• Mild, moderate or severe hypertension
• Pregnancy-related hypertension
• Angina pectoris with concomitant hypertension

Dosage
Population
Adults:

Indication	Dosage
Mild, moderate or severe hypertension	Treatment should start with 100 mg twice a day. If necessary the dose can be increased by 100 mg twice a day and with a range of 2 to 14 days. Many patients' blood pressure is checked with 200 mg twice a day, and up to 800 mg per day can be divided into twotimes a day. In severe refractory hypertension, daily doses up to 2400 mg have been given (divided into three or four doses). Patients hospitalized with severe hypertension may increase the dose daily. Additional antihypertensive effects can be expected if labetalol tablets are given in conjunction with other blood-pressure medicines, such as diuretics, methyl dopa etc. If treatment is stopped for any reason, the dose should be decreased gradually. For long-term control of hypertension after use of labetalol injection, oral treatment with labetalol tablets should start with 100 mg twice a day.
Pregnancy-related hypertension	The initial doses of 100 mg twice a day may be increased if necessary at weekly intervals, with 100 mg twice a day. Severity of hypertension may require three times a day. A total daily dose of 2400 mg should not be exceeded.
Angina Pectoris with concomitant hypertension	The dose labetalol is required to control the hypertension.

Paediatric population:
Safety and effect of labetalol for children aged 0 to 18 years of age have not been established. No clinical data available.

Elderly:
For initiation of antihypertensive treatment, the usual starting dose is 100 mg orally twice daily.

Adequate blood pressure control can be achieved with lower maintenance doses than required in younger patients.

Hepatic Impaired Patients:
For patients with impaired liver function may lower doses of the oral preparation be required (please, see section 4 Warnings and Precautions).

Method of Administration
Labetalol tablets should be taken with food.

- Non-selective beta blockers should not be used in patients with asthma or history of obstructive airway disease. - Labetalol injection and tablets are contraindicated in second or third degree heart block (unless the pacemaker is in situ), cardiogenic shock and other conditions associatedwith severe and prolonged hypotension or severe bradycardia - Uncompensated heart failure Unstable/uncontrolled heart failure - Sick sinus syndrome (including sino-atrial block) unless the pacemaker is in situ Prinzmetal angina - Sinus node dysfunction - Labetalol injection and tablets are contraindicated for patients with known hypersensitivity to the active substance or to any substance listed in section6.1.

Liver disease
Caution should be observed in liver disease. There have hardly ever been reports of severe hepatic cellular damage in labetalol treatment. Liver damage is usually reversible and has occurred after both short and long term treatment. Hepatic necrosis, in some cases with fatal outcome, have been reported, however. Laboratory testing should be carried out at the first sign or symptoms of liver dysfunction. If the laboratory results show liver damage or if the patient has signs of jaundice, the treatment should be suspended and not resumed.
Special caution should be taken when labetalol is used in patients with impaired liver function because they metabolize labetalol slower than patients without impaired liver function. Lower doses may be required (please, see section 4.2 Dosage and method of administration and 5.2 Pharmacodynamic properties - Special Patient Populations).

Renal impairment
Caution should be observed when labetalol is used for patients with severely impaired renal function (GFR = 15-29 ml/min/1.73 m²).

Peripheral vascular disease
Labetalol should be used with caution in patients with peripheral vascular disease because their symptoms may worsen. Caution should be observed in patients with peripheral artery disease (Raynaud's syndrome, intermittent claudication) as labetalol can aggravate their symptoms. Alpha blockers can counteract the undesirable effect of beta blockers.

Symptomatic bradycardia
If the patient develops symptomatic bradycardia, the dose should be reduced.

First degree atrioventricular block
In view of the negative impact of beta-adrenoceptor blocking drugs on the atrioventricular conduction time, labetalol should be given with caution to patients with first-degree atrioventricular block.

Diabetes mellitus
Caution should be taken in the uncontrolled or hard to control diabetes mellitus. As well as any beta- adrenoceptor blocking drugs, labetalol can hide the symptoms of hypoglycaemia (tachycardia and tremor) in diabetic patients. The hypoglycaemic effect of insulin and oral hypoglycaemic agents may be enhanced by beta blockers.

