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PRODUCT INFORMATIONLabetalol Hydrochloride Injection

Product Information Labetalol Hydrochloride Injection (100mg/20mL) Page 1

LABETALOL HYDROCHLORIDE INJECTION 5mg/Ml

(100mg/20mL)

This product is an unapproved therapeutic good in Australia. It is manufactured in a TGA approvedpharmaceutical manufacturing facility in Australia and is provided under Schedule 5A subregulation12(1A) of the Therapeutic Goods Act and Regulations. The product is supplied under contractbetween a public or private hospital or public institution and the licensed manufacturer in Australia inaccordance with a specified formulation.

Approval for use is required from the hospital pharmacist and / or drug committee as appropriate.Informed consent should be obtained in accordance with good medical practice where applicable andpracticable. Records of the use of the product should be fully detailed and include dose, route ofadministration, duration of treatment, clinical, biochemical, haematological and immunologicalmonitoring as appropriate. Adverse events and reactions must be reported to Phebra Pty Ltd and theTherapeutic Goods Administration.

The responsibility for the use of this product remains with the prescriber and the institution. Thefollowing product information has not been evaluated or approved by the Therapeutic GoodsAdministration. Physicians should consult the medical literature for the most recent advice concerningthe appropriate dose, route of administration, warnings and adverse effects.

NAME OF THE MEDICINE

Labetalol hydrochloride

Chemical Name: - 2-hydroxy-5-[1-hydroxy-2-(1-methyl-3-phenylpropylamino) ethyl] benzamide hydrochloride

The molecular weight of the compound is 364.9 and the CAS registry number is 32780-64-6. The molecular formula is C 19 H 24 N 2 O 3HCl.

Structural Formula:

DESCRIPTION

LABETALOL HYDROCHLORIDE INJECTION is a sterile solution containing 5mg/mL labetalol hydrochloride. The excipients areanhydrous dextrose, disodium edetate, methylparaben, propylparaben and citric acid monohydrate. Sodium hydroxide has been used forpH adjustment.

Labetalol hydrochloride has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol,the R,R' stereoisomer, makes up 25% of racemic labetalol hydrochloride. It is a white or almost white powder.

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PHARMACOLOGY

Labetalol combines both selective, competitive alpha1-adrenergic blocking and nonselective, competitive beta-adrenergic blocking activityin a single substance. In man, the ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral andintravenous (IV) administration, respectively.

Single oral doses of labetalol administered in patients with coronary artery disease had no significant effect on sinus rate, intraventricularconduction, or QRS duration. The atrioventricular (AV) conduction time was modestly prolonged in 2 of 7 patients. In another study, IVlabetalol slightly prolonged AV nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effectson AV nodal refractoriness were inconsistent.

Labetalol produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate,presumably through a mixture of its alpha-blocking and beta-blocking effects. Haemodynamic effects are variable with small nonsignificantchanges in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma reninsare reduced.

Doses of labetalol that controlled hypertension did not affect renal function in mild to severe hypertensive patients with normal renalfunction.

Due to the alpha1-receptor blocking activity of labetalol, blood pressure is lowered more in the standing than in the supine position, andsymptoms of postural hypotension can occur. During dosing with IV labetalol, the contribution of the postural component should beconsidered when positioning patients for treatment, and patients should not be allowed to move to an erect position unmonitored until theirability to do so is established.

In a clinical pharmacologic study in severe hypertensives, an initial 0.25 mg/kg injection of labetalol, administered to patients in the supineposition, decreased blood pressure by an average of 11/7 mmHg. Additional injections of 0.5 mg/kg at 15 minute intervals up to a totalcumulative dose of 1.75 mg/kg of labetalol caused further dose-related decreases in blood pressure. Some patients required cumulativedoses of up to 3.25 mg/kg. The maximal effect of each dose level occurred within 5 minutes. Following discontinuation of intravenoustreatment with labetalol, the blood pressure rose gradually and progressively approaching pretreatment baseline values within an averageof 16 to 18 hours in the majority of patients.

