Consumer medicine information

Trandate

Labetalol hydrochloride

BRAND INFORMATION

Brand name

Trandate Tablets

Active ingredient

Labetalol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Trandate.

What is in this leaflet

This leaflet answers some common questions about TRANDATE tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TRANDATE against the benefits he or she expects it will have.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What TRANDATE is used for

The name of your medicine is TRANDATE. The active ingredient is called labetalol hydrochloride.

Labetalol hydrochloride belongs to a group of medicines called the beta-blockers. The beta-blockers are used for the treatment of high blood pressure (hypertension).

TRANDATE is used for the treatment of all degrees of hypertension. Hypertension is a condition marked by high blood pressure.

TRANDATE is used to lower high blood pressure. It works by changing the body’s response to some nerve impulses. Therefore, it widens the blood vessels in the body, causing the blood pressure to fall.

Your doctor may have prescribed this medicine for another condition.

Ask your doctor if you have any questions about why TRANDATE has been prescribed for you.

TRANDATE tablets are only available with a doctor’s prescription.

Before you take it

When you must not take it

Do not take TRANDATE if you are allergic to:

  • labetalol hydrochloride or any other agents used to treat hypertension
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction to TRANDATE may include red, itchy skin rashes, difficulty in breathing, swelling of the face, lips, mouth or throat, faintness or shortness of breath.

Do not use TRANDATE after the expiry date (EXP.) printed on the pack.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

You must tell your doctor if:

  • you are allergic to any other medicines or any foods, dyes or preservatives
  • you are pregnant or intend to become pregnant.
    TRANDATE is rated in Australia as a Category C drug for the use in pregnancy. TRANDATE should not be taken early in pregnancy.
    If it is necessary for you to take TRANDATE later in your pregnancy, your doctor will discuss the risks and benefits of taking it.
  • you are breast-feeding or intend to breast-feed.
    TRANDATE is able to pass into breast milk. There is a possibility that the breast-fed baby may be affected. Therefore, do not take it if you are breast-feeding or plan to breast-feed.

Tell your doctor if you have or have had any other medical conditions/ health problems, especially the following:

  • breathing problems such as asthma
  • any other heart problems
  • allergic disorders including hay fever
  • diabetes
  • kidney problems
  • liver problems such as jaundice
  • an overactive thyroid gland
  • any blood vessel disorders causing poor circulation in the arms and legs
  • phaechromocytoma, which is a rare tumour of the adrenal gland
  • certain types of angina such as Prinzmetal angina or variant angina
  • shock or severe low blood pressure

If you have not told your doctor about any of the above, tell them before you start to take any TRANDATE.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

SOME of these medicines may interfere with TRANDATE. These include:

  • medicines used to treat angina or an irregular heart beat
  • other medicines used to treat high blood pressure such as verapamil, clonidine and methyldopa
  • fluid tablets, also called diuretics
  • some medicines used during surgery and emergency situations such as anaesthetics
  • cimetidine, a medicine commonly used to treat stomach ulcers
  • some medicines used to treat depression
  • guanethidine, a medicine used to treat certain heart conditions
  • insulin or other medicines used to treat diabetes
  • some medicines used to treat fever, pain and inflammation such as paracetamol and aspirin (NSAIDs)

The above medicines either reduce the effectiveness of TRANDATE, reduce its own effectiveness and/or react with TRANDATE resulting in untoward or sometimes dangerous side effects.

This list is not exhaustive. Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking TRANDATE.

Tell your doctor or pharmacist that you are taking TRANDATE before you start to take any other medicine.

How to take it

Your doctor will tell you how much TRANDATE to take and when to take it.

Take it exactly as directed by your doctor.

How much to take

The dose of TRANDATE may vary from patient to patient. Your doctor will decide on the right dose for you.

Adults:
The usual starting dose is 100 to 200 mg twice daily. Your doctor may change this dose depending on how you respond to TRANDATE.

Elderly patients may need smaller doses.

Do not change your dose of TRANDATE unless your doctor tells you to do so.

This medicine is not recommended for use in children.

How to take it

Swallow TRANDATE tablets with a glass of water.

When to take it

It is best to take your TRANDATE tablets immediately after meals.