Thyrotoxicosis
Beta blockers may mask the symptoms of thyrotoxicosis but the thyroid function does not change.

Hypersensitivity to beta blockers
Risk of anaphylactic reaction: When patients with a history of severe anaphylactic reaction to various allergens use beta blockers, they can be more reactive to repeated provocation, whether it happens unintentionally, with diagnostic or therapeutic purposes. These patients may not respond to the usual doses of epinephrine used to treat an allergic reaction.

Adrenaline
If patients receiving labetalol need adrenaline treatment, a reduced adrenaline dose is used as co- administration with labetalol and adrenaline may cause bradycardia and hypertension (please, see section 4.5. Interactions with other drugs and other forms of interactions).

In case of significantly higher levels of adrenaline in the blood, such as pheochromocytoma, labetalol may cause a paradoxical increase of blood pressure.

Rash and/ or dry eyes
Skin rash and/or dry eye, associated with the use of beta-adrenoceptor blocking drugs, have been reported. The reported incidence is small and in most cases, the symptoms subsided when treatment was discontinued. Gradual discontinuation of the drug should be considered if such a response cannot be explained otherwise.

Intraoperative Floppy Iris Syndrome
The emergence of intraoperative floppy iris syndrome (IFIS, a variant of small pupil syndrome) has been observed in connection with cataract surgery in some patients treated with, or previously treated with tamsulosin. Occasional reports have also been received concerning other alpha-1 blockers and risk of drug class effect cannot be ruled out. Because the IFIS may lead to increased incidence of complications during cataract surgery, the eye surgeon should be pre-operatively informed of current or past use of alpha-1 blockers.

Heart failure or ventricular function dysfunction
Special caution should be observed in patients with heart failure or systolic left ventricular dysfunction. Labetalol is contraindicated in uncontrolled heart failure but can be used with caution in patients who are well controlled and symptom free. Heart failure should be controlled with adequate treatment before labetalol is used.

The use of beta blockers points to the risk of emergence of or worsening of heart failure or obstructive lung disease. In heart failure, the myocardial contraction ability should be maintained and the downturn compensated. Patients with reduced contraction ability, especially the elderly, should be monitored on a regular basis with regard to the emerging heart failure.

It is recommended that treatment with Trandate is not abruptly interrupted, especially in patients with congestive heart failure and in patients with angina pectoris (risk of aggravation of angina, myocardial infarction and ventricular fibrillation).

Inhaled anaesthetics
Caution should be taken in the event of simultaneous treatment with inhaled anaesthetics (please, see section 4.5. Interactions with other drugs and other interactions). Treatment with labetalol need not be interrupted before anaesthesia but the patient should intravenously be given atropine before the anaesthesia treatment begins. Labetalol may enhance the hypotensive effects of volatile anaesthetics.

Metabolic acidosis and pheochromocytoma
Caution should be taken in the event of metabolic acidosis and pheochromocytoma. In patients with pheochromocytoma, labetolol should only be given after adequate haemostasis is achieved.

Calcium channel blockers
Caution should be observed if labetalol is used at the same time as calcium channel blockers, particularly calcium flow inhibitors, which negatively affect the contraction ability and the AV conduction.

Caution should be taken in the event of simultaneous administration of adrenaline, verapamil or class I antiarrhythmic drugs (please, see section 4.5. Interactions with other drugs and other interactions).

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

Ischaemic heart disease
Patients, and especially those with ischaemic heart disease, should not abruptly suspend or cancel the labetalol treatment. For patients with ischaemic heart disease, the treatment should, if possible, be gradually finished during 7 to 10 days.

Help topic alerts: lactose and sunset yellow
Patients with rare hereditary problems of galactose intolerance, total lactose deficiency or glucose, galactose malabsorption should not take this medicine.

The medicine contains sunset yellow colouring substance, which may cause hypersensitivity reactions.

