Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Orpha-Devel Handels und Vertriebs GmbH, Wintergasse 85/1B, A-3002 Purkersdorf, Austria
ESMOLOL HYDROCHLORIDE 2500 mg powder for concentrate for solution for infusion must be reconstituted/diluted and used immediately after opening (see section 6).
Incorrect dilutions of ESMOLOL HYDROCHLORIDE 2500 mg powder may result in severe overdoses. These overdoses may result in death or in permanent disability (see section 4.9).
It is advised to terminate the infusion gradually because of the risk of rebound tachycardia.
It is recommended to continuously monitor the blood pressure and the ECG in all patients treated with ESMOLOL HYDROCHLORIDE 2500 mg powder. In the event of a hypotensive episode, the infusion rate should be reduced or, when necessary, be discontinued.
The use of ESMOLOL HYDROCHLORIDE 2500 mg powder 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 2500 mg powder, severe reactions may occur, including loss of consciousness, cardiogenic shock, cardiac arrest. Several deaths have been reported in complex clinical states where ESMOLOL HYDROCHLORIDE 2500 mg powder was presumably being used to control the 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 HYDROCHLORIDE 2500 mg powder). 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. ESMOLOL HYDROCHLORIDE 2500 mg powder 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 2500 mg powder is contraindicated in patients with pre-existing severe sinus bradycardia (see section 4.3). 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.
The elderly should be treated with caution, starting with a lower dosage, but tolerance is usually good in the elderly.
Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and Betablockade 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 HYDROCHLORIDE 2500 mg powder in patients with compromised cardiac function. At the first sign or symptom of impending cardiac failure, ESMOLOL HYDROCHLORIDE 2500 mg powder should be withdrawn. Although withdrawal may be sufficient because of the short elimination half-life of ESMOLOL HYDROCHLORIDE 2500 mg powder , specific treatment may also be considered (see section 4.9). ESMOLOL HYDROCHLORIDE 2500 mg powder is contraindicated in patients with decompensated heart failure (see section 4.3).
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 (see section 4.3).
ESMOLOL HYDROCHLORIDE 2500 mg powder should be used with caution and only after pre-treatment with alpha-receptor blockers in patients with pheochromocytoma (see section 4.3).
Caution is required when ESMOLOL HYDROCHLORIDE 2500 mg powder is used to treat hypertension following induced hypothermia.
Patients with bronchospastic disease should, in general, not receive beta blockers. Because of its relative beta1 selectivity and titratability, ESMOLOL HYDROCHLORIDE 2500 mg powder should be used with caution in patients with bronchospastic diseases. However, since beta1 selectivity is not absolute, ESMOLOL HYDROCHLORIDE 2500 mg powder should be carefully titrated to obtain the lowest possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately and a beta2 agonist should be administered if necessary.
If the patient already uses a beta-2-receptorstimulating agent, it can be necessary to re-evaluate the dose of this agent.
ESMOLOL HYDROCHLORIDE 2500 mg powder should be used with caution in patients with a history of wheezing and asthma.
ESMOLOL HYDROCHLORIDE 2500 mg powder should be used with caution in diabetics or in case of suspected of actual hypoglycaemia.
The severity of hypoglycaemia is less than the one observed with less cardio-selective beta-blockers. Beta-blockers may mask the prodromal symptoms of hypoglycaemia such as tachycardia.
However, dizziness and sweating, however, may not be affected. Concomitant use of beta-blockers and antidiabetic agents can increase the effect of the antidiabetic agents (blood glucose–lowering) (see section 4.5).
Infusions of concentrations of 20 mg/ml have been associated with significant venous irritation and thrombophlebitis in animals and man. Extravasation of 20 mg/ml may lead to a serious local reaction and possible skin necrosis.
Local reactions have also been reported following infusion of concentrations of 10 mg/ml. Infusion into small veins or through a butterfly catheter should therefore be avoided. The administration of the 50 mg/ml solution should be strictly done in a large vein or in a central catheter only using a perfusor pump.
Beta-blockers may increase the number and the duration of anginal attacks in patients with Prinzmetal’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 2500 mg powder can attenuate reflex tachycardia and increase the risk of circulatory collapse. Therefore, ESMOLOL HYDROCHLORIDE 2500 mg powder 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 2500 mg powder, 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 (see section 4.5).
