Brevibloc (Solution) Instructions for Use

ATC Code

C07AB09 (Esmolol)

Active Substance

Esmolol

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Cardioselective blocker of β₁-adrenergic receptors.

Esmolol belongs to the class of phenoxypropanolamine beta-blockers by its chemical nature. It has an enzymatically labile ester linkage (this determines its rapid metabolism and short plasma T_1/2).

It is characterized by a rapid onset of action, a very short duration of action, and at therapeutic doses, it does not possess intrinsic sympathomimetic and membrane-stabilizing activity. It has antianginal, antihypertensive, and antiarrhythmic effects.

It reduces catecholamine-stimulated formation of cyclic AMP from ATP, reduces intracellular calcium ion current, decreases heart rate, slows conduction, and reduces myocardial contractility. The antiarrhythmic effect is determined by the inhibition of impulse conduction in the antegrade and, to a lesser extent, retrograde directions through the AV node and via accessory pathways.

Esmolol, like other beta-blockers, has negative inotropic, chronotropic, bathmotropic, and dromotropic effects.

In elderly patients over 65 years of age, no differences in hemodynamic effects were noted compared to younger patients.

The action begins at the moment of administration, the full therapeutic effect develops 2 minutes after administration and ends 10-20 minutes after the infusion is stopped.

Pharmacokinetics

Distribution and Metabolism

Esmolol is metabolized by erythrocyte esterases to an acidic metabolite ASL-8123, which has weak (less than 0.1% of esmolol hydrochloride) beta-adrenergic blocking activity.

The binding of esmolol to plasma proteins is 55% (for the acidic metabolite this figure is only 10%).

Excretion

The T_1/2 of esmolol after IV administration is about 9 minutes. The T_1/2 of the acidic metabolite by the kidneys is about 3.7 hours. Less than 2% of esmolol is excreted by the kidneys unchanged.

Pharmacokinetics in Special Clinical Cases

In chronic renal failure, the T_1/2 of the acidic metabolite in urine increases 10-fold.

Indications

• Supraventricular tachycardias, including atrial fibrillation and atrial flutter, in the perioperative and postoperative period or in any other situations requiring short-term control of ventricular rate using a short-acting drug;
• Tachycardia and arterial hypertension in the perioperative period;
• Non-compensatory sinus tachycardia.

ICD codes

Dosage Regimen

Solution

The drug is intended for IV administration only and for short-term use only.

The loading dose of the drug is 500 mcg/kg/min for patients with a body weight of 70 kg is 3.5 ml.

The dose should be selected individually and adjusted depending on the clinical response. Dose titration should be performed taking into account the ventricular rate and, if necessary, BP.

Supraventricular tachycardias, including atrial fibrillation and atrial flutter

The effective dose of the drug for the treatment of supraventricular tachyarrhythmia is 50-200 mcg/kg/min. For ventricular rate control, maintenance infusion doses above 200 mcg/kg/min are not recommended. The drug in doses above 200 mcg/kg/min provides a slight decrease in heart rate, while the frequency of adverse reactions increases. Nevertheless, higher doses (250-300 mcg/kg/min) may be required for adequate BP control. The safety of the drug in doses above 300 mcg/kg/min has not been studied.

In supraventricular tachyarrhythmia, the dose of the drug should be selected individually by titration, in which each step includes a loading dose followed by a maintenance dose.

Treatment initiation and administration scheme

1. Administration of a loading dose of 500 mcg/kg/min over 1 min, then – administration of a maintenance dose of 50 mcg/kg/min for 4 min*.
2. In case of positive result administration of a maintenance dose of 50 mcg/kg/min.
3. In case of negative result within 5 min repeat administration of a dose of 500 mcg/kg/min over 1 min; increase the maintenance dose to 100 mcg/kg/min over the next 4 min.
4. In case of positive result administration of a maintenance dose of 100 mcg/kg/min.
5. In case of negative result within 5 min repeat administration of a dose of 500 mcg/kg/min over 1 min; increase the maintenance dose to 150 mcg/kg/min over 4 min.
6. In case of positive result administration of a maintenance dose of 150 mcg/kg/min.
7. In case of negative result repeat administration of a dose of 500 mcg/kg/min over 1 min; increase the maintenance dose to 200 mcg/kg/min and leave at this level.

