•  Severe hypertension, including severe hypertension of pregnancy when rapid control of the blood pressure is necessary.
• Can be used to achieve controlled hypotension during general anaesthesia.

Adults:

Trandate Injection/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.

Bolus injection

If it is essential to reduce blood pressure quickly, as for example, in hypertensive encephalopathy, a dose of 50mg of labetalol hydrochloride should be given by intravenous injection over a period of at least one minute. If necessary, doses of 50mg may be repeated at five minute intervals until a satisfactory response occurs. The total dose should not exceed 200mg. After bolus injection, the maximum effect usually occurs within five minutes and the effective duration of action is usually about six hours but may be as long as eighteen hours.

Intravenous infusion

An alternative method of administering labetalol is intravenous infusion of a solution made by diluting the contents of two 20 ml ampoules or eight 5 ml ampoules (200mg) to 200ml with Sodium Chloride and Dextrose Injection BP or 5% Dextrose Intravenous Infusion BP. The resultant infusion solution contains 1mg/ml solution of labetalol hydrochloride.

In the case of severe hypertension of pregnancy, a slower and increasing rate of infusion should be used: The infusion can be started at the rate of 20mg per hour and this dose may be doubled every thirty minutes until a satisfactory reduction in blood pressure has been obtained or a dosage of 160mg per hour is reached. Occasionally, higher doses may be necessary.

In hypertension due to other causes: The rate of infusion of labetalol hydrochloride should be about 2mg (2ml of infusion solution) per minute, until a satisfactory response is obtained; the infusion should then be stopped. The effective dose is usually in the range of 50-200mg depending on the severity of the hypertension. For most patients it is unnecessary to administer more than 200mg but larger doses may be required especially in patients with phaeochromocytoma. The rate of infusion may be adjusted according to the response, at the discretion of the physician. The blood pressure and pulse rate should be monitored throughout the infusion.

It is desirable to monitor the heart rate and blood pressure after injection and during infusion. In most patients, there is a small decrease in the heart rate; severe bradycardia is unusual but may be controlled by injecting atropine 1-2 mg intravenously. Respiratory function should be observed particularly in patients with any known impairment.

Once the blood pressure has been adequately reduced by bolus injection or infusion, maintenance therapy with labetalol tablets should be substituted with a starting dose of 100 mg tablet twice daily (see labetalol tablet SmPC for further details). Trandate Injection/Labetalol Injection has been administered to patients with uncontrolled hypertension already receiving other hypotensive agents, including beta-blocking drugs, without adverse effects.

To achieve controlled hypotension during anaesthesia, the recommended starting dose of labetalol injection is 10 to 20 mg intravenously depending on the age and condition of the patient.

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

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

Children:
Safety and efficacy have not been established.

• Nonselective beta blockers must not be used in patients with asthma or a history of obstructive airway disease. • Labetalol injections and tablets are contraindicated in second or third degree heart block (unless a pacemaker is present), cardiogenic shock and other conditions associated with severe and prolonged hypotension or severe bradycardia • Uncompensated heart failure • Unstable/uncontrolled cardiac insufficiency • Sick sinus syndrome (including sino-atrial block) unless a pacemaker is present • Prinzmetal angina • Sinus node dysfunction • Labetalol injection and tablets are contraindicated for patients with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hepatic disease
Caution must be observed in the presence of liver disease. There have been very rare reports of severe hepatocellular injury with labetalol therapy. The hepatic injury is usually reversible and has occurred after both short-term and long-term treatment. However, hepatic necrosis has been reported and in some cases been fatal. Laboratory testing should be done at the first sign or symptom of hepatic dysfunction. If laboratory results show hepatic injury or the patient is jaundiced, labetalol therapy should be discontinued and not resumed.

Particular caution must be observed when labetalol is used in patients with hepatic impairment, as such patients metabolise labetalol slower than patients without hepatic impairment.

Renal impairment
Caution must be observed when labetalol is used in patients with severe renal impairment (GFR = 15–29 ml/min/1.73 m²).