Similar results were obtained in the treatment of patients with severe hypertension requiring urgent blood pressure reduction with an initial

dose of 20 mg (which corresponds to 0.25 mg/kg for an 80 kg patient) followed by additional doses of either 40 or 80 mg at 10 minuteintervals to achieve the desired effect or up to a cumulative dose of 300 mg.

Labetalol administered as a continuous intravenous infusion, with a mean dose of 136 mg (27 to 300 mg) over a period of 2 to 3 hours(mean of 2 hours and 39 minutes) lowered the blood pressure by an average of 60/35 mmHg.

Exacerbation of angina and in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abruptdiscontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agentsin patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headacheand malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholaminesbecause of increased numbers of beta-receptors.

Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in whichsympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend onsympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity

on conduction. Beta 2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergicbronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.

Pharmacokinetics

Following intravenous infusion, the elimination half-life is about 5.5 hours and the total body clearance is approximately 33 mL/min/kg. Theplasma half-life of labetalol following oral administration is about 6 to 8 hours. In patients with decreased hepatic or renal function, theelimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due todecreased first-pass metabolism.

The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and areexcreted in the urine and, via the bile, into the faeces. Approximately 55% to 60% of a dose appears in the urine as conjugates orunchanged labetalol within the first 24 hours of dosing.

Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier inanimal studies. Labetalol is approximately 50% protein bound. Neither haemodialysis nor peritoneal dialysis removes a significant amountof labetalol from the general circulation (

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INDICATIONS

Treatment of all grades of hypertension

CONTRAINDICATIONS

LABETALOL HYDROCHLORIDE INJECTION is contraindicated in patients with the following conditions:

1. Bronchospasm. Beta-adrenergic blockade of the smooth muscle of the bronchi and bronchioles may result in an increased airwayresistance. These drugs also reduce the effectiveness of asthma treatment. This may be dangerous in susceptible patients. Therefore,beta-blockers are contraindicated in any patient with a history of airways obstruction or a tendency to bronchospasm. Use ofcardioselective beta-blockers can also result in severe bronchospasm. If such therapy must be used, great caution should be exercised.

Alternative therapy should be considered.

2. Allergic disorders (including allergic rhinitis) which may suggest a predisposition to bronchospasm.

3. Right ventricular failure secondary to pulmonary hypertension.

4. Significant right ventricular hypertrophy (except in specific cases of congenital heart disease, e.g. tetralogy of Fallot, at the discretion of

a cardiologist).

5. Sinus bradycardia (less than 45-50 beats/minute) or sick sinus syndrome.

6. Second and third degree AV block.

7. Shock (including cardiogenic and hypovolaemic shock).

8. Hypersensitivity to the drug.

9. Congestive heart failure.

10. Anaesthesia with agents that produce myocardial depression (e.g. ether, chloroform, cyclopropane).

11. Lactation and early pregnancy (See Use in Lactation and Use in Pregnancy).

PRECAUTIONS1.Anaesthesia and the peri-operative period:Beta-blockade may have beneficial effects in decreasing the incidence of arrhythmias andmyocardial ischaemia during anaesthesia and the post-operative period. It is currently recommended that maintenance beta-blockade becontinued peri-operatively. The anaesthetist must be made aware of beta-blockade because of the potential for interactions with otherdrugs, resulting in severe bradyarrhythmias and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia andregional sympathetic blockade, and the increased propensity for vagal-induced bradycardia. Incidents of protracted severe hypotension ordifficulty restoring normal cardiac rhythm during anaesthesia have been reported. Modern inhalational anaesthetic agents are generallywell tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were sometimes associated with severecirculatory depression in the presence of beta-blockade.

Labetalol need not be discontinued prior to anaesthesia but patients should receive intravenous atropine prior to induction.

Synergistic effects of labetalol and halothane on cardiac output and blood pressure have been reported.

2. Diabetes: Beta-blockers affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as

tachycardia.

In patients with insulin or non-insulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia, beta-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemicagent may need adjustment.

In one study there was an increase in mean fasting glucose levels during labetalol treatment but no alteration in insulin activity or responseto an oral glucose tolerance test.

