Esmolol Hydrochloride AOP Orphan

Esmolol Hydrochloride AOP Orphan is indicated for supraventricular tachycardia (except for pre-excitation syndromes), and for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other circumstances where short-term control of the ventricular rate with a short acting agent is desirable. Esmolol Hydrochloride AOP Orphan is also indicated for tachycardia and hypertension occurring in the perioperative phase and non-compensatory sinus tachycardia where, in the physician's judgment the rapid heart rate requires specific intervention.

Esmolol Hydrochloride AOP Orphan is not indicated for use in children aged up to 18 years. Esmolol Hydrochloride AOP Orphan is not intended for use in chronic settings.

Esmolol Hydrochloride AOP Orphan Premixed 10 mg/ml Solution for Infusion is a ready-to-use 10 mg/ml iso-osmotic solution, recommended for intravenous administration.

Supraventricular Tachyarrhythmia

The Esmolol Hydrochloride AOP Orphan dosage in supraventricular tachyarrhythmias should be individually titrated. Each step consists of a loading dosage followed by a maintenance dose. The effective maintenance dose is between 50 to 200 micrograms/kg/minute, although doses as low as 25 and as high as 300 micrograms/kg/minute have been used.

Flow Chart for Initiation and Maintenance of Treatment

Loading dose and maintenance doses of Esmolol Hydrochloride AOP Orphan to administer for different patient weights are outlined in Table 1 and Table 2 respectively.

Table 1

Volume of Esmolol Hydrochloride AOP Orphan 10 mg/ml required for an INITIAL LOADING DOSE of 500 mcg/ kg / minute

Table 2

Volume of Esmolol Hydrochloride AOP Orphan 10 mg/ml required to provide MAINTENANCE DOSES at infusion rates between 12.5 and 300 mcg/kg/minute

As the desired heart rate or safety end-point (e.g., lowered blood pressure) is approached, OMIT the loading dose and reduce the incremental dose in the maintenance infusion from 50 micrograms/kg/minute to 25 micrograms/kg/minute or lower. If necessary, the interval between the titration steps may be increased from 5 to 10 minutes.

NOTE: Maintenance doses above 200 micrograms/kg/minute have not been shown to have significantly increased benefits, and the safety of doses above 300 micrograms/kg/minute has not been studied.

Perioperative tachycardia and hypertension

For perioperative tachycardia and hypertension the dosing regimen may vary as follows:

For intraoperative treatment - during anaesthesia when immediate control is required:

- A bolus injection of 80 mg is given over 15 to 30 seconds followed by a 150 micrograms/kg/minute infusion. Titrate the infusion rate as required up to 300 micrograms/kg/minute. The volume of infusion required for different patient weights is provided in Table 2.

Upon awakening from anaesthesia

- An infusion of 500 micrograms/kg/minute is given for 4 minutes followed by a 300 micrograms/kg/minute infusion. The volume of infusion required for different patient weights is provided in Table 2.

For post-operative situations when time for titration is available

- A loading dose of 500 micrograms/kg/minute is given over 1 minute before each titration step to produce a rapid onset of action. Use titration steps of 50, 100, 150, 200, 250 and 300 micrograms/kg/minute given over 4 minutes and stopping at the desired therapeutic effect. The volume of infusion required for different patient weights is provided in Table 2.

Potential effects to be aware of during dosing with Esmolol Hydrochloride AOP Orphan:

In the event of an adverse reaction, the dosage of Esmolol Hydrochloride AOP Orphan may be reduced or discontinued. Pharmacological adverse reactions should resolve within 30 minutes.

If a local infusion site reaction develops, an alternative infusion site should be used and caution should be taken to prevent extravasation.

The administration of Esmolol Hydrochloride AOP Orphan for longer than 24 hours has not been thoroughly evaluated. Infusion durations greater than 24 hours should only be used with caution.

It is advised to terminate the infusion gradually because of the risk of rebound tachycardia and rebound hypertension. As with all beta-blockers, because withdrawal effects cannot be excluded, caution should be used in abruptly discontinuing Esmolol Hydrochloride AOP Orphan administration in coronary artery disease (CAD) patients.