Peripheral vascular disease
Labetalol should be used with caution in patients with peripheral vascular disease as their symptoms may deteriorate. Caution is advised for patients with peripheral arterial disease (Raynaud syndrome, intermittent claudication), as labetalol may aggravate symptoms. Alpha blockers can counteract the unwanted effect of beta blockers.

Symptomatic bradycardia
The labetalol dose should be decreased if the patient develops symptomatic bradycardia.

First degree atrioventricular block
Due to the negative effect of beta blockers on atrioventricular conduction time, labetalol should be administered with caution to patients with first degree atrioventricular block.

Diabetes mellitus
Caution must be observed in the presence of uncontrolled or difficult-to-control diabetes. As with other beta blockers, labetalol can mask the symptoms of hypoglycaemia (tachycardia and tremor) in diabetic patients. The hypoglycaemic effect of insulin and oral hypoglycaemic agents may be amplified by beta blockers.

Thyrotoxicosis
Beta blockers can mask the symptoms of thyrotoxicosis, however thyroid function is not affected.

Hypersensitivity to beta blockers
Risk of anaphylactic reaction: while taking beta blockers, patients with a history of severe anaphylactic reaction to various allergens may become more reactive to repeated challenges, regardless of whether these are accidental, diagnostic or therapeutic. Such patients might not respond to the usual doses of adrenaline used to treat allergic reactions.

Adrenaline
A reduced adrenaline dose should be used if patients receiving labetalol require treatment with adrenaline, as concurrent administration of labetalol and adrenaline may result in bradycardia and hypertension (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Labetalol can cause a paradoxical rise in blood pressure if there is a significantly elevated level of adrenaline in the blood, such as in phaeochromocytoma.

Skin rash and/or dry eyes
Skin rash and/or dry eyes have been reported in connection with the use of beta blockers. The reported incidence is small and in most cases the symptoms subsided once the treatment was discontinued. Gradual discontinuation of the medicinal product should be considered if a reaction of this type cannot otherwise be explained.

Intraoperative Floppy Iris Syndrome
The development of intraoperative floppy iris syndrome (IFIS, a type of small pupil syndrome) has been observed in connection with cataract surgery in some patients who were treated with, or previously treated with, tamsulosin. Isolated reports have also been received concerning other alpha-1 blockers; the risk of a drug class effect cannot be excluded. Since IFIS can involve an increase in complications in connection with cataract surgery, the eye surgeon must be informed prior to the procedure of current or previous use of alpha-1 blockers.

Heart failure or impaired left ventricular function
Particular caution must be observed in patients with heart failure or impaired systolic left ventricular function. Labetalol is contraindicated in uncontrolled heart failure, but may be used with caution in symptom-free patients whose condition is well controlled. Heart failure is to be controlled with adequate treatment before using labetalol.

The use of beta blockers indicates a risk of the development or deterioration of heart failure or obstructive lung disease. In the case of heart failure, the heart muscle’s contraction capacity must be maintained, and the failure must be compensated. Patients with reduced contraction capacity, especially the elderly, must be monitored regularly with regard to the development of heart failure.

It is strongly recommended that Trandate therapy should not be discontinued abruptly, especially in patients with heart failure or angina pectoris (risk of aggravated angina, myocardial infarction and ventricular fibrillation).

Inhaled anaesthetics
Caution should be observed in cases of concurrent treatment with inhaled anaesthetics (see section 4.5 Interaction with other medicinal products and other forms of interaction). It is not necessary to discontinue labetalol therapy prior to anaesthesia however the patient should receive intravenous atropine prior to the administration of the anaesthetic. Labetalol can amplify the hypotensive effects of volatile anaesthetics.

Metabolic acidosis and pheochromocytoma
Caution should be observed in cases of metabolic acidosis and pheochromocytoma. Labetalol should only be administered to patients with pheochromocytoma once adequate alpha blockade has been achieved.

Calcium antagonists
Caution should be observed if labetalol is used concurrently with calcium antagonists, especially calcium channel antagonists, which negatively affect contraction capacity and AV conduction.