The hypotensive effect of labetalol may be reduced when used in combination with prostaglandin synthetase inhibitors (NSAIDS). Dose adjustments may therefore need to be done. More interactions may occur with other antihypertensives.

Labetalol fluoresces in alkaline solutions with an excitation wavelength of 334 nanometres and a fluorescence wavelength of 412 nm and can therefore interact with analysis of some fluorescent substances, including Catecholamines.

The presence of labetalol metabolites in the urine may indicate false elevated levels or urine catecholamines, metanephrine, normetanephrine and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. When patients with suspected pheochromocytoma and treated with labetalol hydrochloride are screened, a specific method, such as high-performance liquid chromatography with solid phase extraction, should be used for the determination of catecholamine levels.

Labetalol has been shown to reduce the absorption of radio-isotopes of meta iodo benzyl guanidine (MIBG). Accuracy should therefore be taken when interpreting the results of MIBG scintigraphy.

Co-administration of labetalol and adrenaline may cause bradycardia and hypertension (please, see section 4.4 Warnings and precautions).

Caution to be observed in case labetalol is used at the same time as either class I antiarrhythmic drugs or calcium channel blockers of the type verapamil.

Elevated risk of myocardial depression in combination with class I antiarrhythmic drugs (such as disopyramid and quinidine) and amiodarone (class II antiarrhythmic drugs).

Risk of severe bradycardia and hypotension in combination with calcium channel blockers with negative inotrope effect (e.g., verapamil, diltiazem). Especially for patients with impaired ventricular function and/or disruption of the conduction. When passing from a calcium channel to a beta blocker or vice versa, a new intravenous therapy should not be inserted until at least 48 hours after the last treatment was discontinued.

Simultaneous treatment with calcium channel blockers that are dihydro pyridine derivatives (e.g. nifedipine) may increase the risk of hypotension and may lead to heart failure in patients with heart failure. Digitalis glycosides in combination with beta blockers may extend the atrioventricular conduction time. Labetalol may strengthen digoxinets effect in terms of reducing the ventricular rate.

Beta blockers, particularly non-selective beta blocker, may increase the risk of hypoglycaemia in diabetes patients and hide the symptoms of hypoglycaemia, such as tachycardia and tremor, and slow down the normalization of blood sugar after insulin induced hypoglycaemia. Dose adjustments of oral anti-diabetic drugs and insulin may need to be done.

Caution should be observed in conjunction with general anaesthesia with patients using beta blockers. Beta blockers reduce the risk for arrhythmias during anaesthesia but may result in reduction of reflectance tachycardia and increase the risk of hypotension during anaesthesia. A vehicle with as low a negative inotrop effect as possible should be used for anaesthesia. Heart function must be carefully monitored and bradycardia due to vagal dominance be corrected with intravenous administration of atropine, 1-2 mg intravenously (release prior to surgery, please,see section 4.2 Posology and method of administration).

When it comes to the release of beta blockers and clonidine in patients using both vehicles, a gradual release of beta blocker must be made several days before clonidine is discontinued. The reason is to reduce the potentially recurrent hypertensive crisis resulting from that clonidine is discontinued.
When changing from clonidine to a beta blocker, therefore, it is important to gradually discontinue clonidine and begin treatment with a beta blocker several days after that, clonidine has been discontinued.

Simultaneous treatment with cholinesterase inhibitors may increase the risk of bradycardia.

Simultaneous treatment with alpha adrenergic stimulants may increase the risk of elevated blood pressure (e.g. phenylpropanolamine and adrenaline), whereas simultaneous treatment with beta- adrenergic stimulation results in a mutual reduced effect (antidote effect).

Simultaneous use of ergotamine may increase the risk of vaso spastisc reactions in some patients.

Labetalol has been shown to increase the bioavailability of imipramine with more than 50% depending on the inhibition of its 2-hydroxylation. Labetalol in combination with imipramine may increase the effect of imipramine. Simultaneous use of tricyclic antidepressants may increase the incidence of tremor.

