Esmolol Hydrochloride

Registered South African indications:

• Supraventricular tachycardia in patients with atrial fibrillation or atrial flutter in perioperative, post-operative, or other emergent circumstances
• Intra-operative and post-operative tachycardia and/or hypertension and non-compensatory sinus tachycardia where, the rapid heart rate requires specific intervention

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe sinus bradycardia (less than 50 beats per minute)
• Sick sinus syndrome
• Severe AV-nodal conductance disorders (without pacemaker)
• Second or third degree AV-block
• Cardiogenic shock
• Severe hypotension
• Decompensated heart failure
• Non-treated phaeochromocytoma
• Pulmonary hypertension
• Acute asthmatic attack
• Bronchoconstriction
• History of chronic respiratory diseases
• Metabolic acidosis
• Late phase peripheral vascular disease or Raynaud's phenomenon
• Coadministration with intravenous verapamil (within 48 hours)

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Elderly
• Patients who are compromised hemodynamically
• Pre-existing hypotension
• Low pretreatment heart rates
• Compromised cardiac function
• Prolonged use
• Abrupt withdrawal (in patients with coronary artery disease)
• First degree heart block or other cardiac conduction disturbances
• Pheochromocytoma (pre-treated with alpha-receptor blockers)
• Hypertension following induced hypothermia
• Bronchospastic diseases
• History of wheezing and asthma
• Diabetes mellitus and hypoglycaemia
• Prinzmetal's angina
• Hypovolemic patients
• Personal or family history of psoriasis
• Hyperthyroidism
• Myasthenia gravis
• Peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication)

Forms avail. in SA and covered in this monograph: inj

Superventricular tachycardia 
Intra-operative and post-operative tachycardia and/or hypertension
- Gradual control dosing

• IV: Loading dose: 500μg/kg/min, over one minute; Maintenance: 50μg/kg/min, for the next 4 minutes; Max: 300μg/kg/min

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If an adequate therapeutic effect is observed over the five minutes of medicine administration, maintain the maintenance infusion dosage with periodic adjustments up or down as required

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If an adequate therapeutic effect is NOT observed over the five minutes of medicine administration:

Continue the titration procedure as above, repeating the loading infusion of 500μg/kg/min (0,5mg/kg/min) over one minute, but increasing the maintenance infusion rate over the subsequent four minutes by 50μg/kg/min (0.05mg/kg/min) increments

As the desired heart rate or blood pressure is approached, omit the subsequent loading doses and titrate the maintenance dosage up or down to the endpoint. If required, increase the interval between steps from 5 to 10 minutes

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General dose range: 50-200μg/kg/min

The average effective dosage is approximately 100μg/kg/min (0.1mg/kg/min) even though dosages as low as 25μg/kg/min (0.025mg/kg/min) have been adequate in some patients. Dosages as high as 300μg/kg/min (0.3mg/kg/min) have been used, but these high dosages provide little additional effect and has an increased rate of adverse effects and are therefore not recommended

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The dosage must be individualised by titration in which each step consists of a loading dose followed by a maintenance dose

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The use of infusions of esmolol hydrochloride has been well documented, in addition, limited data from 24-48 hours (N=48) indicate that esmolol hydrochloride is well-tolerated up to 48 hours

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See additional prescribing points for transition to alternative anti-dysrhythmic agents

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Intra-operative and post-operative tachycardia and/or hypertension
- Immediate control during anaesthesia

• IV: Loading dose: 80mg, immediately as a single dose over 30 seconds; Maintenance: 150 μg/kg/min infusion, if required; Max: 300 μg/kg/min

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During intra-operative and post-operative situations, it is not always advisable to slow titrate the dose of esmolol hydrochloride to the therapeutic effect. Therefore, two dosing options are presented: immediate control dosing and gradual control when the physician has time to titrate

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Higher dosages (250-300μg/kg/min) may be required for adequate control of blood pressure and those required for the treatment of atrial fibrillation, flutter and sinus tachycardia. One third of the post-operative hypertensive patients required these higher dosages

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See additional prescribing points for compatible intravenous solutions

Not established for use in children

Pregnancy

• Caution
• There are limited amount of data from the use of esmolol hydrochloride in pregnant women. Studies in animals have shown reproductive toxicity
• Esmolol hydrochloride is not recommended during pregnancy
• There are insufficient data to determine the possible harmful effects of esmolol hydrochloride during pregnancy. To date, there are no indications for an increased risk of birth defect in humans. The potential risk for humans is unknown. Based on the pharmacological action, in the later period of pregnancy, side effects on the foetus and neonate (especially hypoglycemia, hypotension and bradycardia) should be taken into account
• If treatment with esmolol hydrochloride is considered necessary, the uteroplacental blood flow and foetal growth should be monitored. The newborn infant must be closely monitored