Replacing Esmolol Hydrochloride AOP Orphan therapy by alternative drugs

After patients achieve an adequate control of the heart rate and a stable clinical status, transition to alternative drugs (such as antiarrhythmics or calcium antagonists) may be accomplished.

Reducing the dosage:

When Esmolol Hydrochloride AOP Orphan is to be replaced by alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of Esmolol Hydrochloride AOP Orphan as follows:

- Within the first hour after the first dose of the alternative drug, reduce the Esmolol Hydrochloride AOP Orphan infusion rate by one-half (50%).

- After administration of the second dose of the alternative drug, monitor the patient's response and if satisfactory control is maintained for the first hour, discontinue the Esmolol Hydrochloride AOP Orphan infusion.

Additional dosing information

As the desired therapeutic effect or a safety endpoint (e.g., lowered blood pressure) is approached, omit the loading dose and reduce the incremental infusion to 12.5 to 25 micrograms/kg/minute.

Also, if desired, increase the interval between titration steps from 5 to 10 minutes.

Esmolol Hydrochloride AOP Orphan should be discontinued when heart rate or blood pressure rapidly approach or exceed a safety limit, and then restarted without a loading infusion at a lower dose after the heart rate or blood pressure has returned to an acceptable level.

Special populations

Elderly

The elderly should be treated with caution, starting with a lower dosage.

Special studies in the elderly have not been conducted. However, analysis of data from 252 patients over 65 years of age indicated that no variations in pharmacodynamic effects occurred as compared with data from patients under 65.

Patients with renal insufficiency

In patients with renal insufficiency caution is needed when Esmolol Hydrochloride AOP Orphan is administered by infusion, since the acid metabolite of Esmolol Hydrochloride AOP Orphan is excreted unchanged through the kidneys. Excretion of the acid metabolite is significantly decreased in patients with end-stage renal disease, with the elimination half-life increased to about ten-fold that of normal, and plasma levels considerably elevated.

Patients with liver insufficiency

In case of liver insufficiency no special precautions are necessary since the esterases in the red blood cells have a main role in the Esmolol Hydrochloride AOP Orphan metabolism.

Paediatric population

The safety and efficacy of Esmolol Hydrochloride AOP Orphan in children aged up to 18 years have not yet been established.2 but no recommendation on a posology can be made.

- Hypersensitivity to the active substance, to any of the excipients or other beta-blockers (cross sensitivity between beta-blockers is possible);

- Severe sinus bradycardia (less than 50 beats per minute);

- Sick sinus syndrome; severe AV-nodal conductance disorders (without pacemaker); 2nd or 3rd degree AV-block;

- Cardiogenic shock;

- Severe hypotension;

- Decompensated heart failure;

- Concomitant or recent intravenous administration of verapamil. Esmolol Hydrochloride AOP Orphan must not be administered within 48 hours of discontinuing verapamil ;

- Non-treated phaeochromocytoma;

- Pulmonary hypertension;

- Acute asthmatic attack;

- Metabolic acidosis.

Warnings

It is recommended to continuously monitor the blood pressure and the ECG in all patients treated with Esmolol Hydrochloride AOP Orphan.

The use of Esmolol Hydrochloride AOP Orphan for control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised haemodynamically 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 AOP Orphan, severe reactions may occur, including loss of consciousness, cardiogenic shock, cardiac arrest. Several deaths have been reported in complex clinical states where Esmolol Hydrochloride AOP Orphan was presumably being used to control ventricular rate.

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 AOP Orphan). 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.

Bradycardia, including severe bradycardia, and cardiac arrest has occurred with the use of Esmolol Hydrochloride AOP Orphan. Esmolol Hydrochloride AOP Orphan should be used with special caution in patients with low pretreatment heart rates and only when the potential benefits are considered to outweigh the risk.

Esmolol Hydrochloride AOP Orphan is contraindicated in patients with pre-existing severe sinus bradycardia. If the pulse rate decreases to less than 50-55 beats per minute at rest and the patient experiences symptoms related to bradycardia, the dosage should be reduced or administration stopped.

Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure. Beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure.