Cimetidine may enhance the bioavailability of labetalol and caution is needed at oral doses of the latter substance. Improved blood pressure drop may be present at the simultaneous use of e.g. nitrates, antipsychotics (phenothiazines, such as chloropromazine) and other antipsychotics and antidepressants.

Fertility
There is no information on labetalols effect on fertility.

Pregnancy
Based on the experience of pregnancy in humans, labetalol does not increase the risk of birth defects. Animal studies do not indicate teratogenicity. Development of fetal toxic effects have, however, been noted (please, see section 5.3). Depending on the pharmacological mechanism of action of alpha-and beta-adrenoceptor blockers and when used in the latter part of pregnancy, side effects to the fetus and the newborn child are taken into account (bradycardia, hypotension, respiratory depression, hypoglycaemia), as labetalol passes over the placenta. Beta blockers can reduce blood flow in the uterus.

Labetalol should only be used during pregnancy if the benefits to the mother outweigh the risks to the fetus.

Breastfeeding:
Labetalol is secreted in the breast milk in small amounts (about 0,004– 0,7% of the maternal dose). No side effects have so far been reported. Caution should be observed when labetalol is given to breastfeeding women.

The use of labetalol has probably no effect on the patient's ability to drive vehicles or operate machinery. It should be remembered that occasionally dizziness or fatigue may occur.

Summary of the safety profile
The most common side effects observed with labetalol tablets and gathered from the reports after the authorisation include: heart failure, postural hypotension, hypersensitivity, lichenoid rash, drug fever, increased liver function tests, urinary disorders, dizziness, headaches, tingling sensations in the scalp, blurred vision, nasal congestion, nausea, erectile dysfunction and ejaculation failure.

Tabulated list of side effects

The following convention has been used to classify the frequency:
Very common ≥1/10
Common ≥1/100, <1/10
Less common ≥1/1 000, <1/100 Rare ≥1/10 000, <1/1000
Very rare <1/10000

Side effects that are marked with a # are usually transient and occur during the first few weeks of treatment.

Organ system		Adverse effects
Immune system	Very common	Positive antinuclear antibodies not associated with disease
	Common	Hypersensitivity, lichenoid rash, drug fever
Mental disorders	Less common	#Depression
Central and peripheral nervous system	Common	#Dizziness, #headache, #tingling sensation of the scalp
	Very rare	Tremor in the treatment of pregnancy-related hypertension
Eyes	Common	Blurred vision
	Very rare	Eye irritation
Heart	Common	Heart failure
	Rare	Bradycardia
	Very rare	Heart block
Blood vessel	Common	#Postural hypotension
	Very rare	Worsening symptoms of Raynaud's syndrome
Respiratory, thoracic and mediastinal disorders	Common	#Nasal congestion
	Less common	Bronchospasm
Gastrointestinal disorders	Common	Nausea
	Less common	Vomiting, epigastric pain
Hepatobiliary disorders	Common	Elevated liver function tests
	Very rare	Hepatitis, hepatocellular jaundice, cholestatic jaundice, hepatic necrosis
Skin and subcutaneous tissue	Less common	#Sweating
Musculoskeletal system and connective tissue	Less common	Convulsions
	Very rare	Toxic myopathy, systemic lupus erythematosus
Renal and urinary disorders	Common	Urinary disorders
	Very rare	Acute urinary retention
Reproductive system and breast disorders	Common	Erectile dysfunction, ejaculation failure
General symptoms and/or symptoms at the site of administration	Common	#Fatigue, #lethargy
	Very rare	#Foot oedema

Description of some side effects:

Immune system
Hypersensitivity reactions reported include rash (including reversible lichenoid rash), pruritus, dyspnoea, and, very rare drug fever and angio-oedema.

Blood vessel
Postural hypotension is more common in very high doses or if the starting dose is too high or the doses are too quickly increased.

Liver and biliary tract
Signs and symptoms of disorders of the liver and bile ducts are usually reversible upon release of the drug.

