of Landiolol is necessary.[17]
• Esterase Substrates (e.g., Suxamethonium/Succinylcholine) and Cholinesterase Inhibitors (e.g., Neostigmine): Landiolol is metabolized by plasma esterases. Suxamethonium, also an esterase substrate, can compete for these enzymes. Co-administration may lead to prolonged neuromuscular blockade by suxamethonium and potentially increased Landiolol concentrations (Cmax increased by ~20% in one in vitro study with suxamethonium) or prolonged action. Cholinesterase inhibitors, by preserving acetylcholine, could enhance vagal tone and bradycardic effects when combined with a beta-blocker.[17] This interaction with suxamethonium is a key example of pharmacokinetic interaction due to shared metabolic pathways.

Other Relevant Interactions:

• Insulin and Oral Antidiabetic Drugs: Beta-blockers can mask the adrenergic symptoms of hypoglycemia (such as tachycardia) and may affect blood glucose control. Close monitoring of blood glucose is advised in diabetic patients receiving Landiolol.[3]
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs can attenuate the hypotensive effects of beta-blockers, potentially by inhibiting renal prostaglandin synthesis and causing sodium and water retention.[17]
• Sympathomimetic Agents with β-Adrenergic Agonist Activity: These agents (e.g., isoprenaline, dobutamine) will have opposing effects to Landiolol on β-receptors, potentially counteracting Landiolol's therapeutic actions. Dose adjustments of either agent may be required.[17]
• Heparin: An interaction has been observed in cardiovascular surgery patients where intravenous heparin administration during Landiolol infusion led to a significant (approximately 50%) decrease in Landiolol plasma levels. The proposed mechanism involves heparin-induced blood pressure changes affecting Landiolol's circulation time. While heart rate was reportedly unaffected in this specific observation, the potential for altered Landiolol exposure exists.[17]

The predominance of pharmacodynamic interactions, rather than CYP450-mediated pharmacokinetic interactions, simplifies one aspect of drug interaction management but underscores the need for a thorough understanding of the combined cardiovascular effects of all co-administered medications.

13. Regulatory Status and History

Landiolol Hydrochloride has a distinct regulatory history, with approvals spanning several decades and major global regions.

• Japan (PMDA): Landiolol was first approved in Japan in 2002. It is marketed under the brand name Onoact and is indicated for indications such as intraoperative tachyarrhythmias.[1] The original developer was Ono Pharmaceutical.[7]
• Europe (EMA): Landiolol has been approved in Europe for several years. For example, Rapibloc, marketed by Amomed Pharma GmbH (an AOP Health company), received its first authorization in Austria on May 12, 2017.[3] Approved indications typically include the treatment of supraventricular tachycardia, rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative or other short-term settings, and non-compensatory sinus tachycardia.[3]
• United States (FDA): Landiolol Hydrochloride received FDA approval on November 22/27, 2024, under the brand name Rapiblyk, sponsored by AOP Orphan Pharmaceuticals GmbH.[5] The indication is for the short-term reduction of ventricular rate in adults with supraventricular tachycardia, including atrial fibrillation and atrial flutter.[5] Eagle Pharmaceuticals was also involved in the New Drug Application (NDA) submission process in the US.[5]
• Canada (Health Canada): Landiolol was approved in Canada in April 2024.[9]

The staggered global introduction, with a two-decade gap between its initial approval in Japan and its more recent approvals in North America, is noteworthy. This lengthy period may reflect differing regulatory landscapes, market priorities of the developers, or the time required to conduct additional region-specific clinical trials to meet the requirements of agencies like the FDA. The involvement of AOP Orphan Pharmaceuticals, a company specializing in orphan and specialized hospital products, in the European and US markets suggests a strategic focus on Landiolol's niche applications in acute and critical care settings. While SVT and atrial fibrillation are not "orphan" diseases in terms of prevalence, the specific use-case for an ultra-short-acting IV beta-blocker like Landiolol can be considered a specialized hospital market segment where its unique properties offer distinct advantages.

14. Comparative Assessment and Clinical Perspective

Landiolol Hydrochloride's unique pharmacological profile positions it distinctively among beta-blockers, particularly when compared to other agents used for acute rate control.

