Betaloc IV

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Metoprolol tartrate 1 mg/mL;  
Available from:
AstraZeneca Limited
INN (International Name):
Metoprolol tartrate 1 mg/mL
Dosage:
1 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Metoprolol tartrate 1 mg/mL   Excipient: Sodium chloride Water for injection
Units in package:
Ampoule, glass, 5 mL, 5 dose units
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Ipca Laboratories Limited
Therapeutic indications:
Betaloc IV is indicated for the following indications: · Cardiac arrhythmias, especially supraventricular tachycardia, reduction of ventricular rate in atrial fibrillation and ventricular extrasystoles. · Suspected or definite myocardial infarction.
Product summary:
Package - Contents - Shelf Life: Ampoule, glass, 5 mL - 5 dose units - 60 months from date of manufacture stored at or below 25°C protect from light
Authorization number:
TT50-5423/1
Authorization date:
1981-08-28

NEW ZEALAND DATA SHEET

NAME OF MEDICINE

ETALOC IV

metoprolol tartrate 1 mg/mL injection

PRESENTATION

Ampoule–aclear, colourless liquid free from foreign particles containing 5 mL of 1 mg/mL

metoprolol tartrate.

USES

ACTIONS

Metoprolol is a beta

-selectivebeta-blocker, ie. it blocks beta

–receptors at doses much

lower than those needed to block beta

-receptors.

Metoprololhas an insignificant membrane-stabilising effect and does not display partial

agonist activity.

Metoprololreducesorinhibitstheagonisticeffect on the heart of catecholamines (which are

released during physical and mental stress). This meansthattheusualincreaseinheart

rate, cardiac output, cardiac contractility andbloodpressure,producedbytheacuteincrease

in catecholamines, is reduced by metoprolol.

During high endogenous adrenaline levels metoprololinterferesmuchlesswithblood

pressure control than non-selective beta-blockers.

When mandatory, metoprolol , in combination with a beta

2 -agonist, may be given to patients

withsymptomsofobstructivepulmonary disease. When given together with a beta

-agonist,

metoprolol in therapeutic doses interferes less than non-selective beta-blockers withthe

beta

-mediated bronchodilation caused by the beta

-agonist.

Metoprolol interferes less with insulin release and carbohydrate metabolismthandonon-

selective beta-blockers.

Metoprololinterferesmuchlesswith the cardiovascular response to hypoglycaemia than do

non-selective beta-blockers.

Shorttermstudieshaveshownthat metoprolol may cause a slight increase in triglycerides

and a decrease in free fatty acids in the blood. In some cases, a small decrease in the high

density lipoproteins (HDL) fraction has been observed, although to a lesserextentthanthat

following non-selective beta-blockers. However, asignificantreductionintotalserum

cholesterol levels has been demonstrated after metoprolol treatment inonestudyconducted

over several years.

Quality of life is maintained uncompromised, orimproved during treatment with metoprolol .

An improvement in quality of life has been observed after metoprolol treatment in patients

after myocardial infarction.

In men with mild to moderate hypertension metoprolol has been shown to reduce theriskof

deathfrom cardiovascular disease, mainly due to a reduced risk for sudden cardiovascular

death, to reduce the risk for fatal and non-fatal myocardial infarction and for stroke.

Effect on Cardiac Rhythm

Metoprololissuitableforregulatingthe heart rate in cases of supraventricular tachycardia or

atrial fibrillation, and in the presence of ventricular extrasystoles.

Effect on Myocardial Infarction

Metoprolol reduces mortality in patients with suspected or confirmed myocardial infarction

mainly due to a reduction in the risk of sudden death.Thiseffectispresumedtopartlybe

due to the prevention of ventricular fibrillation.The anti-fibrillatory effect is believedtobedue

toadual mechanism: a vagal effect within the blood-brain barrier beneficially influencing

electrical stability of the heart, and a sympathetic direct cardiacanti-ischaemiceffect

beneficially influencing contractility, heart rate and blood pressure. Forbothearlyandlate

intervention the reduction in mortality is also present in high risk patientswithprevious

cardiovascular disease; and in patients with diabetes mellitus.

