Labetalol Injection is indicated for the treatment of:

- Severe hypertension, including severe hypertension of pregnancy, when rapid control of blood pressure is essential.

- Anaesthesia when a hypotensive technique is indicated.

- Hypertensive episodes following acute myocardial infarction.

Adults:

Labetalol injection is intended for intravenous use in hospitalised patients. The plasma concentrations achieved after intravenous dose of labetalol in severe hypertension are substantially greater than those following oral administration of the drug and provide a greater degree of blockade of alpha-adrenoceptors necessary to control the more severe disease. Patients should, therefore, always receive the drug whilst in the supine or left lateral position. Raising the patient into the upright position, within three hours of intravenous labetalol administration, should be avoided since excessive postural hypotension may occur.

Paediatric population:

The safety and efficacy of Labetalol administered to children from 0 to 18 years of age have not been established. No data are available

• Hypersensitivity to the active substance, or any of the excipients listed in section 6.1

• History of wheezing or asthma.

• Second or third degree heart block.

• Cardiogenic shock.

• Hypotension.

• Bradycardia (<45-50bpm).

• Uncontrolled, incipient or digitalis refractory heart failure.

• Sick sinus syndrome (including sino-atrial block).

• Prinzmetal's angina.

• Untreated phaechromocytoma

• Metabolic acidosis

• Severe peripheral circulatory disturbances.

Where peripheral vasoconstriction suggests low cardiac output, the use of labetalol to control hypertensive episodes following acute myocardial infarction is contra-indicated.

Liver Disease

There have been rare reports of severe hepatocellular injury with labetalol therapy. The hepatic injury is usually reversible and has occurred after both short and long term treatment. There have been reports of fatal hepatic necrosis. Appropriate laboratory testing should be done at the first sign or symptom of liver dysfunction. If there is laboratory evidence of liver injury or the patient is jaundiced, labetalol therapy should be stopped and not re-started.

Extra caution needs to be taken when labetalol is used in patients with liver dysfunction, as these patients metabolize labetalol slower than patients without liver dysfunction.

Peripheral circulatory disorders

In patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), beta-blockers should be used with great caution as aggravation of these disorders may occur.

Symptomatic Bradycardia

Beta-blockers may induce bradycardia. If the pulse rate decreases to less than 50-55 beats per minute at rest and if the patient experiences symptoms related to bradycardia, the dosage of Labetalol should be reduced.

First degree atrioventricular block

Due to the negative effect of beta-adrenergic blocking agents on the atrioventricular conduction time, labetalol needs to be administered with caution to patients with first degree atrioventricular block. Patients with liver or kidney insufficiency may need a lower dosage, depending on the pharmacokinetic profile of the compound. The elderly should be treated with caution, starting with a lower dosage but tolerance is usually good in the elderly.

Hypersensitivity to beta-blockers

Risk of anaphylactic reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Skin rashes and/or dry eyes

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

Intraoperative floppy iris syndrome

The occurrence of intraoperative floppy iris syndrome (IFIS, a variation of Horner's syndrome) has been observed during cataract surgeries in some patients who were being treated with tamsulosine, or have been treated with tamsulosine in the past. IFIS has also been reported when other alpha-1- blockers were being used, and the possibility of a class effect cannot be excluded. Since IFIS can lead to a higher chance of complications during cataract surgeries, the ophthalmologist needs to be informed if alpha-1- blockers are currently being used, or have been used in the past.

Heart failure or ischemic heart disease

Due to negative inotropic effects, special care should be taken with patients whose cardiac reserve is poor and heart failure should be controlled before starting labetalol therapy.

Patients, particularly those with ischemic heart disease, should not interrupt or discontinue abruptly labetalol therapy. The dosage should gradually be reduced, i.e. over 1-2 weeks, if necessary at the same time initiating replacement therapy, to prevent exacerbation of angina pectoris. In addition, hypertension and arrhythmias may develop.

Anaesthetics

It is not necessary to discontinue labetalol therapy in patients requiring anaesthesia, but the anaesthetist must be informed and the patient should be given intravenous atropine prior to induction. During anaesthesia labetalol may mask the compensatory physiological responses to sudden haemorrhage (tachycardia and vasoconstriction). Close attention must therefore be paid to blood loss, and the blood volume maintained.

