This information is intended for use by health professionals

1. Name of the medicinal product

Labetalol Synchrony 5mg/ml solution for injection

2. Qualitative and quantitative composition

Labetalol hydrochloride 5mg/ml. Each 10ml ampoule contains 50mg Labetalol Hydrochloride.

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Solution for Injection

The Solution for injection is a clear, colourless liquid, pH 4 (3.5-4.5). Osmolarity 0.03 (0.024-0.036) Osmol/kg

4. Clinical particulars
4.1 Therapeutic indications

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

- Anaesthesia when a hypotensive technique is indicated.

4.2 Posology and method of administration

Dosage

Labetalol injection is intended for intravenous use in hospitalized patients.

Populations

- Adults

Indication

Dosage

Severe hypertension

Bolus injection:

If it is essential to reduce blood pressure quickly, a dose of 50mg of labetalol hydrochloride should be given by intravenous injection (over a period of at least one minute) and, if necessary, may be repeated at five minute intervals until a satisfactory response occurs. The total dosage should not exceed 200mg.

The maximum effect usually occurs within five minutes and the effective duration of action is usually about 6 hours but may be as long as 18 hours.

Intravenous infusion

(instructions for dilution - refer to section 6.6)

A labetalol infusion 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 Sodium Chloride and Dextrose Injection, 5% dextrose Intravenous Infusion, Potassium Chloride and Glucose solution or Ringer Lactate.

The rate of infusion of Labetalol hydrochloride should be about 160mg/hour, but may be adjusted according to the response at the discretion of the physician. The effective dose is usually in the range of 50-200mg but infusion needs to be administered until a satisfactory result has been achieved. A larger dose may be required, especially in patients with phaeochromocytoma.

In severe cases of hypertension of pregnancy a lower, increasing infusion rate needs to be administered. The infusion needs to be started at the rate of 20mg/ hour, and this dose may be doubled every 30 minutes until a satisfactory result has been obtained, or a dosage of

160mg/hour is reached.

Hypotensive Anaesthesia

To control hypotension during anesthesia, the recommended starting dose of Labetalol injection is 10-20mg intravenously, depending on the age and condition of the patient.

If satisfactory hypotension is not achieved after five minutes, increments of 5-10mg should be given until the desired level of blood pressure is attained.

The mean duration of hypotension following 20 to 25mg of labetalol is 50 minutes.

Hypertension due to other causes

The rate of infusion of Labetalol hydrochloride should be 120 - 160mg/hour, until a satisfactory result has been achieved. Then stop the infusion. The effective dose is usually in the range of 50 to 200mg, but a larger dose may be required, especially in patients with phaeochromocytoma.

Pediatric 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

Method of administration

Precautions to be taken before administering the medicinal product:

Patients should always receive the drug whilst in the supine or left lateral position. Raising the patient into the upright position within 3 hours of intravenous labetalol administration should be avoided since excessive postural hypotension may occur.

4.3 Contraindications

• Non-selective beta blockers must not be used on patients with a history of asthma or a history of obstructive pulmonary disease

• Labetalol injections are contraindicated for second or third degree heart block (unless a pacemaker is in-situ), cardiogenic shock and other disorders which are associated with serious and long lasting hypotension and/or bradycardia.

• Decompensated heart failure

• Uncontrolled/ unstable heart failure.

• Sick sinus syndrome (including sino-atrial block), unless a pacemaker is in-situ

• Prinzmetal's angina..

• Sinus node dysfunction

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

4.4 Special warnings and precautions for use

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.

Renal impairment

Caution needs to be taken when Labetalol is used in patients with severe renal impairment (GFR = 15 – 29 ml/min/1,73 m2 ).

Peripheral circulatory disorders

Labetalol should be used with great caution in patients with peripheral circulatory disorders as aggravation of these disorders may occur. Great caution is advised in patients with peripheral arterial diseases (Raynaud's disease or syndrome, intermittent claudication), as aggravation of these disorders may occur. Alpha blockers may counteract the adverse effects of beta blockers.

Symptomatic Bradycardia

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

Diabetes Mellitus

Great caution needs to be taken with untreated or uncontrolled diabetes mellitus. As with other beta-adrenergic blocking agents, labetalol can mask the symptoms of hypoglycemia (tachycardia and tremor) in diabetic patients. The hypoglycemic effect of insulin and oral hypoglycemic agents can be higher when beta-adrenergic blocking agents are used.

Thyrotoxicosis

Beta-blockers can mask the symptoms of thyrotoxicosis, but will not change the thyroid function.

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.

Adrenaline

If patients who are treated with labetalol need adrenaline, a lower dose of adrenaline needs to be used since the use of both adrenaline and labetalol at the same time may cause bradycardia and hypertension (see section 4.5 “interactions with other medicinal products and other forms of interaction”)

When adrenaline has a serious influence, as is the case with phaeochromocytoma, labetalol can lead to a paradoxical blood pressure increase.