How long to take it

To properly control your blood pressure, TRANDATE must be taken every day.

Continue taking TRANDATE as long as your doctor recommends it.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take your dose as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect. If you are unsure about whether to take your next dose, speak to your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (Overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to casualty at your nearest hospital, if you think that you or anyone else may have taken too much TRANDATE. Do this even if there are no signs of discomfort or poisoning. Also, report any other medicine or alcohol which has been taken. You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you take too much TRANDATE you may have the following symptoms: nausea, vomiting, dizziness, light-headedness, faintness, and a very slow heart beat.

While you are using it

Things you must do

Immediately stop taking TRANDATE if a skin rash or any other allergic reaction occurs.

If you become pregnant while taking TRANDATE, tell your doctor immediately.

If you are being treated for diabetes, make sure you check your blood sugar level regularly.

TRANDATE may affect how well your diabetes is being controlled. It may also cover up some of the symptoms of low blood sugar such as fast heart beat.

This medicine may also make low blood sugar last longer. Your doctor may need to change your dose of diabetic medicines, including insulin.

If you have to have any medical tests, tell your doctor you are taking TRANDATE.

It may affect the results of some tests.

Tell your doctor if you do not feel TRANDATE is helping your condition.

Visit your doctor regularly.

Your doctor needs to check your progress and see whether you need to stop taking TRANDATE.

Always discuss with your doctor any problems or difficulties during or after taking TRANDATE.

Things you must not do

Do not take any other medicines while you are taking TRANDATE, without first talking to your doctor.

Do not stop taking TRANDATE without first checking with your doctor.

Your doctor may want you to gradually reduce the amount of TRANDATE you are taking before stopping completely. This may help reduce the possibility of heart complications occurring.

Do not give this medicine to anyone else, even if his or her symptoms seem similar to yours.

Things to be careful of

Do not drive or operate machinery until you know how TRANDATE affects you.

TRANDATE may cause dizziness, light-headedness or drowsiness in some people.

Try to get up slowly when you are getting up from a sitting or lying position, as you may feel dizzy, light-headed, or faint.

If you continue to feel unwell, please contact your doctor.

Make sure you drink a lot of water while you are taking TRANDATE.

If you do not drink enough water, you may begin to feel faint, light-headed, or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, please contact your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking TRANDATE.

This medicine helps most people with the medical condition listed in the beginning of this leaflet, but it may have unwanted side effects in some people.

All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • Dizziness
  • Light-headedness
  • Headache
  • Tiredness
  • Lack of energy
  • Depressed mood
  • Blurred vision
  • Dry, red or sore eyes
  • Muscle cramps
  • Unusual movements including tremor
  • Tingling of the skin, especially the scalp
  • Fever or chills
  • Nausea (feeling sick)
  • Upset stomach
  • Vomiting
  • Swelling of the ankles
  • Problems with sexual function
  • Blocked nose
  • Increased sweating

Tell your doctor or pharmacist immediately if you notice any of the following:

  • Feeling generally unwell, sometimes yellowing of the skin and/or eyes (jaundice)
  • Slow or irregular heart beat
  • Skin rashes which include redness, itching or hives
  • Difficulty passing urine or unable to pass urine

If any of the following occur, tell your doctor immediately or go to casualty at your nearest hospital:

  • Chest tightness, wheezing or shortness of breath
  • Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing

Some people may get other side effects while taking TRANDATE.

Check with your doctor as soon as possible if you have any problems while taking TRANDATE, even if you do not think the problems are connected with this medicine or are not listed in this leaflet.

After using it

Storage

Keep your tablets in the bottle they were provided in until it is time to take them.

Keep it where children cannot reach it.

A locked cupboard at least one and a half metres above the floor is a good place to store medicines.

Keep your medicine in a cool dry place where the temperature stays below 25°C and protect from light.

Do not store it, or any other medicines in a bathroom or near a sink.

Do not leave it in the car or on windowsills.

Heat and dampness can destroy some medicines.

Do not take TRANDATE if the tablets do not look quite right.

Disposal

If your doctor tells you to stop taking this medicine OR it has passed its expiry date, ask your pharmacist what to do with any left over.