Caution should be exercised when using Esmolol Hydrochloride AOP Orphan in patients with compromised cardiac function. At the first sign or symptom of impending cardiac failure, Esmolol Hydrochloride AOP Orphan should be withdrawn. Although withdrawal may be sufficient because of the short elimination half-life of Esmolol Hydrochloride AOP Orphan, specific treatment may also be considered. Esmolol Hydrochloride AOP Orphan is contraindicated in patients with decompensated heart failure.

Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block or other cardiac conduction disturbances.

Esmolol Hydrochloride AOP Orphan should be used with caution and only after pre-treatment with alpha-receptor blockers in patients with pheochromocytoma.

Caution is required when Esmolol Hydrochloride AOP Orphan is used to treat hypertension following induced hypothermia.

Patients with bronchospastic disease should, in general, not receive beta-blockers. Because of its relative beta-1 selectivity and titratability, Esmolol Hydrochloride AOP Orphan should be used with caution in patients with bronchospastic diseases. However, since beta-1 selectivity is not absolute, Esmolol Hydrochloride AOP Orphan should be carefully titrated to obtain the lowest possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately and a beta-2-agonist should be administered if necessary.

If the patient already uses a beta-2-receptor stimulating agent, it may be necessary to re-evaluate the dose of this agent.

Esmolol Hydrochloride AOP Orphan should be used with caution in patients with a history of wheezing or asthma.

Precautions

Esmolol Hydrochloride AOP Orphan should be used with caution in diabetics or in case of suspected or actual hypoglycaemia. Beta-blockers may mask the prodromal symptoms of a hypoglycaemia such as tachycardia. However, dizziness and sweating may not be affected. Concomitant use of beta-blockers and antidiabetic agents can increase the effect of the antidiabetic agents (blood glucose-lowering).

Infusion site reactions have occurred with the use of both Esmolol Hydrochloride AOP Orphan 10 mg/ml and 20 mg/ml. These reactions have included infusion site irritation and inflammation as well as more severe reactions such as thrombophlebitis, necrosis, and blistering, in particular when associated with extravasation. Infusions into small veins or through a butterfly catheter should be avoided. If a local infusion site reaction develops, an alternative infusion site should be used.

Beta-blockers may increase the number and the duration of anginal attacks in patients with Prinzemetal's angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Non-selective beta-blockers should not be used for these patients and beta-1 selective blockers should only be used with the utmost care.

In hypovolemic patients, Esmolol Hydrochloride AOP Orphan can attenuate reflex tachycardia and increase the risk of circulatory collapse. Therefore, Esmolol Hydrochloride AOP Orphan should be used with caution in such patients.

In patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), beta-blockers should be used with great caution as aggravation of these disorders may occur.

Some beta-blockers, especially those administered intravenously, including Esmolol Hydrochloride AOP Orphan, 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.

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.

Beta-blockers have been associated with the development of psoriasis or psoriasiform eruptions and with aggravation of psoriasis. Patients with a personal or family history of psoriasis should be administered beta-blockers only after careful consideration of expected benefits and risks.

Beta-blockers, such as propranolol and metoprolol, 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.

This medicinal product contains approximately 30.45 mmol (or 700 mg) of sodium per bag. To be taken into consideration by patients on a controlled sodium diet.

Not relevant.

In case of undesirable effects, the dose of Esmolol Hydrochloride AOP Orphan can be reduced or discontinued.

Most of the undesirable effects observed have been mild and transient. The most important one has been hypotension. The following undesirable effects are ranked according to MedDRA System Organ Class (SOC) and to their frequency.

Note: The frequency of occurrence of adverse events is classified as follows:

Very common (> 1/10)

Common (> 1/100 to < 1/10)

Uncommon (> 1/1000 to < 1/100)

Very rare (<1/10000)

Not known (Cannot be estimated from the available data)

¹ Dizziness and diaphoresis are in association with symptomatic hypotension.

² In association with Injection and Infusion site reactions.

¹ Dizziness and diaphoresis are in association with symptomatic hypotension.

² In association with Injection and Infusion site reactions.

³ Beta-blockers as a drug class can cause psoriasis in some situations, or worsen it.

