Labetalol Tablets Bp 100 Mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Labetalol 100 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 100 mg labetalol hydrochloride.
Excipient with known effect: Each tablet contains 32 mg of lactose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Orange biconvex, coded LTL 100 and break line one side, twin triangle logo on reverse.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Labetalol Tablets are indicated for the treatment of:
• Mild, moderate and severe hypertension
• Hypertension in pregnancy
• Angina pectoris with existing hypertension
4.2 Posology and method of administration
Posology
Adults
Hypertension:
Initially 100 mg twice a day, which may be enough to control some patients, e.g. those already being treated with other antihypertensive drugs and those of low bodyweight.
Where hypertension is not controlled by the starting dose, increases of 100 mg twice a day may be made at intervals of about 14 days.
Many patients are controlled on 200 mg twice a day; 400 mg twice a day may be given, thereafter the total daily dose should be given as three or four divided doses. Daily doses of up to 2,400 mg have been given for severe, refractory hypertension.
Angina with co-existing hypertension:
The doses needed are those required to control the hypertension.
Hypertension in pregnancy:
Initially, 100 mg twice a day, which may be increased at weekly intervals by 100 mg twice a day to a maximum of 2,400 mg daily in the second or third trimesters if the severity of the hypertension dictates. Higher doses should be divided into a three times daily dosage regimen, the usual range being 100 mg - 400 mg three times a day.
General
Where rapid reduction of blood pressure is a necessity, labetalol injection should be used. Following the use of labetalol injection, and where long term control is required, initial therapy with oral labetalol should start with 100 mg twice a day.
Those patients admitted to hospital may have their dosage increased at daily intervals if needed.
Labetalol may be administered with other antihypertensive agents, e.g. methyldopa and diuretics, where the effects will be additive. When transferring a patient from one form of antihypertensive therapy to labetalol, introduce labetalol at 100 mg twice a day and then withdraw the previous therapy gradually.
Elderly
Initially, 50 mg twice a day, which may be sufficient for some.
Patients with hepatic impairment
In hepatic disease, oral dose reduction may be advised.
Paediatric population
The safety and efficacy of labetalol has not been established. Method of administration
Labetalol tablets should be taken orally with food.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Any condition associated with severe or prolonged hypotension
• Cardiogenic shock.
• Bradycardia of less than 45-50 beats per minute.
• Second or third degree heart block.
• Uncontrolled, incipient or digitalis-refractory heart failure.
• History of wheezing, bronchospasm or bronchial asthma.
• Prinzmetal’s angina.
• Severe peripheral circulatory disturbances.
• Sick sinus syndrome (including sino-atrial block).
• Untreated phaeochromocytoma.
• Metabolic acidosis.
4.4 Special warnings and precautions for use
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 discontinuance of the drug should be considered if any reaction is not otherwise explicable.
There have been rare reports of severe hepatocellular injury with labetalol therapy, which has occurred after both short-term and long-term therapy and is usually reversible. Appropriate laboratory testing should be performed at the first sign or symptom of liver dysfunction. If there is laboratory evidence of liver injury or jaundice, labetalol should be stopped and not restarted.
Due to negative inotropic effects, special care should be taken with patients whose cardiac reserve is poor and heart failure should be controlled with a cardiac glycoside and diuretic therapy before treatment is initiated.
Patients, particularly those with ischaemic heart disease, should not interrupt/discontinue abruptly labetalol therapy. The dosage should be gradually 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.
It is not necessary to discontinue labetalol tablets in patients requiring anaesthesia but anaesthetist must be informed and 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. If beta-blockade is interrupted in preparation for surgery, therapy should be discontinued for at least 24 hours pre-op. Anaesthetic agents causing myocardial depression (eg. cyclopropane, trichloroethylene) should be avoided. Labetalol may enhance the hypotensive effects of halothane
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.
Beta blockers may induce bradycardia. If the pulse rate decrease to less than 50-55 beats per minute at rest and the patients experience symptoms related to bradycardia, the dosage should be reduced.