Product description

What it looks like

TRANDATE tablets (oral) come in 2 strengths:

  • 100 mg, orange, film-coated, biconvex tablets embossed “TRANDATE 100” on one face, in bottles of 100.
  • 200 mg, orange, film-coated, biconvex tablets embossed “TRANDATE 200” on one face, in bottles of 100.

Ingredients

Active ingredient:

  • Labetalol hydrochloride

Other ingredients:

  • Lactose
  • Starch - maize
  • Starch - pregelatinised maize
  • Magnesium stearate
  • Methyl hydroxybenzoate
  • Propyl hydroxybenzoate
  • Pharmacoat 606
  • Opaspray M-1-3499D

TRANDATE is gluten and sucrose free, however contains lactose.

BRAND INFORMATION

Brand name

Trandate Tablets

Active ingredient

Labetalol hydrochloride

Schedule

S4

 

1 Name of Medicine

Labetalol hydrochloride.

6.7 Physicochemical Properties

Chemical formula: Labetalol hydrochloride is a dry powder. The chemical name is 2-hydroxy-5- [1-hydroxy-2- (1-methyl-3- phenylpropylamino)- ethyl] benzamide hydrochloride.
C19H25ClN2O3.

Chemical structure.


CAS number.

32780-64-6.

2 Qualitative and Quantitative Composition

Trandate 100 mg and 200 mg tablets contain labetalol, lactose, maize starch, pregelatinized maize starch, magnesium stearate, Pharmacoat 606, Opaspray M-1-3499D, methyl hydroxybenzoate and propyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Trandate tablets 100 mg are circular biconvex tablets with orange film coat, each containing labetalol hydrochloride 100 mg, marked TRANDATE 100 on one face.
Trandate tablets 200 mg are circular biconvex tablets with orange film coat, each containing labetalol hydrochloride 200 mg, marked TRANDATE 200 on one face.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Trandate antagonises α- and β-adrenoreceptors concurrently by competitive inhibition; it has no intrinsic sympathomimetic activity and less pronounced membrane stabilising activity than propranolol. The β-blockade is nonselective. Trandate has two centres of chirality which means that four isomers are possible, each of the isomers having different relative α- and β-blocking activities.

Mechanism of action.

Trandate lowers blood pressure by blocking α-adrenoreceptors in peripheral arterioles and thereby reducing peripheral resistance. Trandate also concurrently blocks β-adrenoreceptors, notably in the heart, from the reflexly mediated drive caused by the peripheral vasodilatation. Therefore, the reduction in blood pressure is achieved without cardiac stimulation.Trandate does not reduce cardiac output at rest or after moderate exercise. Normally occurring increases in systolic pressure during exercise are, however, lessened by Trandate; corresponding changes in the diastolic pressure are not affected.
The precise relationship between α- and β-blocking effects in contributing to the antihypertensive action is unknown. At therapeutic doses, Trandate is less active at α-adrenoreceptors than β-adrenoreceptors, and adequate vasodilatation is achieved with incomplete blockade of the α-adrenoreceptors in the arterioles. The barostatic reflexes remain sufficiently active to prevent postural and exercise hypotension in most patients, but this phenomenon has been observed at all doses and becomes more common with severe hypertensives on large doses of drug.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Taken orally, Trandate tablets are well absorbed. The drug is extensively metabolised by the liver, and possibly in the gut wall, to O-phenyl-glucuronide, N-glucuronide and a glucuronide formed by conjugation at the secondary alcohol group. Peak plasma levels occur at 1-2 hours, associated with a reduction in blood pressure. On average, 35-40% of an administered oral dose reaches the circulation.
The plasma half-life is approximately 6-8 hours, but a hypotensive effect has been observed up to 11 hours after a given dose.
The absolute bioavailability of labetalol is increased when administered with food.
At therapeutic concentrations, the active drug binds to albumin (52%). Binding also occurs to melanin (0.05%) but the clinical significance is uncertain.
Trandate and its inactive metabolites are excreted by both the liver and the kidneys, so the drug is unlikely to accumulate in the body.
Whilst impairment of renal function does not require a change in dosage, impairment of liver function requires a reduction in dosage, due to the decrease in first-pass metabolism of the drug.
Trandate does not adversely affect renal function and is a particularly suitable drug for use in hypertensive patients with renal disease.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of all grades of hypertension.