* – If the desired degree of heart rate reduction is achieved, but BP decreases, it is necessary to stop the administration of the loading dose and reduce the rate of maintenance administration from 50 mcg/kg/min to 25 mcg/kg/min or lower. If necessary, the time interval between titration steps can be increased from 5 to 10 min.

Note there are no data indicating that maintenance doses above 200 mcg/kg/min lead to a greater therapeutic effect. The safety of doses above 300 mcg/kg/min has not been studied.

After achieving the required heart rate and stable clinical condition in patients with supraventricular tachycardia, a transition to other antiarrhythmic drugs can be made, such as verapamil, propranolol or metoprolol, digoxin or quinidine.

The recommended procedure for such a transition is described below (one should be guided by the instructions for medical use of alternative drugs).

The dose of Brevibloc should be reduced as follows.

1. During the first hour after the first dose of the alternative drug, reduce the infusion rate of Brevibloc by half.
2. After the second dose of the alternative drug, it is necessary to monitor the patient’s heart rate and, if a satisfactory heart rate is maintained during the first hour, the administration of Brevibloc should be discontinued.

Administration of Brevibloc for more than 24 hours has not been evaluated. Administration of Brevibloc for more than 24 hours should be performed with caution.

Tachycardia and arterial hypertension in the perioperative period

When treating tachycardia and/or arterial hypertension in the perioperative period, the following dosing regimens should be used.

A) For intraoperative treatment under general anesthesia, when control of ventricular rate is required – administer a bolus loading dose of 80 mg over 15-30 sec followed by an infusion at a dose of 150 mcg/kg/min. Titrate the infusion rate if necessary up to 300 mcg/kg/min.

B) After emergence from general anesthesia perform an infusion at a rate of 500 mcg/kg/min for 4 min followed by an infusion of 300 mcg/kg/min.

C) In the postoperative period, when time allows for dose titration, a loading dose of 500 mcg/kg/min is given over 1 min before each titration step to ensure rapid onset of drug action. Titration steps of 50, 100, 150, 200, 250 and 300 mcg/kg/min over 4 min each, stopping when the desired therapeutic effect is achieved.

Additional information on doses: upon achieving a therapeutic effect or a decrease in BP, stop the administration of the loading dose and reduce the infusion rate to 12.5-25 mcg/kg/min. Furthermore, the interval between titration steps can be increased from 5 to 10 min if necessary.

If the heart rate or BP falls below the lower limit of normal or rapidly approaches these values, the drug administration should be stopped, and after the heart rate and/or BP return to a satisfactory level, administration should be resumed at a reduced dose without loading doses.

In patients with impaired renal function, the drug should be used with caution.

Instructions for using Intra Via containers

Brevibloc solution for infusion in a container with two PVC ports – a port for withdrawing the primary loading dose (self-sealing, polyisoprene) and a port for drug infusion (for connecting the infusion system).

The port for withdrawing the primary loading dose is used exclusively for obtaining the primary loading dose of the drug and is not intended for the infusion of subsequent loading or maintenance doses.

Strict adherence to aseptic rules is required when withdrawing the primary loading dose.

Do not add additional components to the container!

The contents of the container are intended for single use and do not contain preservatives. After removing the protective cap from the port and starting the infusion, the contents of the container should be used within 24 hours.

Dispose of unused residues.

Do not reconnect partially used containers to the infusion system.

Precautions

Do not connect containers in series, as this may lead to air embolism due to residual air from one container being drawn in before fluid administration from the second container is completed.

Do not remove the outer packaging (bag) until ready for use. Do not use if the bag is opened or partially damaged. The bag protects the container from moisture. The sterility of the solution is ensured by the integrity of the container.

It is not allowed to add other drugs to the solution. The primary loading dose is withdrawn through the appropriate port.

Opening the packaging

1. Open the bag along the notch and remove the container with the solution. Condensation may form between the container and the bag, as well as areas of darkening of the protective laminated bag and container. This is not a deviation from the norm and does not affect the quality and safety of the drug.

2. By firmly squeezing the container, check it for integrity. If mechanical damage is found, the container should be disposed of, as sterility may be compromised.

Do not use the drug in case of color change, solution cloudiness, or packaging integrity violation.

Preparation for infusion

Aseptic conditions should be observed.