3. Renal disease: Labetalol does not adversely affect renal function and is a particularly suitable drug for use in hypertensive patients withrenal disease (See Pharmacokinetics). In patients with severe renal disease, haemodynamic changes following beta-blockade may impairrenal function further.

4. Clonidine: Concurrent use of beta-blockers and clonidine should be avoided because of the risk of adverse interaction and severewithdrawal symptoms. If administered concomitantly, the clonidine should not be discontinued until several days after the withdrawal of thebeta-blocker.

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5. Phaeochromocytoma: Labetalol has been shown to be effective in lowering blood pressure and relieving symptoms in patients withphaeochromocytoma. However, paradoxical hypertension responses have been reported in a few patients with this tumour; therefore, usecaution when administering labetalol to patients with phaeochromocytoma.

In patients with this condition, an alpha-blocking drug (e.g. phentolamine or phenoxybenzamine) should be considered beforeadministration of labetalol, bearing in mind that this drug has alpha- and beta-blocking properties (See Pharmacology).

6. Cross-sensitisation: Cross-sensitisation may occur between beta-blockers and substitution within the group may not necessarilypreclude recurrence of symptoms.

7.Allergic conditions: These may be exaggerated by beta-blockade (e.g. allergic rhinitis during the pollen season and allergic reactions tobee and wasp stings). Beta-blockers should be avoided if there is a risk of bronchospasm.

8. Hyperthyroidism: Since beta-blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomaticimprovement without any change in thyroid hormone status, special care should be exercised in those patients who are hyperthyroid andare also receiving beta-blockers.

9. Postural hypotension: Severe postural hypotension has occurred in some patients (see Adverse Reactions).Furthermore, this may be enhanced by the concurrent administration of other vasodilators.

10.Effects on Motor Ability:Labetalol may cause occasional dizziness or fatigue. Patients should therefore be warned of the possibility ofimpairment of the ability to drive or operate machinery.

WARNINGS

1. Cardiac failure: Beta-blockade depresses myocardial contractility and may precipitate cardiac failure in some patients with a history ofcardiac failure, chronic myocardial insufficiency or unsuspected cardiomyopathy. In patients without a history of cardiac failure, continuingdepression of the myocardium may lead to cardiac failure. If cardiac failure develops, Labetalol should be withdrawn (See Warnings 2).

(Note.Although congestive heart failure has been considered to be a contraindication to the use of beta-blockers, there is a growingliterature on the experimental use of beta-adrenergic blocking drugs in heart failure. As further trials are needed to identify which patientsare most likely to respond to which drugs, beta-blockers should not normally be prescribed for heart failure outside of specialist centres.)

2. Abrupt withdrawal: Care should be taken if beta-blockers have to be discontinued abruptly in patients with coronary artery disease.Severe exacerbation of angina and precipitation of myocardial infarction and ventricular arrhythmias has occurred following abruptdiscontinuation of beta-blockade in patients with ischaemic heart disease. Therefore it is recommended that the dosage be reducedgradually over a period of about 8 to 14 days during which time the patient's progress should be assessed. The drug may be reinstitutedtemporarily if the angina worsens. If the drug must be withdrawn abruptly, close observation is required. In the peri-operative period, beta-blockers should not be withdrawn, unless there are strong clinical reasons to do so.

3. Concomitant therapy with calcium antagonists: The concomitant use of beta-blockers and calcium antagonists with myocardialdepressant and sinus node activity, e.g. verapamil and, to a lesser extent, diltiazem, may cause hypotension, bradycardia and asystole.Extreme caution is required if these drugs have to be used together.The dihydropyridine calcium antagonists (e.g. nifedipine) have a weaker myocardial depressant effect and can be administered cautiouslywith beta-blockers. If excessive hypotension develops, the calcium antagonist should be stopped or the dosage reduced.

4. Peripheral circulation: Beta-blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral vascular disease.

5.Antiarrhythmic drugs: Care should be taken when prescribing beta-blockers with antiarrhythmic drugs. Interactions have been reportedduring concomitant beta-blocker therapy with the Class IA agents disopyramide, and less frequently quinidine; Class IB agents, tocainide,mexiletine and lidocaine; Class IC agents, flecainide and propaferone (not available in Australia); the Class III agent, amiodarone; and theClass IV antiarrhythmic agents.