Metoprolol has also been shown to reduce the risk for non-fatal myocardial infarction.

These anti-ischaemic effects of metoprolol are also reflected in a reduction in chestpain

during the acute infarction phase. Metoprolol has also beenshowntoreducetheincidence

of recurrent myocardial infarction.

PHARMACOKINETICS

Absorption and Distribution

Metoprolol is rapidly distributed during 5-10 minutes after IV injection.Theplasmalevels

show a linear relationship with the dose administered in thedoserange5-20mg.The

plasma protein binding of metoprolol is low, approximately 5-10%.

Metabolism and elimination

Metoprolol undergoes oxidative metabolismintheliver primarily by the CYP2D6 isoenzyme.

Three main metabolites of metoprolol have been identified, though none of them havea

beta-blocking effect of clinical importance.

As a rule over 95% of an oral dose can be recoveredintheurine.About5%ofthegiven

doseisexcretedintheurineinunchanged form, this figure rising up to 30% in isolated

cases.Theelimination half-life of metoprolol in plasma averages 3.5 hours (extremes: 1 and

9 hours). The total clearance rate is approximately 1 litre/minute.

The elderly show no significant changes in the pharmacokineticsofmetoprololascompared

toyoungpersons.Thesystemic bioavailability and elimination of metoprolol is unchanged in

patients with reduced renal function, however the excretion ofmetabolitesisreduced.

Significant accumulation of metabolites was observed in patients with a glomerular filtration

rate(GFR)oflessthan 5 mL/minute. This accumulation of metabolites does not increase the

beta-blockade.

Thepharmacokineticsofmetoprololis little affected by decreased liver function due to its low

proteinbinding.However,in patients with severe liver cirrhosis and a portacaval shunt the

bioavailabilitymayincreaseandthetotalclearance may be reduced. Patients with a

portacaval anastomosis had a total clearance of approximately 0.3 L/min and areaunderthe

plasma concentration-time curve (AUC) values of up to 6 timeshigherthaninhealthy

subjects.

INDICATIONS

Cardiac arrhythmias, especially supraventricular tachycardia, reduction of ventricular rate

in atrial fibrillation and ventricular extrasystoles.

Suspected or definite myocardial infarction.

DOSAGE AND ADMINISTRATION

CARDIAC ARRHYTHMIAS

Initiallyupto5mg injected intravenously at a rate of 1-2 mg per minute. The injection can be

repeated at 5-minute intervals until a satisfactory effect is achieved. A total doseof10-15

mg generally proves sufficient. Doses of 20 mg or more are unlikelytoresultinfurther

therapeutic benefit.

MYOCARDIAL INFARCTION

Metoprolol should be administered intravenously as soon aspossibleaftersymptoms

indicating acute myocardial infarction.

Such treatment should be initiated in a coronary careorsimilarunitimmediatelyafterthe

patient’shaemodynamicconditionhasstabilised. Three 5 mg bolus injections should be

given at 2 minute intervals depending on the haemodynamic status of the patient (ECG,

bloodpressure,heartrate). See CONTRAINDICATIONS and WARNINGS AND

PRECAUTIONS.

In patients who tolerate the full intravenous dose (15mg),B ETALOC CR tablets 47.5 mg four

times daily should be started 15 minutes after the last intravenous injection and be continued

for 24 hours, followed by B ETALOC CR tablets 95 mg twice daily for the next 24 hours

The maintenance dose is B ETALOC CR 190 mg once daily.

Patientswhodonottolerate the full intravenous (15 mg) dose of metoprolol should have their

oral treatment initiated with caution starting with a lower dose.