Beta-blockers, even those with apparent cardioselectivity, should not be used to treat asthmatic patients or individuals prone to bronchospasm or a history of obstructive airways disease unless there are no alternatives. 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 may be controlled by an inhaled selectively-acting bronchodilator such as salbutamol; the required dose may be greater than the normal anti-asthmatic dose. If further treatment is required, intravenous atropine 1 mg should be given.
Due to a negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart 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.
Patients with a history of psoriasis should take beta-blockers only after careful consideration.
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 reaction.
(see section 4.5).
Labetalol interferes with laboratory tests for catecholamines.
Beta-blockers may mask the signs of thyrotoxicosis.
The label will carry the following warning: ‘Important warning: Do not take this medicine if you have a history of wheezing or asthma as it can make your breathing worse’.
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use not recommended
Calcium channel blockers such as verapamil and to a lesser extent diltiazem have a negative influence on contractility and atrio-ventricular conduction. Concurrent use should be avoided.
Digitalis glycosides used in association with B-blockers may increase atrio-ventricular conduction time and precipitate bradycardia.
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 may have potentiating effects on atrial conduction time and induce negative inotropic effect.
Anaesthetic drugs
Certain anaesthetic drugs may cause attenuation of reflex tachycardia and increase the risk of hypotension. Continuation of beta-blockers reduce 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. The hypotensive effect of halothane may be enhanced by labetalol hydrochloride.
Insulin and oral antidiabetic drugs
B-blockers (especially non-selective) may enhance the hypoglycaemic effects of oral antidiabetic agents and insulin and mask the warning signs of hypoglycaemia such as tremor and tachycardia.
Cimetidine, hydralazine and alcohol
Cimetidine, hydralazine and alcohol may increase the plasma concentration of labetalol.
Other drugs/drug classes
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 effects of beta-blockers.
Sympathomimetic agents may counteract the effect of beta-adrenergic blocking agents. Parenteral administration of preparations containing adrenaline to patients who are taking B-blockers may, rarely, result in vasoconstriction, hypertension and bradycardia.
Other antihypertensive agents will have an additive antihypertensive action when used concomitantly with labetalol.
Concomitant use of tricyclic antidepressants, barbiturates, phenothiazines or other antihypertensive agents may increase the incidence of tremor and blood pressure lowering effect of Labetalol.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy
Although there are no reported teratogenic effects in animals, labetalol should only be given in the first trimester if the expected benefits to the mother outweigh the risks to the foetus.
Labetalol crosses the placental barrier; the consequences of re- and B- adrenoceptor blockade in the foetus and neonate should be borne in mind.
Perinatal and neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycaemia, hypothermia) has been rarely reported. Sometimes these symptoms developed a day or two after birth. Response to supportive measures (e.g. intravenous fluids and glucose) 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 but other drugs (e.g. vasodilators, respiratory depressants) and the effects of pre-eclampsia, 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 not recommended.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
Most side-effects are transient and resolve within the first few weeks of therapy.
They include:
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 during pregnancy.
Eye disorders
Blurred/impaired vision, dry eyes, eye irritation
Cardiac disorders
Bradycardia, heart block, heart failure, hypotension.
Vascular disorders
Ankle oedema, increase of an existing intermittent claudication, postural hypertension generally occurs where initial dosing has been too high, increases in doses have been too rapid, or the doses being used are very high. It is otherwise uncommon, cold or cyanotic extremities, Raynaud’s phenomenon, paraesthesia of the extremities
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 and vomiting, diarrhoea.
Hepato-biliary disorders
Raised liver function tests, jaundice (both hepatocellular and cholestatic), hepatitis, hepatic necrosis. Signs and symptoms of hepatic damage usually reversible on withdrawal of labetalol
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, systematic lupus erythematosus, exacerbation of psoriasis.
Musculoskeletal, connective tissue and bone disorders Cramps, toxic myopathy.
Renal and urinary disorders
Acute urinary retention, difficulty in micturition.