Table 6: Comparative Profile of Landiolol vs. Esmolol

Parameter	Landiolol	Esmolol	Reference(s)
β1​-Selectivity Ratio	255:1 (vs. β2​)	Approx. 33:1 (vs. β2​)	1
Elimination Half-life (t1/2​)	Approx. 3-4 minutes	Approx. 9 minutes	1
Onset of Action	Ultra-rapid (immediate with bolus, 2-5 min with loading dose)	Rapid (1-2 minutes after loading dose)	1
Offset of Action	Rapid (HR to baseline within 30 min)	Rapid (effects diminish within 10-30 min after stopping infusion)	1
Impact on Blood Pressure	Less negative effect; minimal impact at therapeutic doses for rate control. Hypotension is most common ADR.	Can cause hypotension, often dose-dependent.	1
Impact on Myocardial Contractility	Limited negative inotropic potential	Dose-dependent negative inotropic effect	1
Metabolism	Plasma/liver esterases	Blood esterases	1
Receptor Re-expression	May not amplify β-receptor re-expression	Can amplify β-receptor re-expression (potential for tolerance/rebound)	1
Key Clinical Advantages	Higher β1​-selectivity, potentially better hemodynamic stability for HR control, possibly less impact on cardiac output in ICU, no/less rebound.	Established use, rapid on/off.	1
Key Disadvantages/Cautions	Hypotension, bradycardia (as with all beta-blockers). Limited data in some specific long-term scenarios.	Hypotension, bradycardia, lower β1​-selectivity than Landiolol.	3

Comparison with Esmolol:

Esmolol is another ultra-short-acting intravenous beta-blocker commonly used for acute rate control, making it a key comparator for Landiolol.

• Selectivity: Landiolol demonstrates significantly higher β1​-selectivity (255:1) compared to esmolol (approximately 33:1).[1] This superior selectivity suggests a potentially lower risk of β2​-mediated side effects (e.g., bronchospasm) with Landiolol. Landiolol is reported to be approximately 8 times more cardioselective than esmolol.[1]
• Half-life: Landiolol has an elimination half-life of approximately 3-4 minutes, which is shorter than that of esmolol (typically cited around 9 minutes).[1] This contributes to an even faster offset of action for Landiolol.
• Hemodynamic Effects: Due to its higher selectivity and potentially more limited negative inotropic effect, Landiolol may offer better hemodynamic stability, particularly concerning blood pressure, during heart rate control compared to esmolol.[1] A propensity score-matched study in ICU patients indicated that Landiolol achieved superior heart rate reduction compared to esmolol, with potentially less impact on cardiac output (inferred from higher ScvO2 and lower PCO2 gap) and shorter ICU and hospital lengths of stay.[20]
• Receptor Re-expression: Landiolol may not amplify β-receptor re-expression to the same extent as esmolol, potentially reducing the risk of drug tolerance with prolonged infusion and rebound phenomena upon discontinuation.[1]

Unique Characteristics and Advantages of Landiolol:

The key distinguishing features of Landiolol include:

• Its status as one of the most highly β1​-selective beta-blockers available clinically.[1]
• Its ultra-short elimination half-life, facilitating rapid titration and quick recovery from effects.[1]
• A rapid onset and offset of action, crucial for acute interventions.[1]
• A pharmacological profile characterized by a potent negative chronotropic effect with a relatively limited negative inotropic effect, which may be beneficial in patients with some degree of cardiac compromise.[1]
• Metabolism to inactive metabolites, ensuring that the therapeutic effect is tied to the parent drug.[1]
• Its formulation as a pure S-enantiomer, which may contribute to its favorable selectivity and potentially reduced hypotensive side effects compared to racemic mixtures.[1]

These characteristics position Landiolol as a "precision tool" for beta-blockade in acute settings. Unlike beta-blockers designed for chronic management, Landiolol allows for real-time, fine-tuned adjustments to heart rate, with the safety net of rapid effect reversal if hemodynamic compromise occurs.

Place in Therapy and Specific Niches:

Landiolol's place in therapy is well-defined within acute and critical care medicine:

• Acute Management of SVT, Atrial Fibrillation/Flutter: When rapid and titratable control of ventricular rate is paramount.
• Perioperative and Postoperative Settings: For managing tachyarrhythmias that arise during or after surgery, and for the prevention of POAF, particularly after cardiac surgery.
• Patients with Comorbidities: Its high β1​-selectivity makes it a potentially safer option for patients with underlying reactive airway disease. Its limited negative inotropic effect may be advantageous in patients with some degree of cardiac dysfunction, where other beta-blockers might be poorly tolerated.
• Hemodynamically Sensitive Situations: In scenarios requiring precise hemodynamic control, such as in septic shock with persistent tachycardia despite adequate fluid resuscitation, Landiolol may offer an advantage. The findings from the ICU comparative study against esmolol, suggesting better ScvO2 and PCO2 gap, are particularly relevant for septic patients where optimizing oxygen delivery is crucial.[20]

While much of the initial focus was on cardiac surgery, the emerging comparative data and its use in broader ICU populations (e.g., sepsis-associated tachycardia [2]) suggest its utility may extend further within critical care.