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 decreased left ventricular function

Extra caution needs to be taken in patients who suffer from heart failure or decreased left ventricular function. Labetalol is contraindicated for uncontrolled heart failure, but may be used with caution in patients whose heart failure is under control and who are free of symptoms. Heart failure needs to be controlled with an appropriate treatment before labetalol should be used.

The use of beta-blockers may induce or aggravate heart failure or obstructive pulmonary disease. In the case of heart failure, the myocardial contractility needs to be maintained and the failure needs to be compensated. Patients with reduced contractility , especially elderly patients, need to be checked regularly on the development of heart failure.

It is strongly recommended not to interrupt or discontinue labetalol therapy abruptly, especially patients with heart failure and patients with angina pectoris (to prevent exacerbation of angina pectoris, myocardial infarction and ventricular fibrillation).

Inhalation Anaesthetics

Caution needs to be taken when inhalation anaesthetics are used concurrently (see section 4.5 “interactions with other medicinal products and other forms of interaction”)

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. Labetalol can increase the hypotensive effect of inhalational anaesthetics.

Metabolic Acidosis and Phaeochromocytoma

Caution needs to be taken with cases of metabolic acidosis and phaeochromocytoma. In patients with phaeochromocytoma, labetalol may only be used after adequate alpha-blockage has been reached.

Calcium Antagonists

Caution needs to be taken when labetalol is used at the same time as calcium antagonists, and especially calcium entry-blockers, which negatively influence the contractility and the atrioventricular conductions.

Caution needs to be take when adrenaline, verapamil or class I antiarrhythmic agents are administered at the same time as labetalol (see section 4.5 “interactions with other medicinal products and other forms of interaction”). Beta-blockers have a negative inotropic effect, but will not influence the positive inotropic effect of digoxin.

Sudden haemorrhage

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.

Administration

It is desirable to check the blood pressure and the heart rate after injection and during infusion. In most patients, the heart rate will decrease slightly.

Severe bradycardia is not usual, but can be controlled by injecting 1 to 2mg of atropine intravenously.

Breathing should be carefully checked in patients with a known airway disease.

As soon as blood pressure is reduced by bolus injection or infusion, the treatment should be maintained with labetalol tablets, with a starting dose of 100mg two times a day.

Labetalol-injection is administered to patients who suffer from an uncontrolled hypotension and who have been given other hypotensive substances, including beta- blockers, without suffering from side effects.

4.5 Interaction with other medicinal products and other forms of interaction

The hypotensive effect of Labetalol may be reduced when used in combination with prostaglandin synthetase inhibiting drugs (NSAID's, nonsteroidal anti-inflammatory drugs). Dose adjustments may be necessary. The combination with other antihypertensives may lead to additive synergism.

Labetalol is fluorescent in alkaline solution with an excitation wavelength of 334 nanometer and a fluorescent wavelength of 412 nanometer, and may therefore interfere with the tests of some fluorescent substances, including catecholamines.

The presence of labetalol metabolites in the urine can lead to false high levels of catecholamines, metanephrines, normetanephrines, and vanillylmandelic acid (VMA) in the urine when measured with fluorimetric or photometric methods. When patients who are suspected to suffer from phaeochromocytoma are screened, and are treated with labetalol hydrochloride, a specific method such as HPLC-assay with solid phase extraction will need to be used to determine the level of catecholamines.

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

The use of both adrenaline and labetalol at the same time may cause bradycardia and hypertension (see section 4.4 “special warnings and precautions for use.”).

Extra care should be taken if labetalol is used at the same time as either class I antiarrhythmic agents or calcium antagonists of the Verapamil class.

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.

If labetalol is used simultaneously with calcium antagonists with a negative inotropic effect (e.g. verapamil, diltiazem), the risk of bradycardia and hypotension may increase, especially in patients with atrioventricular conduction disease or contractility disease. If the patient is switched from calcium antagonists to beta blockers, or the other way around, a new intravenous treatment should not be started until at least 48 hours after the previous treatment has ended.

Simultaneous use of labetalol with calcium antagonists belonging to the dihydropyridine derivates (e.g. nifedipine), may increase the risk of hypotension and may lead to cardiac failure in patients with latent cardiac insufficiency. 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.

Beta-blockers, especially non-selective beta-blockers, can increase the risk of hypoglycemia in diabetic patients and may prevent the appearance of signs of hypoglycemia, such as tachycardia and tremors, and may delay the normalization of glucose levels after insulin induced hypoglycemia. Changes of the dose of oral anti diabetics may be necessary.

Extra caution needs to be taken when general anesthesia is used on patients who are treated with beta-blockers. Beta-blockers reduce the risk of arrhythmia during anesthesia, but can lead to a reduction of the reflex tachycardia and a higher risk of hypotension during anesthesia. An anesthetic with the lowest possible negative inotropic effect should be used. Heart function needs to be monitored closely and bradycardia due to vagal dominance needs to be corrected by administrating 1-2 mg atropine intravenously (stopping before surgery, see section 4.2 “posology and method of administration”).