Reproductive system and breast disorders Ejaculatory failure
General disorders and administration site conditions
Hypersensitivity (rash, pruritis, angioedema, dyspnoea), drug fever, masking of the symptoms of thyrotoxicosis or hypoglycaemia, reversible alopecia.
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 via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Overdosage with labetalol hydrochloride causes excessive hypotension, which is posture sensitive and sometimes, excessive bradycardia, bronchopasm and acute cardiac insufficency. After ingestion of an overdose or in case of hypersensitivity, the patient should be kept under close supervision and be treated in an intensive-care ward.
Absorption of any drug material still present in the gastro-intestinal tract can be prevented by gastric lavage, administration of activated charcoal and a laxative. Artificial respiration may be required.
Patients should be laid supine and their legs raised if necessary to improve blood supply to the brain. Atropine 3 mg or methylatropine should be given intravenously to relieve bradycardia or extensive vagal reactions. Massive overdosage with labetalol hydrochloride in man has not been reported but profound cardiovascular effects are to be expected. Atropine, at least 3 mg intravenously, should always be given. Gastric lavage or induced emesis is warranted for a few hours after oral ingestion of the drug. 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 required by an i.v. infusion of glucagon at an administration rate of 1-3 mg/hour. Administration of calcium ions, or the use of a cardiac pacemaker may also be considered.
Oliguric renal failure has been reported after massive overdosage of 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.
Haemodialysis removes less than 1% labetalol hydrochloride from the circulation.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha and Beta blocking agents and other diuretics ATC code: C07CG
Mechanism of action and pharmacodynamic effects
Labetalol hydrochloride lowers the blood pressure primarily by blocking alpha-adrenoceptors in peripheral arterioles and thereby reducing the peripheral resistance. Concurrent beta-blockade protects the heart from the reflex sympathetic drive normally induced by peripheral vasodilatation. Cardiac output is not significantly reduced at rest or after moderate exercise. Increases in systolic pressure during exercise are, however, reduced after labetalol hydrochloride; corresponding changes in the diastolic pressure are essentially normal.
In patients with co-existing angina the reduced peripheral resistance leads to a decreased left ventricular afterload and, hence, reduced myocardial oxygen demand. All these effects would be expected to benefit hypertensive patients and those with co-existing angina.
5.2 Pharmacokinetic properties
Absorption
Labetalol hydrochloride is readily absorbed from the gastro-intestinal tract but is subject to first pass metabolism.
Distribution
Bioavailability varies widely between patients and may be increased in the presence of food. Peak levels occur at about 1-2 hours after an oral dose.
Elimination
It is metabolised predominantly in the liver, the metabolites being excreted in the urine together with only small amounts of unchanged labetalol; its major metabolite has not been found to have significant alpha-or beta-adrenoceptor blocking effects. Excretion also occurs in the faeces via the bile. The elimination half-life at steady state is reported to be 8 hours. Labetalol crosses the placenta and is excreted in breast milk. Only very small amounts appear to cross the blood-brain barrier in animals. It is about 50% protein bound. Labetalol is not removed by dialysis.
5.3 Preclinical safety data
Not applicable since Labetalol tablets have been used in clinical practice for many years and its effects in man are well known
6.1 List of excipients
Core tablet
Lactose
Starch
Povidone
Isopropanol
Sodium Starch Glycollate Magnesium Stearate
Coating
Hydroxy Propyl Methyl Cellulose Mastercote FA 1293 (E110)
Triacetin
Water
IMS
6.2 Incompatibilities
None known other than those stated in above.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Polypropylene container with a low density polyethylene lid incorporating a tear-off sealing band containing 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 250, 500
2
and 1000 tablets and PVdC coated PVC/Aluminium blister packs (60g/m PVdC on 250pm PVC/20pm Al) containing 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112 and 120 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
MARKETING AUTHORISATION HOLDER
7
Tillomed Laboratories Ltd.
3 Howard Road
Eaton Socon
St Neots
Cambridgeshire
PE198ET
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
PL 11311/0375
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 01/02/1990 Date of latest renewal: 29/07/2009
10 DATE OF REVISION OF THE TEXT
05/07/2016