1. Hang the container by the special hole on a support.

2. Remove the plastic protective cap from the drug infusion port at the bottom of the container.

3. Attach the administration set (follow the instructions supplied with the set).

Adverse Reactions

Adverse reactions presented in this section were identified in clinical studies of the drug during the treatment of supraventricular tachycardia/tachyarrhythmia, as well as in the perioperative period.

Definition of frequency of adverse reactions: very common (≥1/10), common (≥1/100 – <1/10), uncommon (≥1/1000 – <1/100), rare (≥1/10 000 – <1/1000), very rare (<1/10 000).

1 – Includes increased frequency of ventricular extrasystole and paired ventricular extrasystoles.

2 – Based on reports of cases of arterial hypotension in 8 placebo-controlled perioperative studies, arterial hypotension occurred less frequently in patients receiving the drug in the perioperative period than in patients receiving the drug during treatment of supraventricular tachycardia/tachyarrhythmia. Moreover, in these 8 studies, the proportion (or frequency) of arterial hypotension in patients receiving the drug and general anesthesia was the same as the proportion (or frequency) of arterial hypotension in patients receiving placebo and general anesthesia.

3 – Necrosis and blistering at the injection site, as indicated below.

* – Data insufficient to estimate frequency.

Adverse reactions in the post-marketing period

In addition to the adverse reactions recorded in clinical studies, the following adverse reactions have been reported during post-marketing use.

Metabolism and nutrition disorders: metabolic acidosis.

Cardiovascular system disorders: cardiac arrest, pulmonary edema, coronary artery spasm.

Allergic reactions: angioedema, urticaria.

Musculoskeletal system disorders: muscle weakness.

General reactions necrosis at the injection site, vesicles at the infusion site, blistering.

The patient should inform the doctor if any of the side effects listed in the instructions worsen or any other side effects appear.

Contraindications

• Severe bradycardia (heart rate less than 50 beats/min);
• Sick sinus syndrome;
• Second and third degree AV block;
• Cardiogenic shock;
• Severe arterial hypotension;
• Acute heart failure;
• Pulmonary hypertension;
• Pheochromocytoma without simultaneous use of alpha-blockers;
• Age under 18 years;
• Simultaneous IV administration of slow calcium channel blockers (verapamil, diltiazem);
• Hypersensitivity to the components of the drug.

With caution

• First degree AV block;
• Bronchial asthma, COPD;
• Impaired peripheral circulation (Raynaud’s syndrome, intermittent claudication);
• Chronic heart failure;
• Impaired renal function;
• Hyperkalemia;
• Thyrotoxicosis;
• Psoriasis;
• Myasthenia gravis;
• Prinzmetal’s angina;
• Hypovolemia;
• Diabetes mellitus;
• Pheochromocytoma (with simultaneous use of alpha-blockers);
• Secondary arterial hypertension (due to vasoconstriction, during or after surgery, against the background of hypothermia);
• Pregnancy;
• Elderly age.

Use in Pregnancy and Lactation

Data on the use of Brevibloc during pregnancy and breastfeeding are not available. The potential risk to the fetus and the benefit to the mother should be assessed before use. Use of the drug during pregnancy is possible only if the benefit to the mother outweighs the potential risk to the fetus.

If treatment is considered appropriate, constant monitoring of uteroplacental blood flow should be carried out, since beta-blockers can reduce placental blood supply.

It has been reported that the use of the drug in the second and third trimesters of pregnancy or during labor and delivery caused fetal bradycardia, which persisted after the drug infusion was stopped. If pregnant women receive treatment immediately before delivery, the beta-blocking effect may persist in the newborn for several days after birth and may lead to clinically significant bradycardia, respiratory distress, hypoglycemia, and arterial hypotension. Reduced compensatory cardiovascular responses and heart failure may require ICU hospitalization and monitoring of newborns.

It is not known whether Esmolol is excreted in breast milk, so if it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Renal Impairment

In patients with impaired renal function, the drug should be used with caution.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in the elderly.

Special Precautions

During treatment, careful and constant monitoring of ECG, BP, and heart rate is necessary.