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.
The safety and efficacy of ESMOLOL HYDROCHLORIDE 2500 mg powder ESMOLOL HYDROCHLORIDE 2500 mg powder in children have not been established.
Care should always be exercised whenever ESMOLOL HYDROCHLORIDE 2500 mg powder is used with other antihypertensive agents or other drugs that may cause hypotension or bradycardia: the effects of ESMOLOL HYDROCHLORIDE 2500 mg powder may be enhanced or the side-effects of hypotension or bradycardia may be exacerbated.
Calcium antagonists such as verapamil and to a lesser extent diltiazem have a negative influence on contractility and AV-conduction. The combination should not be given to patients with conduction abnormalities and esmolol should not be administered within 48 hours of discontinuing verapamil (see section 4.3).
Calcium antagonists such as dihydropyridine derivatives (e.g., nifedipine) may increase the risk of hypotension. In patients with cardiac insufficiency and who are being treated with a calcium antagonist, treatment with beta-blocking agents may lead to cardiac failure. Careful titration of ESMOLOL HYDROCHLORIDE 2500 mg powder and appropriate haemodynamic monitoring is recommended.
Concomitant use of ESMOLOL HYDROCHLORIDE 2500 mg powder and Class I anti-arrhythmic agents (e.g. disopyramide quinidine) and amiodarone may have potentiating effect on atrial-conduction time and induce negative inotropic effect.
Concomitant use of ESMOLOL HYDROCHLORIDE 2500 mg powder and insulin or oral antidiabetic drugs may intensify the blood sugar lowering effect (especially non-selective beta-blockers). Beta-adrenergic blockade may prevent the appearance of signs of hypoglycemia (tachycardia), but other manifestations such as dizziness and sweating may not be masked.
Anaesthetic drugs: in situations where the patient’s volume status is uncertain or concomitant antihypertensive drugs are utilized, there may be attenuation of the reflex tachycardia and an increase of the risk of hypotension.
Continuation of beta-blockade reduces the risk of arrhythmia during induction and intubation. The anaesthesist should be informed when the patient is receiving a beta-blocking agent in addition to ESMOLOL HYDROCHLORIDE 2500 mg powder. The hypotensive effects of inhalation anaesthetic agents may be increased in the presence of ESMOLOL HYDROCHLORIDE 2500 mg powder. The dosage of either agent may be modified as needed to maintain the desired haemodynamics.
The combination of ESMOLOL HYDROCHLORIDE 2500 mg powder with ganglion blocking agents can enhance the hypotensive effect.
NSAIDs may decrease the hypotensive effects of beta-blockers.
Special caution must be taken when using floctafenine or amisulpride concomitantly with beta- blockers.
Concomitant administration of tricyclic antidepressants (such as imipramine and amitriptyline), barbiturates and phenothiazines (such as chlorpromazine), as well as other antipsychotic agents (such as clozapine) may increase the blood pressure lowering effect. Dosing of ESMOLOL HYDROCHLORIDE 2500 mg powder should be adjusted downward to avoid unexpected hypotension.
When using beta-blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic). Patients using beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions (see section 4.4).
The effects of ESMOLOL HYDROCHLORIDE 2500 mg powder may be counteracted by sympathomimetic drugs having beta- adrenergic agonist activity with concomitant administration. The dose of either agent may need to be adjusted based on patient response, or use of alternate therapeutic agents considered.
Catecholamine-depleting agents, e.g., reserpine, may have an additive effect when given with beta-blocking agents. Patients treated concurrently with ESMOLOL HYDROCHLORIDE 2500 mg powder and a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may result in vertigo, syncope or postural hypotension.
Use of beta-blockers with moxonidine or alpha-2-agonists (such as clonidine), increases the risk of withdrawal rebound hypertension. If clonidine or moxonidine are used in combination with a beta-blocker and both treatments have to be discontinued, the beta blocker should be discontinued first and then the clonidine or moxonidine after a few days.
The use of beta-blockers with ergot derivatives may result in severe peripheral vasoconstriction and hypertension.