Breastfeeding

• Caution
• Esmolol hydrochloride should not be used during breastfeeding.
  It is not known whether esmolol hydrochloride/ metabolites are excreted in human milk. A risk to the newborns/ infants cannot be excluded

Renal impairment

• Caution; no dose adjustment recommended

Hepatic impairment

• No dose adjustment recommended

Elderly

• Caution; no dose adjustment recommended
  Consider starting with a lower dosage

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Prohibited - In certain sports
  Prohibited - In  and out of competition: 
  Archery (WA)
  Shooting (ISSF) (IPC)

  Prohibited - In competition: 
  Automobile (FIA)
  Billiards (all disciplines) (WCBS)
  Darts (WDF)
  Golf (IGF)
  Skiing / Snowboarding (FIS) in ski jumping, freestyle aerials/halfpipe and snowboard halfpipe/big air
  Underwater sports (CMAS) in constant-weight apnoea with or without fins, dynamic apnoea with and without fins, free immersion apnoea, Jump Blue apnoea, spearfishing, static apnoea, target shooting and variable weight apnoea

Central Nervous System Disorders

• Depression
• Anxiety
• Abnormal thinking
• Vivid dreams and nightmares
• Dizziness
• Somnolence
• Headache
• Paraesthesia
• Disturbance in attention
• Confusional state
• Agitation
• Syncope
• Speech disorder
• Fatigue
• Seizures

Cardiovascular Disorders

• Bradycardia
• Atrioventricular block
• Increased pulmonary arterial pressure
• Cardiac failure
• Ventricular extrasystoles
• Nodal rhythm
• Angina pectoris
• Sinus arrest
• Asystole
• Accelerated idioventricular rhythm
• Coronary arteriospasm
• Cardiac arrest
• Hypotension
• Diaphoresis

Respiratory Disorders

• Dyspnoea
• Pulmonary oedema
• Bronchospasm
• Wheezing
• Nasal congestion
• Rhonchi
• Rales
• Chest pain

Gastrointestinal Disorders

• Nausea and vomiting
• Dysgeusia
• Dyspepsia
• Constipation
• Dry mouth
• Abdominal discomfort

Genitourinary Disorders

• Urinary retention

Endocrine and Metabolic Disorders

• Anorexia
• Hyperkalemia
• Metabolic acidosis

Musculoskeletal Disorders

• Musculoskeletal pain or weakness

Skin and Subcutaneous Tissue Disorders

• Diaphoresis
• Skin discolouration 
• Erythema
• Skin necrosis 
• Psoriasis 
• Angioedema
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Peripheral ischaemia
• Pallor 
• Flushing
• Thrombophlebitis
• Chills
• Pyrexia
• Oedema
• Hypersensitivity reactions

Sensory Disorders

• Visual impairment
• Dry eye
• Taste perversion

Others

• Injection site reaction
• Injection site blistering
• Injection site pain
• Infusion site reaction
• Infusion site inflammation
• Infusion site induration
• Infusion site phlebitis
• Infusion site vesicles
• Infusion site blistering
• Infusion site pain
• Local skin necrosis

• Antihypertensive agents
• Calcium antagonists
  - Verapamil
  - Diltiazem
  - Dihydropyridine derivatives (e.g. Nifedipine)
• Class I anti-arrhythmic agents 
  - Disopyramide
  - Quinidine
• Amiodarone
• Insulin 
• Oral antidiabetic agents
• Anaesthetic agents
• Beta-blocking agents (in addition to esmolol hydrochloride)
• Ganglion blocking agents
• Nonsteroidal anti-inflammatory drugs
• Floctafenine
• Amisulpride
• Tricyclic antidepressants
  - Imipramine
  - Amitriptyline
• Barbiturates
• Phenothiazines 
  - Chlorpromazine
• Catecholamine-depleting agents
  - Reserpine
• Moxonidine
• Alpha-2-agonists
  - Clonidine
• Ergot derivatives
• Warfarin
• Digitalis glycosides
  - Digoxin 
• Morphine
• Suxamethonium chloride (Succinylcholine)
• Mivacurium
• Epinephrine (adrenaline)
• Dopamine
• Theophylline
• Aminophylline
• Clozapine