15. Conclusion

Landiolol Hydrochloride is an ultra-short-acting, highly β1​-selective intravenous beta-blocker with a unique pharmacokinetic and pharmacodynamic profile tailored for acute cardiovascular care. Its key attributes—rapid onset and offset of action, high degree of cardioselectivity leading to potent negative chronotropic effects with limited negative inotropy, and metabolism to inactive compounds—make it a valuable agent for the rapid control of supraventricular tachyarrhythmias, including atrial fibrillation and atrial flutter, particularly in perioperative and critical care settings.

The clinical evidence supports its efficacy in achieving prompt heart rate reduction and in the prevention of postoperative atrial fibrillation, with a safety profile characterized primarily by dose-dependent hypotension and bradycardia, which are generally manageable due to its short half-life. Comparisons with other short-acting beta-blockers, notably esmolol, suggest potential advantages for Landiolol in terms of the degree of heart rate control and possibly a more favorable hemodynamic profile in certain critically ill patient populations. Its high β1​-selectivity also offers a theoretical and observed advantage in patients with reactive airway disease, though caution remains paramount.

Landiolol represents an important advancement in beta-blocker therapy, exemplifying a trend towards developing agents with highly specialized profiles for specific, acute clinical scenarios where precision and rapid titratability are essential. Its journey from initial approval in Japan to subsequent adoption in Europe and North America underscores its recognized value in these niche applications.

Future perspectives for Landiolol may include further elucidation of its role in broader ICU populations beyond cardiac surgery, such as in sepsis-associated tachycardia, and continued investigation into its utility and dosing in special populations, including pediatrics, where preliminary data are encouraging. The ongoing acquisition of real-world evidence and further comparative effectiveness research will continue to refine its optimal place in therapy, solidifying its role as a specialized tool for physicians managing acute cardiac arrhythmias and hemodynamic instability.

References

(References to be formatted according to specific journal/publication style. For this report, snippet IDs are used as placeholders.)

15: PubChem. Compound Summary: Landiolol hydrochloride.

7: KEGG DRUG. Entry D01847: Landiolol hydrochloride.

8: Patsnap Synapse. Article: What is the mechanism of Landiolol Hydrochloride? July 17, 2024.

1: Wikipedia. Article: Landiolol. Last edited February 17, 2025.

17: HPRA Ireland. Landiolol 300mg Powder for Solution for Infusion Summary of Product Characteristics. February 15, 2024. 3

16: Igawa, O., et al. (2000). Pharmacokinetics of landiolol hydrochloride, a new ultra-short-acting b-blocker, in patients with cardiac arrhythmias. Journal of Clinical Pharmacology. 16

9: DrugBank Online. Salt Record DBSALT002156: Landiolol hydrochloride. 9

2: DrugBank Online. Article A264733: An Overview of the Pharmacokinetics and Pharmacodynamics of Landiolol (an Ultra-Short Acting beta1 Selective Antagonist) in Atrial Fibrillation. 2

3: AMOMED Pharma GmbH. Rapibloc 300 mg powder for solution for infusion Summary of Product Characteristics. September 2020. 3

4: Madias, C. (2018). Landiolol for rate control management of atrial fibrillation in patients with cardiac dysfunction. Europace. 4

5: Drugs.com. Drug Approval History: Rapiblyk. Last updated November 30, 2024. 5

6: AOP Health Press Release. U.S. FDA approves AOP Health's Rapiblyk™. November 27, 2024. 6

14: DrugCentral. DrugCard 1545: Landiolol.

22: Pharmacompass. Active Pharmaceutical Ingredients: Landiolol Hydrochloride.

18: Plestis, K. A., et al. (2014). Landiolol hydrochloride for prevention of atrial fibrillation after cardiac surgery: a meta-analysis. Pacing and Clinical Electrophysiology. 18

19: Ataka, K., et al. (2011). Landiolol hydrochloride for prevention of atrial fibrillation after coronary artery bypass grafting: new evidence from the PASCAL trial. The Journal of Thoracic and Cardiovascular Surgery. 19

13: Cardiology Innovations. FDA Approves Landiolol for AFib and Atrial Flutter in Critical Care.

20: Liu, Y., et al. (2025). Comparison of the efficacy and safety of Landiolol and Esmolol in critically ill patients: a propensity score-matched study. PubMed.

21: Springermedizin.de. Comparison of the efficacy and safety of landiolol and esmolol in critically ill patients: a propensity score-matched study.

11: Michel-Behnke, I., et al. (2025). Landiolol is effective and safe in paediatric supraventricular tachycardia: results from the prospective multicentre LANDI-PED dose-finding study. Europace.

12: HMA-EMA Catalogues. Institution: AOP Orphan Pharmaceuticals.

10: NewDrugApprovals.org. Landiolol. April 20, 2025.

14: DrugCentral. DrugCard 1545: Landiolol (Targets section).

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