4.3 Contraindications

β-Blockers are usually contraindicated in a variety of conditions and as Trandate has not yet been fully investigated for its effect on these conditions, they should be treated as contraindications until further information is available.
1. Bronchospasm.
β-Adrenergic blockade of the smooth muscle of bronchi and bronchioles may result in an increased airways resistance. These drugs also reduce the effectiveness of asthma treatment. This may be dangerous in susceptible patients.
Therefore, β-blockers are contraindicated in any patient with a history of airways obstruction or a tendency to bronchospasm. Use of cardioselective β-blockers can also result in severe bronchospasm. If such therapy must be used, great caution should be exercised. Alternative therapy should be considered.
2. Allergic disorders (including allergic rhinitis) which may suggest a predisposition to bronchospasm.
3. Right ventricular failure secondary to pulmonary hypertension.
4. Significant right ventricular hypertrophy.
5. Sinus bradycardia (less than 45-50 beats/minute) or sick sinus syndrome.
6. Second and third degree A-V block.
7. Shock (including cardiogenic and hypovolaemic shock).
8. Congestive heart failure.
9. Anaesthesia with agents that produce myocardial depression (e.g. ether, chloroform, cyclopropane).
10. Lactation and early pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).
11. Known hypersensitivity to labetalol hydrochloride.

4.4 Special Warnings and Precautions for Use

1. Cardiac failure.

β-Blockade depresses myocardial contractility and may precipitate cardiac failure in some patients with a history of cardiac failure, chronic myocardial insufficiency or unsuspected cardiomyopathy. In patients with no history of cardiac failure, continuing depression of the myocardium may lead to cardiac failure. If cardiac failure develops, the β-blocker should be withdrawn (see Abrupt withdrawal).

Note.

Although congestive heart failure has been considered to be a contraindication to the use of β-blockers, there is a growing literature on the experimental use of β-adrenergic blocking drugs in heart failure. As further trials are needed to identify which patients are most likely to respond to which drugs, β-blockers should not normally be prescribed for heart failure outside of specialist centres.

2. Abrupt withdrawal.

Care should be taken if β-blockers have to be discontinued abruptly in patients with coronary artery disease. Severe exacerbation of angina and precipitation of myocardial infarction and ventricular arrhythmias has occurred following abrupt discontinuation of β-blockade in patients with ischaemic heart disease. Therefore, it is recommended that the dosage be reduced gradually over a period of about 8 to 14 days during which time the patient's progress should be assessed. The drug may be reinstituted temporarily if the angina worsens. If the drug must be withdrawn abruptly, close observation is required. In the perioperative period, β-blockers should not be withdrawn, unless indicated.

3. Concomitant therapy with calcium antagonist.

The concomitant use of β-blockers and calcium antagonists with myocardial depressant and sinus node activity, e.g. verapamil and to a lesser extent diltiazem, may cause hypotension, bradycardia and asystole. Extreme caution is required if these drugs have to be used together.
The dihydropyridine calcium antagonists (e.g. nifedipine) have a weaker myocardial depressant effect and can be administered cautiously with β-blockers. If excessive hypotension develops, the calcium antagonist should be stopped or the dosage reduced.

4. Antiarrhythmic drugs.

Care should be taken when prescribing β-blockers with antiarrhythmic drugs. Interactions have been reported during concomitant β-blocker therapy with the class IA agents disopyramide, and less frequently quinidine; class IB agents, tocainide, mexiletine and lidocaine; class IC agents, flecainide and propafenone (not available in Australia); the class III agent, amiodarone; and the class IV antiarrhythmic agents.

5. Beta-blockers.

β-Blockers, even those with apparent cardioselectivity, should not be used in patients with asthma or a history of obstructive disease unless no alternative treatment is available. In such cases, the risk of inducing bronchospasm should be appreciated and appropriate precautions taken. If bronchospasm should occur after the use of Trandate it can be treated with a β2-agonist by inhalation, e.g. salbutamol (the dose of which may need to be greater than the usual dose in asthma), and, if necessary, intravenous atropine 1 mg.
There have been reports of skin rashes and/or dry eyes associated with the use of β-adrenoreceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment was withdrawn. Gradual discontinuance of the drug should be considered if any such reaction is not otherwise explicable.