Data from an interaction study between ESMOLOL HYDROCHLORIDE 2500 mg powder and warfarin showed that concomitant administration of ESMOLOL HYDROCHLORIDE 2500 mg powder and warfarin does not alter warfarin plasma levels. ESMOLOL HYDROCHLORIDE 2500 mg powder concentrations, however, were equivocally higher when given with warfarin.
When digoxin and ESMOLOL HYDROCHLORIDE 2500 mg powder were concomitantly administered intravenously to normal volunteers, there was a 10-20% increase in digoxin blood levels at some time points. The combination of digitalis glycosides and ESMOLOL HYDROCHLORIDE 2500 mg powder may increase AV conduction time. Digoxin did not affect ESMOLOL HYDROCHLORIDE 2500 mg powder pharmacokinetics.
When intravenous morphine and ESMOLOL HYDROCHLORIDE 2500 mg powder interaction was studied in normal subjects, no effect on morphine blood levels was seen. The ESMOLOL HYDROCHLORIDE 2500 mg powder steady-state blood levels were increased by 46% in the presence of morphine, but no other pharmacokinetic parameters were changed.
The effect of ESMOLOL HYDROCHLORIDE 2500 mg powder on the duration of suxamethonium chloride-induced or mivacurium-induced neuromuscular blockade has been studied in patients undergoing surgery. ESMOLOL HYDROCHLORIDE 2500 mg powder did not affect the onset of neuromuscular blockade by suxamethonium chloride, but the duration of neuromuscular blockade was prolonged from 5 minutes to 8 minutes. ESMOLOL HYDROCHLORIDE 2500 mg powder moderately prolonged the clinical duration (18.6%) and recovery index (6.7%) of mivacurium.
Although the interactions observed in studies of warfarin, digoxin, morphine suxamethonium chloride or mivacurium are not of major clinical importance, ESMOLOL HYDROCHLORIDE 2500 mg powder should be titrated with caution in patients being treated concurrently with warfarin, digoxin, morphine or suxamethonium chloride or mivacurium.
There are limited amount of data from the use of esmolol hydrochloride in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Esmolol hydrochloride is not recommended in 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 on birth defects 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.
Esmolol hydrochloride should not be used during breast-feeding.
It is not known whether esmolol hydrochloride/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.
There are no human data on the effects of esmolol hydrochloride on fertility.
Not relevant.
In case of undesirable effects, the dose of ESMOLOL HYDROCHLORIDE 2500 mg powder can be reduced or discontinued.
Most of the undersirable 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 (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Common: Anorexia
Not known: Hyperkalemia, Metabolic acidosis
Common: Depression, Anxiety
Uncommon: Thinking abnormal
Common: Dizziness1, Somnolence, Headache, Paraesthesiae, Disturbance in attention, Confusional state, Agitation
Uncommon: Syncope, Convulsion, Speech disorder
Uncommon: Visual impairment
Uncommon: Bradycardia, Atrioventricular block, Pulmonary arterial pressure increased, Cardiac Failure, Ventricular extrasystoles, Nodal rhythm, Angina pectoris
Very rare: Sinus arrest, Asystole
Not known: Accelerated idioventricular rhythm, Coronary arteriospasm, Cardiac arrest.
Very common: Hypotension
Uncommon: Peripheral ischaemia, Pallor, Flushing
Very rare: Thrombophlebitis2
Uncommon: Dyspnoea, Pulmonary oedema, Bronchospasm, Wheezing, Nasal congestion, Rhonchi, Rales
Common: Nausea, Vomiting
Uncommon: Dysgeusia, Dyspepsia, Constipation, Dry mouth, Abdominal pain
Very common: Diaphoresis1
Uncommon: Skin discolouration2, Erythema2
Very rare: Skin necrosis2 (due to extravasation)
Not known: Psoriasis3, Angioedema, Urticaria
Uncommon: Musculoskeletal pain4
Uncommon: Urinary retention
Common: Asthenia, Fatigue, Injection site reaction, Infusion site reaction, Infusion site inflammation, Infusion site induration
Uncommon: Chills, Pyrexia, Oedema2, Pain2, Infusion site burning, Infusion site ecchymosis, Chest Pain
Not known: Infusion site phlebitis, Infusion site vesicles, Blistering2
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 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 reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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