⁴ Including midscapular pain and costochondritis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse events via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Cases of massive accidental overdoses with concentrated solutions of Esmolol Hydrochloride AOP Orphan have occurred. Some of these overdoses have been fatal while others have resulted in permanent disability. Loading doses in the range of 625 mg to 2.5 g (12.5 to 50 mg/kg) have been fatal.

Symptoms

In case of overdose the following symptoms can occur: severe hypotension, sinus bradycardia, atrioventricular block, heart insufficiency, cardiogenic shock, cardiac arrest, bronchospasm, respiratory insufficiency, loss of consciousness to coma, convulsions, nausea, vomiting, hypoglycaemia and hyperkalaemia.

Treatment

Because of the short elimination half-life of Esmolol Hydrochloride AOP Orphan (approximately 9 minutes), the first step in the management of toxicity should be to discontinue the administration of the drug. The time taken for symptoms to disappear following overdosing will depend on the amount of Esmolol Hydrochloride AOP Orphan administered. This may take longer than the 30 minutes seen with discontinuation at therapeutic dose levels of Esmolol Hydrochloride AOP Orphan. Artificial respiration may be necessary. Based on the observed clinical effects, the following general measures should also be considered:

Bradycardia: atropine or another anticholinergic drug should be given i.v. When the bradycardia cannot be treated sufficiently a pacemaker may be necessary.

Bronchospasm: nebulised beta-2-sympathomimetics should be given. If this is not sufficient intravenous beta-2-sympathomimetics or aminophylline can be considered.

Symptomatic hypotension: fluids and/or pressor agents should be given i.v.

Cardiovascular depression or cardiac shock: diuretics or sympathomimetics can be administered. The dose of sympathomimetics (depending on the symptoms: dobutamine, dopamine, noradrenaline, isoprenaline, etc.) depends on the therapeutic effect.

In case further treatment is necessary, the following agents can be given i.v. based on the clinical situation and judgement of the treating healthcare professional:

- Atropine;

- Inotropic agents;

- Calcium ions.

Pharmacotherapeutic group: Beta-blocking agents, selective.

ATC code: C07AB09

Esmolol Hydrochloride AOP Orphan is a beta-selective (cardioselective) adrenergic receptor blocking agent. At therapeutic doses Esmolol Hydrochloride AOP Orphan has no significant intrinsic sympathomimetic activity (ISA) or membrane stabilising activity.

Esmolol hydrochloride, the active ingredient of Esmolol Hydrochloride AOP Orphan, is chemically related to the phenoxy propanolamine class of beta-blockers.

Based on the pharmacological properties Esmolol Hydrochloride AOP Orphan has a rapid onset and a very short duration of action by which the dose can be quickly adjusted.

When an appropriate loading dose is used, steady state blood levels are obtained within 5 minutes. However, the therapeutic effect is achieved sooner than the stable plasma concentration. The infusion rate can then be adjusted to obtain the desired pharmacological effect.

Esmolol Hydrochloride AOP Orphan has the known haemodynamic and electrophysiologic effect of beta-blockers:

- Reduction of the heart frequency during rest and exercise;

- Reduction of the isoprenaline caused increase of the heart frequency;

- Increase of the recovering time of the SA-node;

- Delay of the AV-conductance;

- Prolonging the AV-interval with normal sinus rhythm and during atrium stimulation without delay in the His-Purkinje tissue;

- Prolonging of PQ time, induction of AV block grade II;

- Prolonging the functional refractory period of atria and ventricles;

- Negative inotropic effect with decreased ejection fraction;

- Decrease in blood pressure.

Children

An uncontrolled pharmacokinetic/efficacy study was undertaken in 26 paediatric patients aged 2 to 16 years with supraventricular tachycardia (SVT). A loading dose of 1000 micrograms/kg of Esmolol Hydrochloride AOP Orphan was administered followed by a continuous infusion of 300 micrograms/kg/minute. SVT was terminated in 65% of patients within 5 minutes of the commencement of esmolol.