6. Peripheral circulation.

β-Blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral vascular disease.

7. Hepatic injury.

Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with labetalol therapy. The hepatic injury is usually reversible, but hepatic necrosis and death have been reported. Injury has occurred after both short- and long-term treatment and may be slowly progressive despite minimal symptomatology.
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 should be stopped and not restarted.

8. Prinzmetal angina.

There is a risk of exacerbating coronary artery spasm if patients with Prinzmetal or variant angina are treated with a β-blocker. If this treatment is essential, it should only be undertaken in a coronary or intensive care unit.

9. Euthyroid hyperthyroxinaemia.

The effects of β-blockers on thyroid hormone metabolism may result in elevations of serum free thyroxine (T4) levels. In the absence of any signs or symptoms of hyperthyroidism, additional investigation is necessary before a diagnosis of thyrotoxicosis can be made.

10. Anaesthesia and the perioperative period.

β-Blockade may have beneficial effects in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the postoperative period. It is currently recommended that maintenance β-blockade be continued perioperatively. The anaesthetist must be made aware of β-blockade because of the potential for interactions with other drugs, resulting in severe bradyarrhythmias and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and the increased propensity for vagal induced bradycardia. Incidents of protracted severe hypotension or difficulty restoring normal cardiac rhythm during anaesthesia have been reported. Modern inhalational anaesthetic agents are generally well tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were sometimes associated with severe circulatory depression in the presence of β-blockade.
Trandate tablets need not be discontinued prior to anaesthesia but patients should receive intravenous atropine prior to induction.
Synergistic effects of labetalol and halothane on cardiac output and blood pressure have been reported.

11. Diabetes.

β-Blockers affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia.
In patients with insulin or noninsulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia, β-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need adjustment.
In one study, there was an increase in mean fasting glucose levels during labetalol treatment but no alteration in insulin activity or response to an oral glucose tolerance test.

12. Other metabolic effects.

β-Adrenoreceptors are involved in the regulation of lipid as well as carbohydrate metabolism. Some drugs affect the lipid profile adversely although the long-term clinical significance of this change is unknown and the effect appears to be less for drugs with intrinsic sympathomimetic activity.

13. Use of catecholamine depleting agents.

Concomitant use of drugs such as reserpine and guanethidine requires careful monitoring since the added effect of a β-blocker may produce an excessive reduction of the resting sympathetic nervous tone.

14. Eye and skin reactions.

Various skin rashes and conjunctival xeroses have been reported with β-blocking agents. Cross reactions may occur between β-blockers, and substitutions within the group may not necessarily preclude occurrence of symptoms.
During the long-term treatment with the β-blocking drug practolol, a specific rash bearing a superficial resemblance to psoriasis was occasionally described. In a number of patients affected, this rash was accompanied by adverse effects on the eye (xerophthalmia and/or keratoconjunctivitis) of varying severity. This condition is called the oculomucocutaneous syndrome or practolol syndrome. In a few patients, these eye changes occurred independently of a skin rash. On rare occasions, otitis media, sclerosing peritonitis, pericarditis and pleurisy have been reported. Although this syndrome has not been observed in patients taking other β-blockers, the possibility of such side effects occurring should be borne in mind.
More recently an association between Peyronie's disease, a fibrosing induration of the penis, and various β-blockers has been suggested but is not proven.
It has been found in animal studies that labetalol binds to the melanin pigment of the uveal tract. The significance of this in humans is not known but regular checks on visual function should be made as a precaution.
Extensive ophthalmological monitoring of 72 patients treated with labetalol at doses of 300 to 2400 mg daily for between 6 months and 3 years and routine monitoring of eye complaints from over 6,000 patients has not revealed any adverse effects on the eye.

15. Cross sensitisation.

Cross sensitisation may occur between β-blockers, and substitution within the group may not necessarily preclude recurrence of symptoms.

16. Sclerosing peritonitis.

Sclerosing peritonitis has been reported in association with practolol therapy but not with other β-blockers or Trandate. Nevertheless, the possibility of such a reaction must be borne in mind.