To report any side effect(s):
- In Saudi Arabia:

- The National Pharmacovigilance and Drug Safety Centre (NPC): - Fax: 00966112057662 - Call NPC at 00966112038222, Exts: 2317-2356-2353-2354-2334-2340. - Toll free phone: 8002490000 - E-mail: npc.drug@sfda.gov.sa - Website: www.sfda.gov.sa/npc

- Other GCC States:

- Please contact the relevant competent authority.

 

Symptoms and signs
Significant cardiovascular effects can be expected, for example, comprehensive, postural hypotension and bradycardia at some point. Kidney failure with oliguria has been reported after massive oral overdose of labetalol. In one case, the use of dopamine in order to raise the blood pressure, has aggravated the kidney failure.

Treatment:
Patients should be placed supine with legs high up.

Parenteral adrenergic/anticholinergic therapy should be given as needed to improve circulation.

Haemodialysis removes less than 1% labetalol hydrochloride from the bloodstream.

Continued operation should be carried out as clinically indicated or in accordance with the recommendation of the poison control centre, if available.

Pharmacotherapeutic group: Alpha-and beta-receptor blocking resources, ATC-code: C07AG01

MOA
Labetalol reduces blood pressure by blocking peripheral arteriolar alpha-adrenoceptors, thus reducing the peripheral resistance, and with simultaneous beta blockers, it protects the heart from reflex sympathetic work that would otherwise arise.

Pharmacodynamic effects
The cardiac volume is not significantly reduced at rest or after moderate exertion. Increase of systolic blood pressure in exertion will be smaller but the corresponding changes of diastolic pressure is basically normal. All of these effects can be expected to be beneficial for hypertensive patients.

In patients with angina pectoris and with hypertension, the reduced peripheral resistance reduces the heart load and oxygen demand. All these effects can be expected to be to the benefit of the hypertensive patients and those with simultaneous angina.

Pharmacodynamics

Absorption
Labetalol chemically consists of four stereoisomers with different pharmacodynamic effects. Labetalol is rapidly absorbed from the gastrointestinal tract and the highest plasma levels occur 1 to 2 hours after oral administration. There is a significant first passageway metabolism that produces a bioavailability of about 25% but with considerable variations. The bioavailability of labetalol increases in older people.

Distribution
About 50% is protein-bound labetalol. Only negligible amounts of labetalol have crossed the blood- brain barrier in animal studies. Labetalol passes the placenta barrier and is excreted in breast milk.

Metabolism
Labetalol is metabolised mainly by conjugation to inactive glucuronide metabolites.

Elimination:
Glucuronide metabolites secreted both in urine and via the bile to the faeces. Less than 5% of the labetalol dose secreted unchanged in urine and bile. Half-life of labetalol in plasma is about 4 hours.

Special patient populations

Liver failure
Labetalol undergoes significant but varying first passageway metabolism when orally taken. In a study of 10 patients with histologically proven cirrhosis, exposure was increased to oral labetalol about three times compared to the healthy control group. Individual variations in both patients and control group were large (approximately 2.5 times). Patients with liver failure might need to be given lower oral doses of labetalol (please, see section 4.2 Posology and method of administration and section 4.4. Warnings and precautions).

Carcinogenic, mutagenic, and teratogenic effects
There was no evidence of mutagenic potential in studies in vitro and in vivo.
Labetalol showed no evidence of carcinogenicity in long-term studies in mice and rats.
No teratogenicity was observed in rats and rabbits at oral doses of 6 and 4 times the maximum recommended dose for humans. Increased fetal resorptions could be seen in both species at doses approaching the maximum dose recommended for human use. A teratology study, performed with labetalol, on rabbit with intravenous doses up to 1.7 times the maximum recommended dose for human use, gave no evidence of drug-related harm to the fetus.

Tablet core:
Anhydrous lactose 
Magnesium stearate
Microcrystalline cellulose

Tablet coating:
Opaspray orange M-1-3499D (dye, contains: sodium benzoate (E211), hypromellose, titanium dioxide (E171), sunset yellow (E110)) Hypromellose

Not relevant.

2 years

Must be kept at a temperature not exceeding 25°C.

100 mg: plastic jar 100 pcs
200 mg: plastic jar 100 pcs

No special requirements.