Caution should be observed in cases of concurrent administration of adrenaline, verapamil or class I antiarrhythmics (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Beta blockers have a negative inotropic effect but do not affect the positive inotropic effect of digitalis.

Sudden haemorrhage
During general anaesthesia, labetalol may mask the compensatory physiological responses to sudden haemorrhage (tachycardia and vasoconstriction). Blood loss and the blood volume maintained must therefore be monitored closely.

Administration
Monitoring of the blood pressure and heart rate after injection and during infusion is recommended. In most patients there is a small decrease in the heart rate. Severe bradycardia is unusual but may be controlled by injecting atropine 1–2 mg intravenously.

Respiratory function should be monitored, particularly in patients with any known impairment.

Once the blood pressure has been reduced to an adequate level by a bolus injection or infusion, treatment should be switched to maintenance therapy with labetalol tablets, with a start dose of 100 mg twice daily.

Labetalol for injection has been administered to patients with uncontrolled hypertension already receiving other hypotensive agents, including beta blockers, without adverse effects.

4.5 Interaction with other medicinal products and other forms of interaction

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 atrio-ventricular conduction time.
•  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 antiarrhythmic agents (e.g. disopyramide, quinidine) and amiodarone (Class II antiarrhythmics) may have potentiating effects on atrial conduction time 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 hypoglycaemia (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 intubation. 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 (imipramine), barbiturates, phenothiazines or other antihypertensive agents may increase the blood pressure lowering effect of labetalol. Concomitant use of tricyclic antidepressants 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. Labetalol fluoresces in alkaline solutions with an excitation wavelength of 334 nm and a fluorescence wavelength of 412 nm, and can therefore interact with the analysis of certain fluorescent substances including catecholamines.
• The presence of labetalol metabolites in the urine may indicate falsely elevated levels of urinary catecholamines, metadrenaline, normetadrenaline and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. When patients with suspected pheochromocytoma who are treated with labetalol hydrochloride are screened, a specific method such as high-performance liquid chromatography with solid phase extraction should be used to determine catecholamine levels.

Fertility
There is no information on the effect of labetalol on fertility.

Pregnancy
Based on experience of pregnancy in humans, labetalol is not expected to increase the risk of birth defects. Animal studies do not indicate teratogenicity. However, toxic effects on foetal development have been noted (see section 5.3). Depending on the pharmacological mechanism of action of alpha and beta-adrenoceptor blockade, and when these are used in late pregnancy, undesirable effects to the foetus and the neonate should be taken into consideration (bradycardia, hypotension, respiratory depression, hypoglycaemia), as labetalol crosses the placenta. Beta blockers can reduce the blood flow in the uterus.
Labetalol should be only used during pregnancy when the benefits to the mother outweigh the risks for the foetus.

Breastfeeding

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).

Not relevant.

Summary of the safety profile
The most common adverse reactions observed with labetalol for injection and gathered from post-marketing reports include: heart failure, postural hypotension, hypersensitivity, drug fever, elevated liver function tests, nasal congestion and erectile dysfunction.

Tabulated list of adverse reactions

The following convention has been used to classify the frequency: 
Very common ≥1/10
Common ≥1/100 to <1/10 
Uncommon ≥1/1,000 to <1/100 
Rare ≥1/10,000 to <1/1,000
Very rare <1/10,000

The adverse reactions marked with # are usually transient and occur during the first few weeks of treatment.

Organ system		Adverse reactions
Immune system disorders	Common	Hypersensitivity, drug fever
Cardiac disorders	Common	Heart failure
	Rare	Bradycardia
	Very rare	Heart block
Vascular disorders	Common	#Postural hypotension
	Very rare	Aggravated symptoms of Raynaud syndrome
Respiratory, thoracic and mediastinal disorders	Common	#Nasal congestion
	Uncommon	Bronchospasm
Hepatobiliary disorders	Common	Elevated liver function tests
	Very rare	Hepatitis, hepatocellular jaundice, cholestatic jaundice, hepatic necrosis
Reproductive system and breast disorders	Common	Erectile dysfunction
	Not known	Nipple pain, Raynaud's phenomenon of the nipple

Description of selected adverse reactions:

Immune system disorders
Hypersensitivity reactions including rash, pruritus, dyspnoea and, very rarely, drug fever and angioedema have been reported.