IMPAIRED RENAL FUNCTION

Dose adjustment is not needed in patients with impaired renal function

IMPAIRED HEPATIC FUNCTION

Dose adjustment is not normally needed in patients suffering from liver cirrhosis because

metoprolol has low protein binding (5-10%). When there are signs of serious impairmentof

liver function (e.g. shunt-operated patients) a reduction in dose should be considered.

ELDERLY

Dose adjustment is not needed.

CHILDREN

There is limited experience with metoprolol treatment in children.

CONTRAINDICATIONS

Bronchial asthma or other obstructive lung disorders.

Grade 2 and 3 A-V block and intranodal A-V block.

Patients with unstable decompensated cardiacheartfailure(pulmonaryoedema,

hypoperfusion or hypotension), and patients with continuous or intermittentinotropic

therapy acting through beta-receptor agonism.

Marked clinically relevant bradycardia.

Sick-sinussyndrome.

Cardiogenicshock.

Severe peripheral arterial circulatory disorder.

Metoprolol should not be given to patients with suspected acutemyocardialinfarctionaslong

astheheartrateis<45beats/minute,theP-Qinterval is > 0.24 seconds or the systolic blood

pressure is <100 mmHg.

ETALOC iscontraindicatedinpatientswho have shown hypersensitivity to metoprolol tartrate

or to other beta-blockers.

WARNINGS AND PRECAUTIONS

Intravenous administration of calcium antagonistsof the verapamil-type should not be given

to patients treated with beta-blockers.

Duringtreatmentwithmetoprolol,therisk of interfering with carbohydrate metabolism or

masking hypoglycaemia is less than with non-selective beta-blockers.

Patientssufferingfromheartfailureshould have their decompensation treated both before

and during treatment with metoprolol.

Veryrarelyapre-existingA-V conduction disorder of moderate degree may become

aggravated (possibly leading to A-V block) by beta-blockade.

Ifthepatientsdevelopincreasingbradycardia, metoprolol should be given in lower doses or

gradually withdrawn.

Metoprololmayaggravatethe symptoms of peripheral arterial circulatory disorders, mainly

due to its blood pressure lowering effect.

Where metoprolol is prescribed for a patientknowntobesufferingfrom

phaeochromocytoma, an alpha-blocker should be given concomitantly.

During oral treatment abrupt interruption of the medication is to be avoided.Iftreatmenthas

tobewithdrawnit should, when possible, be done gradually over a period of at least 10-14

daysindiminishingdosesto23.75mg daily for the last 6 days. During this period especially

patientswithknownischaemicheart disease should be kept under close observation. The

riskfor coronary events, including sudden death, may increase during the withdrawal of beta-

blockade.

Priorto surgery, the anaesthetist should be informed that the patient is receiving metoprolol.

It is not recommended to stop beta-blocker treatment in patients undergoing surgery. Acute

initiationof high-dose metoprolol to patients undergoing non-cardiac surgery should be

avoided, since it has been associated withbradycardia,hypotensionandstrokeincluding

fatal outcomein patients with cardiovascular risk factors.

In patients taking beta-blockers anaphylactic shock assumes a more severe form.

Incaseswherethesystolicbloodpressure is below 100 mmHg metoprolol should only be

given intravenously if specialprecautionsare observed, because there is a risk that

administrationofthemedicinebythisroute may cause a further fall in blood pressure, (i.e. in

patient’s with cardiac arrhythmias).

When treating patients with suspected or definite myocardial infarction thehaemodynamic

status of the patient should be carefully monitored after each of the three5mgintravenous

doses.

Thesecond or third dose should not be given if the heart rate is <40 beats/minute, the P-Q

intervalis>0.26 seconds and the systolic blood pressure is <90 mmHg or if there is any

aggravation of dyspnoea or cold sweating.

USE IN PREGNANCY

Aswithmostmedicines, metoprolol should not be given during pregnancy and lactation

unless its use is considered essential. Aswithallantihypertensiveagents,beta-blockers

maycause side effects (e.g. bradycardia) in the foetus and in the newborn and breast-fed

infant.