Effect on BP, heart rate, rhythm and cardiac contractility

Adverse reactions to beta-blockers, including Brevibloc, from the heart and blood vessels can be severe, especially in patients with hemodynamic impairment and patients taking drugs that increase the risk of cardiovascular reactions. Severe reactions may include loss of consciousness, cardiogenic shock, cardiac arrest, which can be fatal. Brevibloc, in the absence of contraindications, should be used with caution and only after a thorough individual assessment of risks and expected benefits in patients with hemodynamic impairment and patients at increased risk due to possible drug interactions.

Arterial hypotension

Arterial hypotension, including severe, has been observed during the use of the drug. Arterial hypotension is dose-dependent. Close monitoring of patients, especially in case of low BP, should be performed before initiation of treatment. In case of a sharp decrease in BP, the dose of the drug should be reduced or its administration discontinued. Arterial hypotension usually resolves within 30 minutes after discontinuation of the drug infusion. In some cases, additional treatment may be required.

Bradycardia

Bradycardia, including severe bradycardia, and cardiac arrest have been observed during the use of the drug. The drug should be used with particular caution in patients with low heart rate prior to treatment and only when the potential benefit is considered to outweigh the risk. The drug is contraindicated in patients with existing severe sinus bradycardia. In case of severe bradycardia development, the dose of the drug should be reduced or its administration discontinued. In some cases, additional treatment may be required.

Heart failure

Due to beta-adrenergic receptor blockade, myocardial contractility decreases, which may provoke or worsen heart failure. At the first sign or symptom of clinically significant myocardial depression, the dose of the drug should be reduced or its administration discontinued. In some cases, additional treatment may be required. Caution should be exercised when using the drug in patients with impaired myocardial contractility (the drug is contraindicated in patients with severe heart failure or cardiogenic shock).

Beta-blockers affect the function of the sinus node, as well as sinoatrial and AV conduction, and may lead to the development of sick sinus syndrome, sinoatrial and AV block, including complete block, which may lead to cardiac arrest. This effect is most characteristic for patients with pre-existing sinus node dysfunction and conduction disorders (the drug is contraindicated in patients with second- or third-degree AV block and in patients with sick sinus syndrome).

The drug should be used with caution in patients with other cardiac conduction disorders, including first-degree AV block.

Use in patients with pheochromocytoma

It should be used with caution in patients with pheochromocytoma and only with concurrent use of alpha-adrenergic blockers.

Brevibloc should not be used as a means for treating arterial hypertension caused mainly by vasoconstriction during hypothermia.

Use in patients with bronchospastic syndrome

Patients with bronchospastic syndrome should not receive beta-blockers. Brevibloc, due to its relative beta₁-selectivity and titratability, should be used with caution in patients with bronchospastic syndrome. However, since selectivity for β₁-adrenergic receptors is not absolute, precise dose titration is required to achieve the lowest possible effective dose. In case of bronchospasm or worsening of existing bronchospasm, the infusion should be stopped immediately; if the condition allows, beta₂-adrenergic agonists may be administered.

Use in patients with diabetes mellitus or patients prone to hypoglycemia

The drug should be used with caution in patients susceptible or prone to hypoglycemia, as well as in patients with diabetes mellitus who are receiving insulin or oral hypoglycemic agents.

Beta-blockers may mask tachycardia occurring during hypoglycemia, although other manifestations, such as dizziness and increased sweating, may be present.

Concomitant use of beta-blockers and hypoglycemic agents may enhance the hypoglycemic effect of the latter.

Reactions at the injection site

Reactions at the injection site have been observed during the use of Brevibloc. They included signs and symptoms of irritation and inflammation at the injection site.

Control of tachycardia in patients receiving drugs with vasoconstrictive and positive inotropic effects

Due to the risk of reduced cardiac contractility against a background of high systemic vascular resistance, the drug should not be used to control tachycardia in patients receiving drugs that have vasoconstrictive and positive inotropic effects, including epinephrine, norepinephrine, dopamine.

Use in patients with Prinzmetal’s angina

Beta-blockers may increase the number and duration of angina attacks in patients with Prinzmetal’s angina due to unopposed alpha-adrenergic receptor-mediated coronary artery spasm. Non-selective beta-blockers should not be used in such patients, and selective beta₁-blockers should be used only with special precautions.

Use in patients with hypovolemia

In patients with hypovolemia, the drug may attenuate reflex tachycardia and increase the risk of arterial hypotension. In this regard, the drug should be used in such patients with special precautions.

Discontinuation of Brevibloc

Since withdrawal syndrome cannot be excluded, as with all beta-blockers, caution should be exercised when abruptly discontinuing the drug in patients with coronary artery disease. In a clinical electrophysiological study, the increase in heart rate 30 minutes after drug discontinuation was moderate but significantly higher than the baseline heart rate. Beta-blockers also increase the risk of rebound arterial hypertension upon discontinuation of clonidine, guanfacine, and moxonidine.

Use of the drug in patients with peripheral circulatory disorders

The drug should be used with caution in patients with peripheral circulatory disorders (including Raynaud’s disease or syndrome and occlusive peripheral vascular disease), as beta-blockers may exacerbate peripheral circulatory disorders.

Use in patients with impaired renal function

The drug should be administered with caution to patients with impaired renal function. The acidic metabolite of the drug is excreted by the kidneys mainly unchanged. Its excretion is significantly reduced in patients with kidney disease. In patients with end-stage renal failure, T_1/2 increased 10-fold, and plasma concentration significantly increased.

Use in patients with hepatic insufficiency

Since the drug is metabolized by erythrocyte esterases, no special precautions are required in patients with hepatic insufficiency.

Hyperkalemia

The use of beta-blockers, including Brevibloc, has been accompanied by an increase in plasma potassium levels and hyperkalemia. The risk increases in patients with factors such as renal failure. Intravenous administration of beta-blockers has been reported to cause potentially life-threatening hyperkalemia in patients on hemodialysis.

Use in patients with metabolic acidosis

Beta-blockers, including Brevibloc, have been reported to cause or contribute to hyperkalemic renal tubular acidosis. In addition, acidosis is usually accompanied by reduced myocardial contractility. The drug should be used with caution in patients with pre-existing metabolic acidosis.

Use in patients with thyrotoxicosis

Beta-adrenergic blockade may mask some clinical signs of hyperthyroidism (e.g., tachycardia). Abrupt discontinuation of beta-blockade may provoke a thyrotoxic crisis. In this regard, patients in whom thyrotoxicosis is expected to develop upon discontinuation of beta-blocker therapy should be closely monitored.

Patients at increased risk of severe hypersensitivity reactions

When using beta-blockers, patients at increased risk of anaphylactic reactions may respond more vigorously to allergen exposure (accidental, diagnostic, or therapeutic). Patients using beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions.

Use in patients with a history of psoriasis

The use of beta-blockers has been associated with exacerbation of psoriasis, or the appearance of psoriasis symptoms or psoriasiform rashes. In patients with a history of psoriasis, beta-blockers should be prescribed only after careful analysis of the expected benefit and risk of therapy.

Use in patients with muscle weakness

Beta-blockers, including Brevibloc, have caused muscle weakness. The drug should be used with caution in patients with muscle weakness.

Use in elderly patients

The drug should be administered to elderly patients with caution. Generally, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased renal or cardiac function, concomitant disease, or other drug therapy.

Effect on ability to drive and operate machinery

Some side effects that occur after using the drug, such as dizziness or drowsiness, may affect the patient’s ability to drive vehicles and operate machinery. Patients should not drive automobiles or operate machinery until such effects have resolved.

Overdose

Symptoms: from the cardiovascular system – pronounced bradycardia, AV block (first, second and third degree), nodal rhythm, slowed intraventricular conduction, decreased myocardial contractility, pronounced arterial hypotension, acute heart failure (including cardiogenic shock), cardiac arrest, electromechanical dissociation; from the CNS – respiratory depression, convulsions, sleep and mood disorders, fatigue, lethargy, coma may occur. Bronchospasm, mesenteric ischemia, peripheral cyanosis, hyperkalemia and hypoglycemia are also possible. Overdose may lead to life-threatening conditions and fatal outcome.

Treatment discontinue administration of the drug. For bradycardia, intravenous administration of atropine is indicated. Catecholamines that increase heart rate may be indicated and/or placement of an artificial pacemaker may be required. For heart failure, intravenous administration of diuretics and/or cardiac glycosides is indicated. For shock due to inadequate myocardial contractility, intravenous administration of a positive inotropic agent, such as dopamine, dobutamine, isoprenaline, or amrinone, is indicated. For symptomatic arterial hypotension, consideration should be given to intravenous administration of plasma substitutes and/or vasopressor agents, such as dopamine or norepinephrine. For bronchospasm, beta₂-adrenergic agonists and/or theophylline derivatives are administered intravenously.

In case of overdose, continuous monitoring of the patient is required.

Drug Interactions

Pharmacokinetic interaction

With simultaneous intravenous administration of digoxin and Brevibloc, an increase in digoxin blood concentration by 10-20% is noted. The pharmacokinetics of the drug did not change.

With simultaneous intravenous administration of morphine and Brevibloc, no changes in morphine plasma concentration were observed. The blood concentration of esmolol increased by an average of 46%, while other pharmacokinetic parameters remained unchanged.

Pharmacodynamic interaction and other types of interactions

When used concomitantly with class I antiarrhythmic drugs (e.g., quinidine, disopyramide) or amiodarone, the effect on intra-atrial conduction time may be enhanced and the negative inotropic effect may be increased.

When the drug is used concomitantly with other antihypertensive agents, drugs that depress myocardial contractility, or drugs that inhibit sinus node function or conduction of electrical impulses in the myocardium, the drug’s effects on BP, myocardial contractility, and myocardial impulse conduction may be enhanced. Pharmacodynamic interaction with such drugs may lead, for example, to pronounced arterial hypotension, heart failure, severe bradycardia, sinus pause, sinoatrial block, AV block and/or cardiac arrest. In addition, the use of some drugs against a background of beta-blockade may lead to enhanced withdrawal syndrome. Therefore, the drug should be used with caution and only after careful individual assessment of risk and expected benefit with drugs that may cause such pharmacodynamic interaction, including, but not limited to, the following drugs: alfuzosin, doxazosin and other alpha-blockers; amifostine; amiodarone; anticholinesterase agents; antipsychotic agents; apomorphine; baclofen; verapamil, diltiazem and other cardiac-depressant slow calcium channel blockers (cases of fatal cardiac arrest have been reported with concomitant use of the drug and verapamil in patients with reduced myocardial function); cardiac glycosides; disopyramide, lidocaine, phenytoin, flecainide; inhalational anesthetics; levodopa; MAO inhibitors; mefloquine; opioid receptor agonists, including fentanyl; short-acting barbiturates; tricyclic antidepressants (e.g., imipramine, amitriptyline); clonidine, guanfacine, moxonidine. Beta-blockers increase the risk of rebound arterial hypertension upon discontinuation of clonidine, guanfacine, and moxonidine. Therefore, the beta-blocker must be discontinued first, and the discontinuation must be gradual.

When using beta-blockers, patients at risk of anaphylactic reactions may respond more vigorously to allergen exposure (accidental, diagnostic, or therapeutic). Patients receiving beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Beta-blockers, including Brevibloc, have caused muscle weakness. Therefore, beta-blockers are theoretically capable of reducing the effectiveness of anticholinesterase agents in the treatment of muscle weakness.

Concomitant use of beta-blockers and oral hypoglycemic agents or insulin may enhance the hypoglycemic effect of the latter. Beta-blockers may mask tachycardia occurring during hypoglycemia, although other manifestations, such as dizziness and increased sweating, may be present.

Reserpine and other drugs that deplete catecholamine stores may have an additive effect when used concomitantly with beta-blocking agents. Therefore, patients receiving catecholamine inhibitors concomitantly with Brevibloc should be closely monitored for signs of arterial hypotension or marked bradycardia, which may lead to dizziness, syncope, or orthostatic arterial hypotension.

Concomitant use of beta-blockers with ergot alkaloid derivatives may lead to severe peripheral vasoconstriction and arterial hypertension.

Weakening of the effects of glucagon associated with increased blood glucose levels is possible.

NSAIDs may cause a reduction in the antihypertensive effect of beta-blockers.

The effect of the drug may be reduced when used concomitantly with sympathomimetic drugs possessing beta-adrenergic agonist activity. The dose of each drug may need adjustment based on the patient’s response, or alternative therapeutic agents may be considered.

The drug increases the duration of succinylcholine-induced neuromuscular blockade.

When used concomitantly with sulfinpyrazone, a weakening of the antihypertensive effects of beta-blockers is possible.

Pharmaceutical interaction

The drug is incompatible with 5% sodium bicarbonate solution due to limited stability; with furosemide – due to precipitation.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is intended for use in hospitals only.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.