17. Allergic manifestations.

Allergic manifestations may be exaggerated by β-blockade (e.g. allergic rhinitis during the pollen season and allergic reactions to bee and wasp stings). β-Blockers should be avoided if there is a risk of bronchospasm.

18. Phaeochromocytoma.

Labetalol has been shown to be effective in lowering blood pressure and relieving symptoms in patients with phaeochromocytoma. However, paradoxical hypertension responses have been reported in a few patients with this tumour; therefore, use caution when administering labetalol to patients with phaeochromocytoma.
In patients with this condition, an α-blocking drug (e.g. phentolamine/ phenoxybenzamine) should be considered before administration of labetalol, bearing in mind that this drug has α- and β-blocking properties (see Section 5 Pharmacological Properties).

19. Hyperthyroidism.

Since β-blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomatic improvement without any change in thyroid hormone status, special care should be exercised in those patients who are hyperthyroid and are also receiving labetalol as an antihypertensive agent.

20. Postural hypotension.

Severe postural hypotension has occurred in some patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Furthermore, this may be enhanced by the concurrent administration of other vasodilators.
If Trandate tablets are prescribed with diuretics or other antihypertensive agents, an additive effect can be expected. When transferring patients from other treatment regimens, Trandate should be introduced in the manner described, see Section 4.2 Dose and Method of Administration, and the dosage of other treatments should be reduced gradually.

21. Individual variations.

There is a large variation in hypotensive response between patients and this may be due to variable rate of absorption and first-pass metabolism during the passage of labetalol through the intestinal wall and liver.

22. Significant cardiomegaly.


23. Clonidine.

Concurrent use of β-blockers and clonidine should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If administered concomitantly, the clonidine should not be discontinued until several days after the withdrawal of the β-blocker.

Use in renal impairment.

Trandate does not adversely affect renal function and is a particularly suitable drug for use in hypertensive patients with renal disease (see Section 5.1 Pharmacodynamic Properties). In patients with severe renal disease, haemodynamic changes following β-blockade may impair renal function further.

Use in the elderly.

The bioavailability and half-life of labetalol hydrochloride are increased in the elderly. In addition, the hypotensive response is greater in this age group following oral or intravenous administration. Therefore, lower doses of Trandate are likely to be required in elderly patients.

Paediatric use.

There is little reported clinical experience of the use of labetalol in children. Thus, care should be taken in establishing individual dosage requirements in children. Safety and effectiveness in children have not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Postural hypotension may be enhanced by the concurrent administration of other vasodilators.
The interaction of Trandate with methyldopa and with clonidine has been examined on blood pressure and heart rate in animals. The results indicate that Trandate, given together with methyldopa or clonidine, should exert an additional hypotensive effect in human beings who are sensitive to both drugs in the combined therapy.
Concomitant use of tricyclic antidepressants may increase the incidence of tremor.
Cimetidine increases the oral bioavailability of labetalol and care is required in determining the dose of labetalol in patients who are also taking cimetidine.
The hypotensive effect of labetalol may be reduced when used in combination with prostaglandin synthetase inhibitors (e.g. NSAIDs). Dosage adjustment may therefore be necessary.

Interactions with laboratory tests.

Trandate fluoresces in alkaline solution at an excitation wavelength of 334 nanometer and a fluorescence wavelength of 412 nanometer and may, therefore, interfere with the assays of certain fluorescent substances including catecholamines.
The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. In screening patients suspected of having a phaeochromocytoma and being treated with labetalol hydrochloride, a specific method, such as high performance liquid chromatographic assay with solid phase extraction, should be employed in determining levels 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.
Labetalol may produce a false positive result when urine is screened for amphetamines. Care must be taken to corroborate any such result with a more specific method.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
β-Adrenergic blocking agents may cause bradycardia in the foetus and the newborn infant. During the final part of pregnancy and parturition these drugs should therefore only be given after weighing the needs of the mother against the risk to the foetus.
Trandate is known to cross the placental barrier and has been found to bind to the eyes of foetal animals. Trandate has been used successfully in the treatment of hypertension arising in the second and third trimester of pregnancy. Trandate crosses the placental barrier and the possibility of the consequences of α- and β-adrenoreceptor 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. Intrauterine and neonatal deaths have been reported but other drugs (e.g. vasodilators, respiratory depressants) and the effects of pre-eclampsia, intrauterine growth retardation and prematurity were implicated. Such clinical experience warns against unduly prolonging high dose labetalol and delaying delivery and against coadministration of hydralazine.
Administration of Trandate in the first trimester of pregnancy is not recommended. Trandate does not appear to be teratogenic in rats or rabbits, but it is embryolethal when given in a dose of 50 mg/kg orally.
Trandate is excreted in breast milk. No adverse reactions in breastfeeding infants have been reported. It is not recommended for nursing mothers unless the expected benefits outweigh any potential risks.