6. Prinzmetal angina: There is a risk of exacerbating coronary artery spasm if patients with Prinzmetal or variant angina are treated with abeta-blocker. If this treatment is essential, it should only be undertaken in a Coronary or Intensive Care Unit.

7. Euthyroid hyperthyroxinaemia: The effects of beta-blockers on thyroid hormone metabolism may result in elevations of serum freethyroxine (T4) levels. In the absence of any signs or symptoms of hyperthyroidism, additional investigation is necessary before a diagnosisof thyrotoxicosis can be made.

8. Hepatic injury: Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with labetalol therapy. Thehepatic injury is usually reversible, but hepatic necrosis and death have been reported. Injury has occurred after both short- and long-termtreatment and may be slowly progressive despite minimal symptomatology.

Appropriate laboratory testing should be done at the first sign or symptom of hepatic dysfunction. If there is laboratory evidence of hepaticinjury or the patient is jaundiced, labetalol therapy should be stopped and not restarted.

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9. Beta-blockers: Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with asthma or a history ofobstructive disease unless no alternative treatment is available. In such cases, the risk of inducing bronchospasm should be appreciatedand appropriate precautions taken. If bronchospasm should occur after the use of labetalol, it can be treated with a beta 2-agonist byinhalation, e.g. salbutamol (the dose of which may need to be greater than the usual dose in asthma), and, if necessary, intravenous

atropine 1 mg.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoreceptor blocking drugs. The reportedincidence is small and in most cases the symptoms have cleared when treatment was withdrawn. Gradual discontinuation of the drugshould be considered if any such reaction is not otherwise explicable.

Use in Pregnancy

Category C - Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on thehuman fetus or neonate without causing malformations. These effects maybe reversible. Accompanying text should be consulted forfurther details.

Beta-adrenergic blocking agents may cause pharmacological effects such as bradycardia in the fetus and newborn infant.

Labetalol is known to cross the placental barrier and has been found to bind to the eyes of fetal animals. Labetalol has been usedsuccessfully in the treatment of hypertension arising in the second and third trimester of pregnancy. Labetalol crosses the placental barrier

and the possibility of the consequences of alpha- and beta-adrenoreceptor blockade in the fetus and neonate should be borne in mind.Perinatal and neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycaemia, hypothermia) has been rarely reported.Sometimes these symptoms developed a day or two after birth. Response to supportive measures (e.g. intravenous fluids and glucose) isusually prompt but with severe pre-eclampsia, particularly after prolonged intravenous labetalol, recovery may be slower. This may berelated to diminished hepatic metabolism in premature babies. Intrauterine and neonatal deaths have been reported but other drugs (e.g.vasodilators, respiratory depressants) and the effects of pre-eclampsia, intrauterine growth retardation and prematurity were implicated.Such clinical experience warns against unduly prolonging high dose labetalol and delaying delivery and against co-administration ofhydralazine.

Administration of labetalol in the first trimester of pregnancy is not recommended. Labetalol does not appear to be teratogenic in rats orrabbits, but it is embryolethal when given in a dose of 50 mg/kg orally.

Use in Lactation

Labetalol is excreted in breast milk. No adverse reactions in breastfeeding infants have been reported. It is not recommended for nursing

mothers unless the expected benefits outweigh any potential risks.

Use in the Elderly

The bioavailability and half-life of labetalol hydrochloride are increased in the elderly. In addition, the hypotensive response is greater inthis age group following administration. Therefore, lower doses of labetalol are likely to be required in elderly patients.

Paediatric Use

There is little reported clinical experience of the use of labetalol in children. Thus, care should be taken in establishing individual dosagerequirements in children. Safety and effectiveness in children have not been established.

Interactions with other drugs

Postural hypotension may be enhanced by the concurrent administration of other vasodilators.

The interaction of labetalol with methyldopa and with clonidine has been examined on blood pressure and heart rate in animals. Theresults indicate that labetalol, given together with methyldopa or clonidine, should exert an additional hypotensive effect in human beingswho are sensitive to both drugs in the combined therapy.

Concomitant use of tricyclic antidepressants may increase the incidence of tremor.

