New Zealand - English - Medsafe (Medicines Safety Authority)
NEW ZEALAND DATA SHEET
NAME OF MEDICINE
metoprolol tartrate 1 mg/mL injection
Ampoule–aclear, colourless liquid free from foreign particles containing 5 mL of 1 mg/mL
Metoprolol is a beta
-selectivebeta-blocker, ie. it blocks beta
–receptors at doses much
lower than those needed to block beta
Metoprololhas an insignificant membrane-stabilising effect and does not display partial
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
metoprolol in therapeutic doses interferes less than non-selective beta-blockers withthe
-mediated bronchodilation caused by the beta
Metoprolol interferes less with insulin release and carbohydrate metabolismthandonon-
Metoprololinterferesmuchlesswith the cardiovascular response to hypoglycaemia than do
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.
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
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
Cardiac arrhythmias, especially supraventricular tachycardia, reduction of ventricular rate
in atrial fibrillation and ventricular extrasystoles.
Suspected or definite myocardial infarction.
DOSAGE AND ADMINISTRATION
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
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
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.
Dose adjustment is not needed.
There is limited experience with metoprolol treatment in children.
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.
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
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-
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
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
USE IN LACTATION
The amount of metoprolol ingested via breast-milk seemstobenegligibleasregardsbeta-
blockingeffectintheinfantifthemother is treated with metoprolol doses within the normal
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Patients should know how they react to metoprolol beforetheydriveorusemachines
because occasionally dizziness or fatigue may occur.
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
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%).
Common: Bradycardia, postural disorders (very rarely with syncope), cold hands and feet,
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
Common: Dizziness, headache.
Uncommon: Paraesthesiae, muscle cramps.
Common: Nausea, abdominal pain, diarrhoea, constipation.
Rare: Dry mouth
Rare: Liver function test abnormalities
Uncommon:Depression, concentration impaired, somnolence or insomnia, nightmares
Rare: Nervousness, anxiety, impotence / sexual dysfunction.
Veryrare: Amnesia / memory impairment, confusion, hallucinations.
Common:Dyspnoea on exertion.
Rare: Disturbances of vision, dry and/or irritated eyes, conjunctivitis
Veryrare: Tinnitus, taste disturbances
Uncommon: Rash (in the form of urticariapsoriasiformanddystrophicskinlesions),
Rare: Loss of hair
Veryrare:Photosensitivity reactions, aggravated psoriasis.
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
Patients receiving concomitant treatment withsympathetic ganglion blocking agents, other
beta-blockers (i.e. eye drops) or monoamine oxidase inhibitorsshouldbekeptunderclose
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
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
Thedosagesoforalantidiabeticsmay have to be readjusted in patients receiving beta-
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.
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.
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
Metoprolol tartrate solution for injection 1 mg/mL should not be added to Macrodex.
Ampoules 5 mL, 1 mg/mL – pack of 5 x 5 mL
LIST OF EXCIPIENTS
Sodium chloride for injection and water for injection.
NAME AND ADDRESS
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
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