USE IN LACTATION

The amount of metoprolol ingested via breast-milk seemstobenegligibleasregardsbeta-

blockingeffectintheinfantifthemother is treated with metoprolol doses within the normal

therapeutic range.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Patients should know how they react to metoprolol beforetheydriveorusemachines

because occasionally dizziness or fatigue may occur.

ADVERSE EFFECTS

ETALOC is well tolerated and adverse reactions have generally beenmildandreversible.

The following events have been reported as adverse events in clinical trials or reported from

routine use..

Thefollowingdefinitionsoffrequencies are used: Very common ( ≥ 10%), common (1-9.9%),

uncommon (0.1–0.9%), rare (0.01–0.09%) and very rare (<0.01%).

CARDIOVASCULAR SYSTEM

Common: Bradycardia, postural disorders (very rarely with syncope), cold hands and feet,

palpitations.

Uncommon: Deterioration of heart failure symptoms, cardiogenicshockinpatientswith

acute myocardial infarction*, first degree heart block, oedema, pericordial pain.

Rare: Disturbances of cardiac conduction, cardiac arrhythmias.

Veryrare: Gangrene in patients with pre-existing severe peripheral circulatory disorders.

* Excess frequency of 0.4% compared with placebo in a study of 46,000patients with acute

myocardial infarction where the frequency ofcardiogenic shock was 2.3% in the metoprolol group and

1.9% in the placebo group in the subset of patients with low shockriskindex.The stock risk index

wasbasedon the absolute risk of shock in each individual patient derived from age, sex, time delay,

Killipclass,blood pressure, heart rate, ECG abnormality, and prior history of hypertension. The

patient group with low shock risk index correspondstothe patient in which metoprolol is

recommended for use in acute myocardial infarction.

CENTRAL NERVOUS SYSTEM

Verycommon: Fatigue

Common: Dizziness, headache.

Uncommon: Paraesthesiae, muscle cramps.

GASTROINTESTINAL

Common: Nausea, abdominal pain, diarrhoea, constipation.

Uncommon: Vomiting

Rare: Dry mouth

HAEMATOLOGIC

Veryrare:Thrombocytopenia

HEPATIC

Rare: Liver function test abnormalities

Veryrare:Hepatitis

METABOLISM

Uncommon:Weight gain

MUSCULOSKELETAL

Veryrare:Arthralgia

PSYCHIATRIC

Uncommon:Depression, concentration impaired, somnolence or insomnia, nightmares

Rare: Nervousness, anxiety, impotence / sexual dysfunction.

Veryrare: Amnesia / memory impairment, confusion, hallucinations.

RESPIRATORY

Common:Dyspnoea on exertion.

Uncommon: Bronchospasm

Rare: Rhinitis

SENSE ORGANS

Rare: Disturbances of vision, dry and/or irritated eyes, conjunctivitis

Veryrare: Tinnitus, taste disturbances

SKIN

Uncommon: Rash (in the form of urticariapsoriasiformanddystrophicskinlesions),

increased sweating.

Rare: Loss of hair

Veryrare:Photosensitivity reactions, aggravated psoriasis.

INTERACTIONS

Metoprolol is a metabolic substrate for the cytochrome P450isoenzymeCYP2D6.Drugs

that act as enzyme-inducing andenzyme-inhibiting substances may exert an influence on the

plasma level of metoprolol. Plasma levels ofmetoprolol may beraisedbyco-administration

of compounds metabolised by CYP2D6 eg. antiarrhythmics,antihistamines,histamine-2-

receptorantagonists,antidepressants, antipsychotics and COX-2 inhibitors. The plasma

concentration of metoprolol is lowered by rifampicin and may be raised byalcoholand

hydralazine.

Patients receiving concomitant treatment withsympathetic ganglion blocking agents, other

beta-blockers (i.e. eye drops) or monoamine oxidase inhibitorsshouldbekeptunderclose

surveillance.

If concomitant treatment with clonidine is tobediscontinued,thebeta-blockermedication

should be withdrawn several days before clonidine.

Increasednegativeinotropicand chronotropic effects may occur when metoprolol is given

togetherwithcalcium antagonists of the verapamil and diltiazem type. In patients treated

with beta-blockers, intravenous administration of calcium antagonists of theverapamiltype

should not be given.

Beta-blockers may enhance the negative inotropic and negativedromotropiceffectof

antiarrhythmic agents (of the quinidine type and amiodarone).

Digitalisglycosides, in association with beta-blockers, may increase atrioventricular

conduction time and may induce bradycardia.

In patients receiving beta-blocker therapy, inhalationanaestheticsenhancethe

cardiodepressant effect.

Concomitant treatment with indomethacin orother prostaglandin synthetaseinhibitingagents

may decrease the antihypertensive effect of beta-blockers.

Under certain conditions, when adrenaline is administered to patientstreatedwithbeta-

blockers,cardioselectivebeta-blockersinterfere much less with blood pressure control than

non-selective beta-blockers.

Thedosagesoforalantidiabeticsmay have to be readjusted in patients receiving beta-

blockers.

OVERDOSAGE

Thesymptomsofoverdosage may include bradycardia, hypotension, acute cardiac

insufficiency and bronchospasm.

General treatment should include:

Close supervision, treatment in an intensive care ward and theuseofplasmaorplasma

substitutes to treat hypotension and shock.

Excessive bradycardia can be countered with atropine 1-2 mg intravenously and/oracardiac

pacemaker. If necessary, this may be followed by a bolus doseofglucagon10mg

intravenously. If required, this may be repeated or followed by an intravenousinfusionof

glucagon1-10mg/hourdependingonresponse. If no response to glucagon occurs or if

glucagon is unavailable, a beta adrenoceptor stimulantsuchasdobutamine2.5to

10 micrograms/kg/minute by intravenous infusion may be given.

Dobutamine,becauseofitspositiveinotropic effect could also be used to treat hypotension

and acute cardiac insufficiency. It is likely that thesedoseswouldbeinadequatetoreverse

the cardiac effects of beta blockade if a large overdose has beentaken.Thedoseof

dobutamine should therefore be increased if necessarytoachievetherequiredresponse

according to the clinical condition of the patient.

Administrationof calcium ions may alsobe considered. Bronchospasm can usually be

reversed by bronchodilators.

PHARMACEUTICAL PRECAUTIONS

SHELF-LIFE

Shelf-life: Ampoules 1 mg/mL: 5 years

Diluted metoprolol tartrate injection 1 mg/mL should be used within 12 hours.

SPECIAL PRECAUTIONS FOR STORAGE

ETALOC IV should be stored at or below 25°C.

COMPATIBILITIES

Metoprololtartrateinjection1mg/mLcorrespondingto 40 mg metoprolol can be added to

1000 mL of the following infusion solutions:

Sodium chloride 0.9%, Mannitol 150 mg/mL, Dextrose 100 mg/mL, Dextrose50mg/mL,

Fructose 200 mg/mL, Invert sugar 100 mg/mL, Ringer’s injection,Ringer-dextroseand

Acetated Ringer’s.

INCOMPATIBILITIES

Metoprolol tartrate solution for injection 1 mg/mL should not be added to Macrodex.

MEDICINE CLASSIFICATION

Prescription Medicine.

PACKAGE QUANTITIES

Ampoules 5 mL, 1 mg/mL – pack of 5 x 5 mL

FURTHER INFORMATION

LIST OF EXCIPIENTS

Sodium chloride for injection and water for injection.

NAME AND ADDRESS

AstraZeneca Limited

Level 5, 15 Hopetoun Street

Freemans Bay, Auckland 1011.

P299 Private Bag 92175, Auckland 1142

Telephone: (09) 306 5650

DATE OF PREPARATION

5 April 2011

CDS 0309

© This data sheet is copyrighted to AstraZenecaLimited and may be reproduced but not altered in

any way.

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