Cimetidine increases the oral bioavailability of labetalol. Care is required in determining the dose of labetalol in patients who are also takingcimetidine.

Concurrent administration of some nonsteroidal anti-inflammatory drugs may impair the antihypertensive effects of labetalol, possibly dueto their inhibition of renal synthesis of vasodilatory prostaglandins. Dosage adjustment may be necessary.

See also Warnings and Precautions.

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Effects on laboratory tests

Labetalol fluoresces in alkaline solution at an excitation wavelength of 334 nm and a fluorescence wavelength of 412 nm and may,therefore, interfere with the assays of certain fluorescent substances including catecholamines.

The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine,normetanephrine, and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. In screening patientssuspected of having a phaeochromocytoma and being treated with labetalol, a specific method, such as high performance liquidchromatographic assay with solid phase extraction, should be employed in determining levels of catecholamines.

Labetalol may produce a false positive result when urine is screened for amphetamines. Care must be taken to corroborate any such resultwith a more specific method.

Labetalol has been shown to reduce the uptake of radioisotopes of metaiodobenzylguanidine (MIBG). Care should therefore be taken ininterpreting results from MIBG scintigraphy.

ADVERSE EFFECTS

Labetalol is normally well tolerated. Symptoms of postural hypotension may occur if the initial dosage is too high or if the dose is increasedtoo rapidly.

Cardiovascular: Postural hypotension may occur if the initial dosage is too high or if the dose is increased too rapidly. Occasionallybradycardia and heart block have been reported.

Nervous system: Transient dizziness, headache, tiredness, depressed mood and lethargy may occur. There have been reports of a tinglingsensation of the skin (especially of the scalp) associated with labetalol treatment usually occurring early in treatment and which is transientin nature.

Collagen disorders: There have been occasional reports of positive antinuclear antibodies unassociated with disease as well as theoccasional case of systemic lupus erythematosus and very occasionally drug fever.

Ocular: Blurred vision, eye irritation and dry eyes have been reported.

Hepatic: Reports of raised liver function tests; jaundice (both hepatocellular and cholestatic) and hepatitis have on occasion been reported,the signs and symptoms of which are usually reversible on withdrawal of the drug.

Hepatic necrosis has been reported (See Warnings).

Musculoskeletal: There has been one report of toxic myopathy. Tremor has been reported in the treatment of hypertension of pregnancy.Muscle cramps have been reported.

Respiratory: Bronchospasm may occur in susceptible individuals.

Dermatological: Rashes of various types such as generalised maculopapular, lichenoid, urticarial, bullous, lichen planus, psoriasiform andfacial erythema, Peyronie's disease and reversible alopecia.

Genitourinary:Acute retention of urine and difficulty in micturition have occurred during labetalol treatment.

Gastrointestinal: Epigastric pain, nausea and vomiting.

Hypersensitivity: Rash, pruritis, angio-oedema and dyspnoea.

Other:Ankle swelling; failure of ejaculation; nasal congestion and sweating.

DOSAGE AND ADMINISTRATION

LABETALOL HYDROCHLORIDE INJECTION is intended for IV use in hospitalised patients.

DOSAGE MUST BE INDIVIDUALISED depending upon the severity of hypertension and the response of the patient during dosing.

Patients should always be kept in a supine position during the period of IV drug administration. A substantial fall inblood pressure on standing should be expected in these patients. The patients ability to tolerate an upright position should be establishedbefore permitting any ambulation, such as using toilet facilities.

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Either of two methods of administration of LABETALOL HYDROCHLORIDE INJECTION may be used:

a) repeated IV injection, orb) slow continuous infusion.

Repeated Intravenous Injection: Initially, LABETALOL HYDROCHLORIDE INJECTION should be given in a 20 mg dose (whichcorresponds to 0.25 mg/kg for an 80-kg patient) by slow IV injection over a 2 minute period.

Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response.Additional injections of 40 or 80 mg can be given at 10 minute intervals until a desired supine blood pressure is achieved or a total of 300mg of labetalol hydrochloride has been injected. The maximum effect usually occurs within 5 minutes of each injection.

Slow Continuous Infusion: LABETALOL HYDROCHLORIDE INJECTION is prepared for continuous IV infusion by diluting the vial contentswith commonly used IV fluids (see below). Examples of two methods of preparing the infusion solution are: Add 40 mL of LABETALOLHYDROCHLORIDE INJECTION to 160 mL of a commonly used IV fluid such that the resultant 200 mL of solution contains 200 mg oflabetalol hydrochloride, 1 mg/mL. The diluted solution should be administered at a rate of 2 mL/min to deliver 2 mg/min.

Alternatively, add 40 mL of LABETALOL HYDROCHLORIDE INJECTION to 250 mL of a commonly used IV fluid. The resultant solution

will contain 200 mg of labetalol hydrochloride, approximately 2 mg/3 mL. The diluted solution should be administered at a rate of 3 mL/minto deliver approximately 2 mg/min.

The rate of infusion of the diluted solution may be adjusted according to the blood pressure response, at the discretion of the physician. Tofacilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g. graduated buretteor mechanically driven infusion pump.

Since the half-life of labetalol hydrochloride is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would notbe reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and shouldthen be stopped and oral labetalol hydrochloride started (see below). The effective IV dose is usually in the range of 50 to 200 mg. A totaldose of up to 300 mg may be required in some patients.

Blood Pressure Monitoring: The blood pressure should be monitored during and after completion of the infusion or IV injection. Rapid orexcessive falls in either systolic or diastolic blood pressure during IV treatment should be avoided. In patients with excessive systolichypertension, the decrease in systolic pressure should be used as an indicator of effectiveness in addition to the response of the diastolicpressure.

For subsequent outpatient titration or maintenance dosing see Labetalol Hydrochloride Tablets Product Information DOSAGE ANDADMINISTRATION for additional recommendations

Compatibility with commonly used intravenous fluids: parenteral drug products should be inspected visually for particulate matter anddiscolouration before administration.

LABETALOL HYDROCHLORIDE INJECTION was tested for compatibility with commonly used IV fluids at final concentrations of 1.25 to3.75 mg of labetalol hydrochloride per milliliter of the mixture. LABETALOL HYDROCHLORIDE INJECTION was found to be compatiblewith and stable (for 24 hours refrigerated or at room temperature) in mixtures with the following solutions: Ringers Injection, LactatedRingers Injection; 5% dextrose and Ringers Injection; 5% Lactated Ringers and 5% dextrose injection; 5% dextrose injection; 0.9%sodium chloride injection; 5% dextrose and 0.2% sodium chloride injection; 2.5% dextrose and 0.45% sodium chloride injection; 5%dextrose and 0.9% sodium chloride injection; and 5% dextrose and 0.33% sodium chloride injection.

LABETALOL HYDROCHLORIDE INJECTION was NOT compatible with 5% sodium bicarbonate injection. Care should be taken whenadministering alkaline drugs, including furosemide, in combination with labetalol. Compatibility should be assured prior to administeringthese drugs together.

OVERDOSAGE

Overdosage with LABETALOL HYDROCHLORIDE INJECTION causes excessive hypotension that is posture sensitive and, sometimes,excessive bradycardia. Patients should be placed supine and their legs raised if necessary to improve the blood supply to the brain. Ifoverdosage with LABETALOL HYDROCHLORIDE INJECTION follows oral ingestion, gastric lavage or pharmacologically induced emesis(using syrup of ipecac) may be useful for removal of the drug shortly after ingestion. The following additional measures should beemployed if necessary:

Excessive bradycardia - Administer atropine or epinephrine.

Cardiac failure - Administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful.

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Hypotension - Administer vasopressors, e.g., norepinephrine. There is pharmacological evidence that norepinephrine may be the drug ofchoice.

Bronchospasm - Administer epinephrine and/or an aerosolized beta 2-agonist.

Seizures - Administer diazepam.

In severe beta-blocker overdose resulting in hypotension and/or bradycardia, glucagon has been shown to be effective when administeredin large doses (5 to 10 mg rapidly over 30 seconds, followed by continuous infusion of 5 mg/h that can be reduced as the patientimproves). Neither haemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the general circulation (

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