Anaesthetic agents causing myocardial depression (e.g. cyclopropane, trichloroethylene) should be avoided. Labetalol may enhance the hypotensive effects of halothane.

Asthma and obstructive airways disease

Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with asthma or a history of obstructive airways disease unless no alternative treatment is available. In such cases the risk of inducing bronchospasm should be appreciated and appropriate precautions taken. If bronchospasm should occur after the use of labetalol it can be treated with a beta2-agonist by inhalation, e.g. salbutamol (the dose of which may need to be greater than the usual in asthma) and, if necessary, intravenous atropine 1mg.

Psoriasis

Patients with a history of psoriasis should take beta-blockers only after careful consideration.

Sodium

This medicinal product contains less than 1mmol sodium (23mg) per dose, that is to say essentially 'sodium-free'.

Concomitant use not recommended:

• Calcium antagonists such as verapamil and to a lesser extent diltiazem have a negative influence on contractility and atrio-ventricular conduction. Digitalis glycosides used in association with beta-blockers may increase atrioventricular conduction time. Labetalol can heighten the effect of digoxin on the reduction of ventricular flow.

• Clonidine: Beta-blockers increase the risk of rebound hypertension. When clonidine is used in conjunction with non-selective beta-blockers, such as propranolol, treatment with clonidine should be continued for some time after treatment with the beta-blocker has been discontinued.

• Monoamineoxidase inhibitors (except MOA-B inhibitors).

Use with caution:

• Class I antiarrhytmic agents (e.g. disopyramide, quinidine) and amiodarone (antiarrhytmic Class II) may have potentiating effects on atrial conduction and induce negative inotropic effect.

• Insulin and oral antidiabetic drugs may intensify the blood sugar lowering effect, especially of non-selective beta-blockers. Beta-blockade may prevent the appearance of signs of hypoglycemia (tachycardia). Anaesthetic drugs may cause attenuation of reflex tachycardia and increase the risk of hypotension. Continuation of beta-blockade reduces the risk of arrhythmia during induction and intubationa, The anaesthesiologist should be informed when the patient is receiving a beta-blocking agent. Anaesthetic agents causing myocardial depression, such as cyclopropane and trichlorethylene, are best avoided.Cimetidine, hydralazine and alcohol may increase the bioavailability of labetalol.

• Several different drugs or drug classes may enhance the hypotensive effects of labetalol: ACE inhibitors; angiotensin-II antagonists; aldesleukin, alprostadil; anxiolytics; hypnotics; moxisylyte; diuretics; alpha-blockers.

• Several different drugs or drug classes may antagonise the hypotensive effects of labetalol: NSAIDs, corticosteroids; oestrogens; progesterones

Take into account:

• Calcium antagonists: dihydropyridine derivates such as nifedipine, The risk of hypotension may be increased. In patients with latent cardiac insufficiency, treatment with beta-blockers may lead to cardiac failure. Prostaglandin synthetase inhibiting drugs may decrease the hypotensive effect of beta-blockers.

• Sympathicomimetic agents may counteract the effect of beta-adrenergic blocking agents.

• Concomitant use of tricyclic antidepressants, barbiturates, phenothiazines or other antihypertensive agents may increase the blood pressure lowering effect of labetalol. Concomitant use of tricyclic antidepressant may increase the incidence of tremor.

• Labetalol has been shown to reduce the uptake of radioisotopes of metaiodobenzylguanidine (MIBG), and may increase the likelihood of a false negative study. Care should therefore be taken in interpreting results from MIBG scintigraphy. Consideration should be given to withdrawing labetalol for several days at least before MIBG scintigraphy, and substituting other beta or alpha-blocking drugs.

• Antimalarials such as mefloquine or quinine may increase the risk of bradycardia.

• Ergot derivatives may increase the risk of peripheral vasoconstriction.

• Tropisetron may increase the risk of ventricular arrhythmia.

• Labetalol interferes with laboratory tests for catecholamines.

Pregnancy:

Although no teratogenic effects have been demonstrated in animals, labetalol should only be used during the first trimester of pregnancy if the potential benefit outweighs the potential risk. Labetalol crosses the placenta barrier and the possibility of the consequences of alpha- and beta- adreneceptor blockade in the foetus and neonate should be borne in mind. Perinatal and neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycemia,hypothermia) has been rarely reported. Sometimes these symptoms have developed a day or two after birth. Response to supportive measures (e.g. intravenous fluids and glucose) is usually prompt but with severe pre-eclampsia, particularly after prolonged intravenous labetalol, recovery may be slower. This may be related to diminished liver metabolism in premature babies. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. There is an increased risk of cardiac and pulmonary complications in the neonate in the post-natal period.

Intra-uterine and neonatal deaths have been reported with labetalol but other drugs (e.g. vasodilators, respiratory depressants) and the effects of preeclampsia, intra-uterine growth retardation and prematurity were implicated. Such clinical experience warns against unduly prolonging high dose labetalol and delaying delivery and against co-administration of hydralazine.

Breast-feeding:

Labetalol is excreted in breast milk. Breast-feeding is therefore not recommended. Nipple pain and Raynaud's phenomenon of the nipple have been reported (see section 4.8). Monitoring is needed if Labetalol is used in lactating mothers.

Fertility:

There is no information available on the effect labetalol has on the fertility.

There are no studies on the effect of this medicine on the ability to drive. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur.

Summary of safety profile

Labetalol injection is usually well tolerated. Excessive postural hypotension may occur if patients are allowed to assume an upright position within three hours of receiving labetalol injection.

Tabulated list of undesirable effects

The frequency of adverse reactions is defined as follows:

Very common ≥ 1/10

Common ≥ 1/100 <1/10

Sometimes ≥ 1/1000 <1/100

Rarely ≥ 1/10,000 < 1/1000

Very rarely < 1/10,000

Undesirable effects marked with a hash sign (#), Most side-effects are transient and occur during the first few weeks of treatment with labetalol.

They include:

Description of some undesired effects:

Blood and the lymphatic system disorders

Rare reports of positive antinuclear antibodies unassociated with disease, hyperkalaemia, particularly in patients who may have impaired renal excretion of potassium, thrombocytopenia.

Psychiatric disorders

Depressed mood and lethargy, hallucinations, psychoses, confusion, sleep disturbances, nightmares.

Nervous system disorders

Headache, tiredness, dizziness, tremor has been reported in the treatment of hypertension of pregnancy.

Eye disorders

Impaired vision, dry eyes.

Respiratory, thoracic and mediastinal disorders

Bronchospasm (in patients with asthma or a history of asthma), nasal congestion, interstitial lung disease.

Gastrointestinal disorders

Epigastric pain, nausea, vomiting, diarrhoea.

Skin and subcutaneous tissue disorders

Sweating, tingling sensation in the scalp, usually transient, may occur in a few patients early in treatment, reversible lichenoid rash, systemic lupus erythematosus, exacerbation of psoriasis.

Musculoskeletal, connective tissue and bone disorders:

Cramps, toxic myopathy.

Renal and urinary disorders

Acute retention of urine, difficulty in micturition.

General disorders and administration site conditions

Drug fever, masking of the symptoms of thyrotoxicosis or hypoglycaemia, reversible alopecia.

Immune system disorder:

Reports of hypersensitivity include rash, pruritus, angioedema and dyspnea.

Vascular disorders:

Ankle oedema, increase of an existing intermittent claudication, cold or cyanotic extremities, Raynaud's phenomenon, paraesthesia of the extremities.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions through the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms of overdosage:

Symptoms of overdosage are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency Oliguric renal failure has been reported after massive overdosage on labetalol orally. In one case, the use of dopamine to increase the blood pressure may have aggravated the renal failure.

Labetalol does have membrane stabilising activity which may have clinical significance in overdosage.

Treatment:

After an overdose or in case of hypersensitivity, the patient should be kept under close supervision and be treated in an intensive-care ward. Artificial respiration may be required. Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine. Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines. The beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5mcg/min, or dobutamine, starting with a dose of approximately 2.5mcg/min, until the required effect has been obtained. If this does not produce the desired effect, intravenous administration of 8-10 mg glucagon may be considered. If required the injection should be repeated within one hour, to be followed, if necessary, by an iv infusion of glucagon at 1-3 mg/hour. Administration of calcium ions, or the use of a cardiac pacemaker, may also be considered. Haemodialysis removes less than 1% labetalol hydrochloride from the circulation.