Vascular disorders
Pronounced postural hypotension can occur if patients are permitted to assume an upright position within 3 hours after receiving a labetalol injection.

Hepatobiliary disorders
Signs and symptoms of hepatic and biliary passage disturbances are usually reversible on discontinuation of the medicinal product.

To reports any side effect(s):

• Saudi Arabia:

The National Pharmacovigilance Centre (NPC): -       SFDA Call Center: 19999 -       E-mail: npc.drug@sfda.gov.sa -       Website: https://ade.sfda.gov.sa/

-    Other GCC States:

-         Please contact the relevant competent authority.

 

Symptoms and signs:
Significant cardiovascular effects can be expected, e.g. excessive postural hypotension and occasional bradycardia. Renal failure with oliguria has been reported following massive overdose of oral labetalol. In one case, the use of dopamine to increase blood pressure may have aggravated the renal failure.

Treatment:
The patient should be recumbent, with the legs in an elevated position.
Parenteral adrenergic/anticholinergic treatment should be administered as required, to improve circulation.
Haemodialysis removes less than 1 % of labetalol hydrochloride from the blood circulation. Continued management is to proceed according to the clinical indications or as recommended by the Poisons Information Centre, if available.

Pharmacotherapeutic group: Alpha and beta blocking agents, ATC code: C07AG01

Mechanism of action
Labetalol lowers the blood pressure by blocking alpha adrenoceptors on peripheral arterioles, thus reducing the peripheral resistance; the concurrent beta blockade protects the heart from the reflex sympathetic drive that would otherwise occur.

Pharmacodynamic effects
Cardiac output is not significantly reduced at rest or after moderate exertion. The increase in systolic blood pressure during exertion is reduced, but the corresponding changes in the diastolic pressure are essentially normal. All these effects would be expected to benefit hypertensive patients.

Pharmacokinetics
Chemically, labetalol consists of four stereoisomers with different pharmacodynamic effects.

Distribution
Labetalol is around 50 % protein bound in the blood. In animal studies, only negligible amounts of labetalol have passed the blood-brain barrier. Labetalol passes the placental barrier and is excreted in human milk.

Biotransformation
Labetalol is metabolised primarily 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 is excreted unmodified in the urine and bile. The half life of labetalol in plasma is approximately 4 hours.

Specific patient populations

• Hepatic failure

Labetalol undergoes significant but varying first pass metabolism when administered orally. In a study of 10 patients with histologically confirmed cirrhosis, the exposure for oral labetalol increased approximately threefold compared with the healthy control group.

Individual variations in both patients and the control group were large (approximately 2.5 times). Patients with hepatic failure may require lower oral doses of labetalol (see section 4.2 Posology and method of administration and section 4.4 Special warnings and precautions for use).

•  Carcinogenic, mutagenic and teratogenic effects

No signs of mutagenic potential were seen in in vitro and in vivo examinations.

Labetalol showed no signs of carcinogenicity in long-term studies of mice and rats.

No teratogenicity was observed in rats and rabbits at oral doses of 6 and 4 times the maximum recommended human dose. Increased foetal resorptions were seen in both species at doses approaching the maximum recommended human dose. A teratology study performed with labetalol in rabbits with intravenous doses up to 1.7 times the maximum recommended human dose gave no evidence of drug-related foetal injury.

Dilute Hydrochloric acid or sodium hydroxide for adjustment to pH 4.

Water for injections.

Labetalol must not be mixed with sodium bicarbonate solution for injection.

2 years. The prepared solution for infusion has a shelf life of 24 hours.

Store below 25 C.

Pack of 5x20 ml (glass ampoule).

No special requirements.