• ECG
• Blood pressure
• Serum potassium
• Respiratory rate
• Heart rate

Transition to alternative anti-dysrhythmic agents in patients with supraventricular tachycardia 

• After achieving an adequate control of the heart rate and a stable clinical status in patients with supraventricular tachycardia, transition to alternative anti-dysrhythmic agents such as propranolol or digoxin may be accomplished
• A recommended guideline for such transition is provided below but the physician should carefully consider the labelling instructions for the alternative agent selected:
  Alternative agent: Propranolol hydrochloride: 10-20mg, four to six hourly
  Alternative agent: Digoxin: 0.125-0.5mg, six hourly (Oral or IV)
• Reduce the dosage of esmolol hydrochloride as follows:
  1. Thirty minutes after the first dose of the alternative agent, reduce the infusion rate of esmolol hydrochloride by one half (50%)
  2. After the second dose of the alternative agent, monitor the patient's response and if satisfactory control is maintained for the first hour, discontinue esmolol hydrochloride

Compatible intravenous solutions 

• Dextrose (5%) and Sodium chloride (0.45%)
• Sodium chloride (0.9%) injection
• Dextrose (5%) injection
• Dextrose (5%) in Lactate Ringers' injection
• Lactate Ringers' injection
• Dextrose 5% in sodium chloride (0.9%) injection
• Sodium chloride (0.45%) injection
• Potassium chloride (40mEq/litre) in Dextrose (5%)

Esmolol hydrochloride injection is not compatible with Sodium bicarbonate (5%) injection.

Administration directions for esmolol hydrochloride 100mg/10 ml

• The single dose vial is pre-diluted to provide a ready-to-use 10mg/ml concentration solution recommended for esmolol hydrochloride intravenous administration. It may be used to administer the appropriate loading dose infusions by hand-held syringe while the maintenance dose infusion is being prepared. When using the 10 mg/ml solution a loading dose of 0.5mg/kg/min for a 70 kg patient would be 3.5ml. Any unused portion should be discarded

General administration precautions

• Infusions of concentrations of 20mg/ml have been associated with significant venous irritation and thrombophlebitis in animals and man. Extravasation of 20mg/ml may lead to a serious local reaction and possible skin necrosis
• Local reactions have also been reported following infusion of concentrations of 10mg/ml. Infusion into small veins or through a butterfly catheter should, therefore, be avoided
•  The safety of dosages above 300μg/kg/min (0.3mg/kg/min) has not been studied. In the event of an adverse reaction, the dosage may be reduced or discontinued. If a local infusion site reaction develops, an alternative infusion site should be used, and caution should be taken to prevent extravasation. The use of butterfly needles should be avoided
• It is advised to terminate the infusion gradually because of the risk of rebound tachycardia

Control of ventricular response in patients with supraventricular arrhythmias

• The use of esmolol hydrochloride for control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium. Despite the rapid onset and offset of the effects of esmolol hydrochloride 10mg/ml, severe reactions may occur, including loss of consciousness, cardiogenic shock, cardiac arrest. Several deaths have been reported in complex clinical states where esmolol hydrochloride 10mg/ml was presumably being used to control the ventricular rate

Hypotension

• The most frequently observed side effect is hypotension, which is dose related but can occur at any dose. This can be severe. In the event of a hypotensive episode, the infusion rate should be lowered or, if necessary, be discontinued. Hypotension is usually reversible (within 30 minutes after discontinuation of administration of esmolol hydrochloride). In some cases, additional interventions may be necessary to restore blood pressure. In patients with a low systolic blood pressure, extra caution is needed when adjusting the dosage and during the maintenance infusion

Increases in serum potassium levels and hyperkalemia

• Some beta-blockers, especially those administered intravenously, including esmolol hydrochloride have been associated with increases in serum potassium levels and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment and those on haemodialysis

Anaphylactic reactions

• Beta-blockers may increase both the sensitivity toward allergens and the seriousness of anaphylactic reactions. Patients using beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions

Masking of clinical signs

•  Beta-blockers may mask certain clinical signs of hyperthyroidism (such as tachycardia). Abrupt withdrawal of existing therapy with beta-blockers in patients at risk or suspected of developing thyrotoxicosis may precipitate thyroid storm and these patients must be monitored closely

Esmolol hydrochloride is a beta1 cardioselective adrenergic receptor blocking agent with rapid onset and very short duration of action. Esmolol hydrochloride has no significant intrinsic sympathomimetic activity (ISA) or membrane stabilising activity at therapeutic doses.

Injection (per 10ml) 100mg

• Esmocard (Equity Pharmaceuticals)