Further treatment should be provided as clinically appropriate or as advised by a national anti-toxins laboratory, if available.

Pharmacotherapeutic group: Alpha and beta blocking agents.

ATC code: C07A G01

Mechanism of action

Labetalol lowers the blood pressure primarily by blocking peripheral arteriolar alpha- adrenoceptors thus reducing peripheral resistance and, by concurrent beta-blockade protects the heart from reflex sympathetic drive that would otherwise occur.

Pharmacodynamic effects

Cardiac output is not significantly reduced at rest or after moderate exercise. Increases in systolic blood pressure during exercise are, however, reduced but corresponding changes in diastolic pressure are essentially normal.

In patients with angina pectoris co-existing with hypertension, the reduced peripheral resistance decreases myocardial afterload and oxygen demand. All these effects would be expected to benefit hypertensive patients.

Pharmacokinetics

Chemically, labetalol consists of 4 stereo-isomers with different pharmacodynamic effects.

Distribution

About 50% of labetalol in the blood is protein bound. Only negligible amounts of the drug cross the blood brain barrier in animal studies. Labetalol crosses the placenta barrier and is excreted in breast milk.

Bio-transformation

Labetalol is metabolised mainly through conjugation to inactive glucuronide metabolites.

Elimination

The glucuronide metabolites are excreted both in urine and via the bile into the faeces. Less than 5% of the labetalol dose will be excreted in the urine and the bile unchanged. The plasma half-life of labetalol is around 4 hours.

Special patient populations

- Liver dysfunction

Labetalol undergoes a significant but variable first-pass metabolism when it is taken orally. In a study with 10 patients with historically proven cirrhosis the exposure to oral Labetalol was around three times as much compared to healthy members of the control group. The variability between the subjects in both the control group and the patient group was high (around 2.5 times).

- Renal dysfunctionIn patients with renal dysfunction lower oral dosages of Labetalol may be necessary (See 4.2 section 4.2 “ posology and method of administration” , and section 4.4 “ Special warnings and precautions for use” )

- Carcinogenesis, mutagenesis, teratogenesis

No evidence of mutagenic potential was shown in in-vitro and in-vivo tests.

Labetalol did not show any evidence of carcinogenicity in long term studies performed in rats and mice. No teratogenesis has been observed in rats or rabbits after oral dosages respectively 6 to 4 times as high as the maximum advised human dose.

Increased foetal resorption has been noted in both species treated with dosages about equal to the maximum advised human dosage, a teratology study using labetalol in rabbits, with intravenous dosages of 1.7 times the maximum advised human dosage, showed no evidence of drug-related damage to the foetus.

Hydrochloric acid (E507)

(for pH adjustment)

Sodium hydroxide (E524)

(for pH adjustment)

Water for Injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Labetalol Injection has been shown to be incompatible with sodium bicarbonate injection 4.2% w/v

2 years.

Chemical and physical in-use stability diluted in dextrose 5% (w/v); sodium chloride 0.18% (w/v) and dextrose 4.3% (w/v); potassium chloride 0.3% (w/v) and dextrose 5% (w/v) and Ringer Lactate has been demonstrated for 24 hours at 25 ° C.From a microbiological point of view, the product should be used immediately after dilution. If not used immediately in-use storage time and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8° C, unless dilution has taken place in controlled and validated aseptic conditions.

Any unused dilution should be disposed after 24 hours.

The medicinal product does not require any special temperature storage conditions.

Store in the original package to protect ampoules from light.

For storage of the product once opened or diluted, refer to section 6.3.

Type I amber glass ampoules: 10 ampoules of 10ml (per pack). Ampoules have a white break ring.

Labetalol Synchrony 5mg/ml solution for injection is compatible with the following solutions for infusion:

- Dextrose 5% (w/v)

- Sodium Chloride 0.18% (w/v) and dextrose 4% (w/v)

- Potassium Chloride 0.3% (w/v) and dextrose 5% (w/v)

- Ringer Lactate

For intravenous infusion of Labetalol Synchrony 5mg/ml solution for injection a solution containing 1mg/ml needs to be used. This solution can be made by diluting the contents of four 10ml ampoules (200mg) to 200ml with the solution for infusion.

Any unused product and waste should be disposed in accordance with local requirements.