In a randomised but uncontrolled dose comparison study, efficacy was assigned in 116 paediatric patients aged 1 week to 7 years with hypertension following repair of coarctation of the aorta. Patients receiving an initial infusion of either 125 micrograms/kg, 250 micrograms/kg, or 500 micrograms/kg, followed by a continuous infusion of 125 micrograms/kg/minute, 250 micrograms/kg/minute, or 500 micrograms/kg/minute respectively. There was no significant difference in hypotensive effect between the 3 dosage groups. 54% of patients overall required medication other than Esmolol Hydrochloride AOP Orphan to achieve satisfactory blood pressure control. No difference was apparent in this regard between the different dose groups.

The kinetics of esmolol are linear in healthy adults, the plasma concentration is proportional to the dose. If a loading dose is not used then steady-state blood concentrations are reached within 30 minutes with doses of 50 to 300 micrograms/Kg per minute.

The distribution half-life of esmolol hydrochloride is very fast, about 2 minutes.

The volume of distribution is 3.4 l/kg.

Esmolol hydrochloride is metabolised by esterases into an acid metabolite (ASL-8123) and methanol. This occurs through hydrolysis of the ester group by esterases in the red blood cells.

The metabolism of esmolol hydrochloride is independent when the dose is between 50 and 300 micrograms/kg/minute.

Esmolol hydrochloride is 55% bound to human plasma protein compared with only 10% for the acid metabolite.

The elimination half-life after intravenous administration is approximately 9 minutes.

The total clearance is 285 ml/kg/minute; this is independent of the circulation of the liver or any other organ. Esmolol hydrochloride is excreted by the kidneys, partly unchanged (less than 2% of the administered amount), partly as acid metabolite that has a weak (less than 0.1% of esmolol) beta-blocking activity. The acid metabolite is excreted in the urine and has a half-life of about 3.7 hours.

Children

A pharmacokinetic study was undertaken in 22 paediatric patients aged 3 to 16 years. A loading dose of 1000 micrograms/kg of Esmolol Hydrochloride AOP Orphan was administered, followed by a continuous infusion of 300 micrograms/kg/minute. The observed mean total body clearance was 119 ml/kg/minute, the mean volume of distribution 283 ml/kg and the mean terminal elimination half-life 6.9 minutes, indicating that Esmolol Hydrochloride AOP Orphan kinetics in children are similar to those in adults. However, large inter-individual variability was observed.

No teratogenic effect has been observed in animal studies. In rabbits an embryo toxic effect has been observed (increase in fetal resorption) which was probably caused by Esmolol Hydrochloride AOP Orphan. This effect was observed at doses at least 10 times higher than the therapeutic dose. No studies have been done on the effect of Esmolol Hydrochloride AOP Orphan on the fertility and on peri- and postnatal effects. Esmolol Hydrochloride AOP Orphan was found to be not mutagenic in several in vitro and in vivo test systems. The safety of Esmolol Hydrochloride AOP Orphan has not been examined in long-term studies.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products or sodium bicarbonate solutions.

Esmolol Hydrochloride AOP Orphan Premixed 10 mg/ml Solution for Infusion is provided in 250 ml PL-2408 bags, which are ready-to-use, non-latex, polyolefinic bags with two PVC ports, a medication port and a delivery port. In the case of Esmolol Hydrochloride AOP Orphan Premixed 10 mg/ml Solution for Infusion, the medication port is to be used only for withdrawing an initial bolus from the bag; the medication withdrawal port is not intended for repeat bolus administration. Use aseptic technique when withdrawing the bolus dose. Do not add any additional medications to Esmolol Hydrochloride AOP Orphan Premixed 10 mg/ml Solution for Infusion.

Each bag is for single-patient use only. Once the seal on the port has been broken and product withdrawn from the container, the bag should be used within 24 hours. Any unused solution and the containers should be disposed of in accordance with local requirements. Do not reconnect partially used bags.

CAUTION

Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

TO OPEN

Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution.

Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard the solution as sterility may be impaired. Visually inspect the solution for particulate matter and discolouration prior to administration. Only a clear and colourless or slightly coloured solution should be used.

Do not introduce additives to Esmolol Hydrochloride AOP Orphan Premixed 10 mg/ml Solution for Infusion.

PREPARATION FOR INTRAVENOUS ADMINISTRATION (use aseptic technique)

1. Suspend container from eyelet support.

2. Remove plastic protector from delivery port at bottom of container.

3. Attach administration set. Refer to complete directions accompanying set.