When treatment is discontinued in patients who use both beta-blockers and clonidine, the beta-blocker should be phased out a couple of days before the treatment with clonidine is discontinued. This needs to be done to avoid a recurrence of hypertensive crisis as a result of the discontinuance of the clonidine treatment. For the same reasons it is also important to phase out the clonidine when a switch to beta-blockers is being made, and to start the treatment with the beta-blocker some time before the clonidine is discontinued.

Concomitant use of labetalol and cholinesterase inhibitors can increase the risk on bradycardia.

Concomitant use with alpha adrenergic agonists (e.g. phenylpropanolamine and adrenalin) can increase the risk of high blood pressure, while concomitant use with beta adrenergic agonists may counteract the beta adrenergic agonists (antidotum- effect).

Concomitant use of ergot derivatives may increase the risk of peripheral vasoconstriction in some patients.

It has been demonstrated that labetalol increased the biological availability of imipramine by more than 50% through the inhibition of 2-hydroxylation. Labetalol in combination with imipramine can increase the effect of imipramine and the concurrent use of tricyclic antidepressants. Concomitant use of tricyclic antidepressants may increase tremors.

Labetalol may increase the hypotensive effect of volatile anaesthetics.

An increase in blood pressure reduction may occur during concomitant use of, for example, nitrates, anti-psychotics (phenothiazine derivatives like chloropromazine) and other anti-psychotics and anti-depressants.

4.6 Fertility, pregnancy and lactation

Fertility:

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

Pregnancy:

On the basis of experience during human pregnancy, it is unexpected that labetalol increases the risk of birth defects. Animal studies have not demonstrated reproductive toxicity. However, toxicity has been demonstrated in embryo-foetal development (see section 5.3). Labetalol crosses the placenta barrier and because of the pharmacological activity of alpha- and beta- adreneceptor blockade, side effects in the foetus and neonate should be borne in mind (bradycardia, hypotension, respiratory depression, hypoglycemia, hypothermia). Close observation up to 24 to 48 hours after birth is required. Beta-blockers may reduce placental perfusion.

Labetalol should only be used during the pregnancy if the potential benefit for the mother outweighs the potential risk for the foetus.

Breast-feeding:

Labetalol is excreted in breast milk in small amounts (approximately 0.004-0.07% of the dose administered to the mother). No side-effects have been reported. Monitoring is needed if Labetalol is used in lactating mothers.

4.7 Effects on ability to drive and use machines

No general information

4.8 Undesirable effects

Summary of safety profile

The most frequently reported undesirable effects during the use of labetalol injection and those reported in post-marketing studies include: congestive heart failure, postural hypotension, hypersensitivity, drug fever, increased liver functions, nasal congestion and erectile dysfunctions.

Tabulated list of undesirable effects

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 (#), are usually transient in nature and occur in the first weeks of treatment.

Organ system

Undesired effect

Immune system disorders

Common

Sensitivity, drug fever

Cardiac disorders

Common

Congestive heart failure

Rarely

Bradycardia

Very rarely

Heart block

Vascular disorder

Common

# Postural hypotension

Very rarely

Worsening of the symptoms of Raynaud's syndrome

Respiratory, thoracic, and mediastinal disorders

Common

# Nasal congestion

Rarely

Bronchospasm

Hepato-biliary disorders

Common

Raised liver function tests

Very rarely

Hepatitis, hepatocellular jaundice

cholestatic jaundice, hepatic necrosis

Reproductive system and breast disorders

Common

Erectile dysfunction

Description of some undesired effects:

Immune system disorder:

Reports of hypersensitivity include rash, pruritus, angioedema and dyspnea, and very rarely drug fever and angioedema.

Vascular disorder:

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

Hepato-biliary disorder

The signs and symptoms of hepato-biliary disorders are usually reversible after discontinuing the treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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.

4.9 Overdose

Symptoms of overdosage:

Acute cardiac insufficiency is to be expected, e.g. excessive hypotension and sometimes bradycardia. 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.

Treatment:

The patient should be placed on their back, with the legs up.

Parental adrenal/ anticholinergic treatment should be provided if necessary to improve blood flow.

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

Pharmacokinetic

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 dysfunction

In 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”)

5.3 Preclinical safety data

- 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.

6. Pharmaceutical particulars
6.1 List of excipients

Hydrochloric acid (E507)

(for pH adjustment)

Sodium hydroxide (E524)

(for pH adjustment)

Water for Injections

6.2 Incompatibilities

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

6.3 Shelf life

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.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal and other handling

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 4.3% (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.

7. Marketing authorisation holder

Synchrony Pharma Ltd., Business Technology Centre,

Bessemer Drive, Stevenage, Hertfordshire, SG1 2DX,

United Kingdom

8. Marketing authorisation number(s)

PL 39280/0009

9. Date of first authorisation/renewal of the authorisation

09/05/2018

10. Date of revision of the text

18/02/2019