4.8 Adverse Effects (Undesirable Effects)

Trandate is normally well tolerated. Symptoms of postural hypotension may occur if the initial dosage is too high or if the dose is increased too rapidly.
These side effects include the following.

Cardiovascular.

Postural hypotension may occur if the initial dosage is too high or if the dose is increased too rapidly. Occasionally bradycardia and heart block have been reported.

Central and peripheral nervous system.

Transient dizziness, headache, tiredness, depressed mood and lethargy may occur. There have been reports of a tingling sensation of the skin (especially of the scalp) associated with Trandate treatment usually occurring early in treatment and which is transient in nature.

Collagen disorders.

There have been occasional reports of positive antinuclear antibodies unassociated with disease as well as the occasional case of systemic lupus erythematosus and very occasionally drug fever.

Eyes.

Blurred vision, eye irritation and dry eyes have been reported.

Hepatic system.

Reports of raised liver function tests; jaundice (both hepatocellular and cholestatic) and hepatitis have on occasion been reported, the signs and symptoms of which are usually reversible on withdrawal of the drug. Hepatic necrosis has been reported (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal system.

There has been one report of toxic myopathy. Tremor has been reported in the treatment of hypertension of pregnancy. Muscle cramps have been reported.

Respiratory system.

Bronchospasm may occur in susceptible individuals.

Skin and appendages.

Rashes of various types such as generalised maculopapular, lichenoid, urticarial, bullous, lichen planus, psoriaform and facial erythema, Peyronie's disease and reversible alopecia.

Urinary system.

Acute retention of urine and difficulty in micturition have occurred during Trandate treatment.

Gastrointestinal system.

Epigastric pain, nausea and vomiting.

Hypersensitivity.

Rash, pruritus, angioedema and dyspnoea.

Other symptoms.

Ankle swelling; failure of ejaculation; nasal congestion and sweating.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Trandate tablets are to be taken orally, preferably after meals.
For all patients, the dosage of Trandate must be titrated against blood pressure response.
The recommended starting dose for all patients is 100-200 mg twice daily. The dosage should then be increased at weekly intervals until satisfactory control of blood pressure is attained. It is important to follow these dosage instructions and to increase the dosage gradually, in order to minimise side effects.
Effective daily doses vary between 200 and 2400 mg. In those patients on high doses, a regime of 3 to 4 doses a day may be necessary.
Hypertension may be controlled by Trandate alone. If Trandate tablets are prescribed with diuretics or other antihypertensive agents, an additive effect can be expected.
When transferring patients from other treatment regimes, Trandate should be introduced in the manner described above and the dosage of other treatments should be reduced gradually.

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned that labetalol hydrochloride may cause occasional dizziness or fatigue, therefore resulting in the impairment of ability to drive or operate machinery.

4.9 Overdose

Overdosage with Trandate causes excessive hypotension which is posture sensitive and sometimes, excessive bradycardia. Patients should be laid supine and, if necessary, their legs should be raised to improve the blood supply to the brain. Atropine 3 mg intravenously should be given to relieve the bradycardia. Gastric lavage or induced emesis is recommended if the overdosage is recent (2-3 hours). Oliguric renal failure has been reported after massive overdosage of Trandate orally.
If further measures are required to obtain adequate circulatory function, intravenous noradrenaline may be preferable to isoprenaline, the established pharmacological treatment for excessive cardiac β-blockade. The recommended starting dose of noradrenaline in patients is 5-10 microgram by intravenous injection, repeated as required, according to the response. Alternatively, noradrenaline may be infused at a rate of 5 microgram/minute until a satisfactory response is achieved.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or identified as part of the registration of this medicine.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

HDPE bottle containing 100 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes