Consumer medicine information

Enalapril AN

Enalapril maleate

BRAND INFORMATION

Brand name

Enalapril AN Tablets

Active ingredient

Enalapril maleate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Enalapril AN.

What is in this leaflet

This leaflet answers some common questions about Enalapril AN.

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 this medicine against the benefits it is expected to have for you.

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 Enalapril AN is used for

The name of your medicine is Enalapril AN. It contains the active ingredient enalapril maleate.

Enalapril AN is used to lower high blood pressure (hypertension). It is also used to treat heart failure.

Hypertension
Everyone has blood pressure. This pressure helps to circulate the blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems. You may feel fine and have no symptoms, but eventually hypertension can cause stroke, heart disease and kidney failure. Enalapril AN helps to lower your blood pressure.

Heart Failure
Heart failure means that the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops working. Heart failure may start off with no symptoms, but as the condition progresses, patients may feel short of breath or may get tired easily after light physical activity such as walking. Some patients may wake up short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet.

Enalapril AN helps to treat heart failure, whether you have symptoms or not. In many patients with heart failure who have symptoms, Enalapril AN may slow the progression of heart failure and reduce the need to go to hospital as a result of heart failure. Enalapril AN may help some of these patients live longer.

In many patients with heart failure who have no symptoms, Enalapril AN may help to stop the heart muscle from getting weaker. Enalapril AN may also slow down the development of symptoms, such as shortness of breath, tiredness after light physical activity, or swelling of the ankles and feet. These patients may be less likely to have hospital stays due to heart failure.

By taking Enalapril AN, heart failure patients may have less chance of having a heart attack.

When used to treat heart failure, Enalapril AN is almost always used with other medicines called diuretics or fluid tablets. These medicines help the kidney get rid of excess fluid from the body.

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

Your doctor may have prescribed it for another reason.

How Enalapril AN works

Enalapril AN belongs to a group of medicines called angiotensin converting enzyme (ACE) inhibitors.

One of the ways Enalapril AN helps lower blood pressure and treat heart failure is that it widens your blood vessels, which reduces pressure in the vessels, making it easier for your heart to pump blood around your body. This helps increase the supply of oxygen to your heart, so that when you place extra demands on your heart, such as during exercise, your heart may cope better and you may not get short of breath as easily.

There is no evidence that Enalapril AN is addictive.

Before you take Enalapril AN

When you must not take it

Do not take this medicine if:

  • you have an allergy to the active ingredient enalapril maleate, or to any of the other ingredients listed at the end of this leaflet under Product Description. Some of the symptoms of an allergic reaction may include: shortness of breath; wheezing or difficulty in breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin; muscle pain or tenderness or joint pain.
  • you have taken any other 'ACE inhibitor' medicines for high blood pressure or heart failure before, which caused your face, lips, tongue, throat, hands or feet to swell up, or made it hard for you to breathe.
  • you have a history or a family history of swelling of the face, lips, tongue, throat, hands or feet for no apparent reason.
  • you have diabetes and are taking a medicine called aliskiren to reduce blood pressure.

Do not take this medicine if you are pregnant, plan on becoming pregnant or are breast-feeding.

Your baby may absorb this medicine in the womb or from breast milk and therefore there is a possibility of harm to the baby.

Do not give this medicine to children.

The safety and effectiveness in children have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to:

  • any other medicines, especially if they are in the same drug class as enalapril maleate
  • any other substances, including foods, preservatives or dyes.

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

  • kidney problems, or if you are undergoing dialysis treatment
  • heart problems
  • diabetes.

Tell your doctor if you have recently suffered from excessive vomiting or diarrhoea.

Tell your doctor if you are following a very low salt diet.

Tell your doctor if you are or intend to become pregnant or intend to breastfeed.

Enalapril AN should not be used during pregnancy or while breastfeeding.

Tell your doctor if you suffer from low blood pressure (you may notice this as faintness or dizziness, especially when standing).

Tell your doctor if you plan to have surgery and anaesthesia (even at the dentist office) are scheduled, as there may be a sudden fall in blood pressure associated with anaesthesia.

If you have not told your doctor about any of the above, tell him/her before you start taking Enalapril AN.

Taking other medicines

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

Some medicines and Enalapril AN may interfere with each other. These include:

  • other medicines used to treat high blood pressure
  • diuretics, also known as fluid or water tablets
  • non-steroidal anti-inflammatory drugs (NSAIDs or Coxibs/COX-2 inhibitors), medicines used to relieve pain, swelling and other symptoms of inflammation
  • arthritis medicines including gold therapy
  • potassium supplements or potassium-containing salt substitutes
  • potassium-sparing agents (e.g. spironolactone, eplerenone, triamterene, amiloride); medicines which may increase potassium levels (e.g. heparin, trimethoprim/sulfamethoxazole)
  • lithium, a medicine used to treat mood swings and some types of depression
  • insulin or oral antidiabetic medicines. You should be closely monitored for low blood glucose levels, especially during the first month of treatment with Enalapril AN
  • mammalian target of rapamycin inhibitors (e.g. temsirolimus, sirolimus, everolimus).

These medicines may be affected by Enalapril AN, or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Enalapril AN

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets you need to take each day. This depends on your condition and whether you are taking other medicines. Take Enalapril AN only when prescribed by your doctor.

For high blood pressure:
For most patients, the usual starting dose is 5mg taken once a day. Some patients may need a lower starting dose. The dose may need to be increased depending on your blood pressure. Most patients take between 10 to 40mg each day.

For heart failure:
The usual starting dose is 2.5mg taken once a day. Depending on your response, this dose may need to be increased up to 20mg each day. This dose may be taken once a day or divided into two doses per day.

How to take it

Take your Enalapril AN at about the same time each day. Taking your tablet(s) at the same time each day will have the best effect. It will also help you remember when to take the tablets.

Swallow Enalapril AN with a glass of water. It does not matter if you take Enalapril AN before or after food.

If you need to break Enalapril AN, place the tablet on a flat surface with the notch side facing up and press down on the scored side with the thumb.

How long to take it

Enalapril AN helps control your high blood pressure and helps improve your heart failure, but does not cure it. Therefore this medicine must be taken every day.

Continue taking your medicine for as long as your doctor prescribes.

If you forget to take your dose

Take your dose as soon as you remember, and continue to take it as you would normally.

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

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

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask 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 the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Enalapril AN. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too many tablets, you will probably feel light-headed or dizzy, or you may faint.

While you are taking Enalapril AN

Things you must do

Always follow your doctor's instructions carefully.

Have your blood pressure checked when your doctor says, to make sure Enalapril AN is working.

If you feel any light-headedness or dizziness after you take your first dose of Enalapril AN or if your dose is increased, tell your doctor immediately. This is especially important if you are taking Enalapril AN for heart failure. If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up.

You may feel light-headed or dizzy, especially if you are also taking a diuretic (fluid tablet). This may be because your blood pressure is falling suddenly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem gets worse or continues, talk to your doctor.

If you become pregnant, or plan on becoming pregnant while taking Enalapril AN, tell your doctor immediately.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Enalapril AN.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking Enalapril AN.

Your blood pressure may drop suddenly.

If you are about to have any blood tests, tell your doctor that you are taking Enalapril AN.

It may interfere with the results of some tests.

Make sure you drink enough water during exercise and hot weather when you are taking Enalapril AN, especially if you sweat a lot.

If you do not drink enough water while taking Enalapril AN, you may faint or feel light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.

If you have excessive vomiting and/or diarrhoea while taking Enalapril AN, tell your doctor.

This can also mean that you are losing too much water and salt, and may drop your blood pressure too much.

Go to your doctor regularly for a check-up.

Your doctor may occasionally do a blood test to check your potassium level in the blood and to see how your kidneys are working.

Things you must not do

Do not stop taking Enalapril AN without your doctor's permission.

Do not take Enalapril AN to treat any other complaint unless your doctor tells you to.

Do not give this medication to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how Enalapril AN affects you.

Enalapril AN may cause dizziness or light-headedness in some people, especially after the first dose or if the dose is increased. Make sure you know how you react to Enalapril AN before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If you drink alcohol, dizziness or light-headedness may be worse.

Things that would be helpful for your blood pressure or heart failure

Some self-help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information.

  • Alcohol

Your doctor may advise you to limit your alcohol intake.

  • Diet

Eat a healthy diet which includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar.

  • Exercise

Regular exercise helps to reduce blood pressure and helps the heart get fitter, but it is important not to overdo it. Walking is good exercise, but try to find a route that is fairly flat. Before starting any exercise, ask your doctor about the best kind of programme for you.

  • Salt

Your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake you should avoid using salt in cooking or at the table.

  • Smoking

Your doctor may advise you to stop or at least cut down smoking.

  • Weight

Your doctor may suggest losing some weight to help lessen the amount of work your heart has to do. Some people may need a dietician's help to lose weight.

Side effects

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

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

Do not be alarmed by the following lists of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

  • light-headedness or dizziness because your blood pressure is too low
  • headache
  • fatigue
  • dry cough
  • mild stomach upsets such as feeling sick, diarrhoea, or stomach pains
  • muscle cramps
  • feelings of deep sadness and unworthiness (depression)

These are the usually mild side effects of Enalapril AN, but may be serious.

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

  • changes in the way your heart beats, for example, if you notice it beating faster
  • fainting
  • yellowing of the skin and eyes, also called jaundice
  • itchy skin rash or other skin problems
  • signs of worrying or frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • passing less urine than is normal for you
  • signs of dehydration such as nausea, vomiting, muscle cramps, headache, drowsiness and tiredness. If untreated, mental confusion and fits may develop. Your doctor may need to monitor your blood sodium levels.
  • strange dreams or unusual dreams
  • hallucinations (seeing or hearing things that are not there).

These may be serious side effects. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop taking Enalapril AN, and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • swelling of the hands, feet or ankles
  • pinkish, itchy swelling on the skin, also called hives or nettlerash
  • chest pain, angina
  • wheeziness due to tightness in the chest
  • collapse, numbness or weakness of arms or legs.

These are serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice any other effects.

After taking Enalapril AN

Storage

Keep your medicine in the original packaging until you need to take it.

If you take it out of its original packaging it may not keep well.

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

Do not store Enalapril AN or any other medicine in the bathroom or near a sink. Do not leave it in the car or on a window sill.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

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

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What Enalapril AN looks like

Enalapril AN comes in three types of tablets:

Enalapril AN 5mg - oval, convex, white tablets, with one side scored and marked EN 5.

Enalapril AN 10mg - oval, convex, red-brown tablets, with one side scored and marked EN 10.

Enalapril AN 20mg - oval, convex, orange tablets, with one side scored and marked EN 20.

Available in blisters of 30 tablets.

Ingredients

Active Ingredient

Each Enalapril AN 5mg tablet contains 5mg enalapril maleate

Each Enalapril AN 10mg tablet contains 10mg enalapril maleate

Each Enalapril AN 20mg tablet contains 20mg enalapril maleate

Inactive Ingredients

  • sodium bicarbonate
  • lactose
  • maize starch
  • purified talc
  • magnesium stearate
  • hydroxypropylcellulose (5mg tablets only)
  • iron oxide red (10 and 20mg tablets only)
  • iron oxide yellow (20mg tablets only).

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in Aug 2017.

Australian Register Numbers

Enalapril AN 5mg tablets: AUST R 188552

Enalapril AN 10mg tablets: AUST R 188553

Enalapril AN 20mg tablets: AUST R 188554

BRAND INFORMATION

Brand name

Enalapril AN Tablets

Active ingredient

Enalapril maleate

Schedule

S4

 

1 Name of Medicine

Enalapril maleate.

6.7 Physicochemical Properties

The chemical name of enalapril maleate is (2S)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino] propanoyl] pyrrolidine-2-carboxylic acid (Z)-butenedioate. Its molecular formula is C20H28N2O5.C4H4O4 (Molecular Weight: 492.5).

Chemical structure.

Its chemical structure is:

CAS number.

76095-16-4.

2 Qualitative and Quantitative Composition

Enalapril is the ethyl ester of the parent diacid, enalaprilat. Enalapril maleate is a white to off-white crystalline powder.
Melting point: approximately 144°C.
Solubility: sparingly soluble in water, freely soluble in methanol, practically insoluble in methylene chloride. It dissolves in dilute solutions of alkali hydroxides.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Enalapril AN 5 mg (AUST R 188552) - oval, convex, white tablets, with one side scored and marked EN 5.
Enalapril AN 10 mg (AUST R 188553) - oval, convex, red-brown tablets, with one side scored and marked EN 10.
Enalapril AN 20 mg (AUST R 188554) - oval, convex, orange tablets, with one side scored and marked EN 20.

5 Pharmacological Properties

Enalapril maleate is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Enalapril maleate is a prodrug which when administered orally is hydrolysed to release a specific, long acting angiotensin converting enzyme (ACE) inhibitor, enalaprilat.

5.1 Pharmacodynamic Properties

Administration of Enalapril-AN to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.
Symptomatic postural hypotension is infrequent. In some patients, the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril has not been associated with rapid increase in blood pressure.
Effective inhibition of ACE activity usually occurs two to four hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by four to six hours after administration.
The duration of effect is dose related. However, at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours.
In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate there was an increase or no change in renal blood flow; glomerular filtration rate was unchanged. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.
When given together with thiazide type diuretics, the blood pressure lowering effects of enalapril maleate are at least additive. Enalapril may reduce or prevent the development of thiazide induced hypokalaemia.
In patients with heart failure on therapy with digitalis and diuretics, treatment with oral or parenteral enalapril maleate was associated with decreases in peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure was also reduced. Exercise tolerance and severity of heart failure, as measured by New York Heart Association criteria, improved. These actions continued during chronic therapy.
In a multicentre, placebo controlled clinical trial (SOLVD), 2,569 patients with all degrees of symptomatic heart failure and ejection fraction less than or equal to 35% were randomised to placebo or enalapril and followed for up to 55 months (SOLVD-Treatment).
A second multicentre trial used the SOLVD protocol for a study of patients with minimal or no symptoms of heart failure. SOLVD-Prevention patients, who had left ventricular ejection fraction less than or equal to 35% and no history of symptomatic heart failure were randomised to placebo (n = 2,117) or enalapril (n = 2,111) and followed for up to five years. These patients had little or no limitation of exercise tolerance due to dyspnoea or fatigue at randomisation and did not require treatment with digitalis, diuretics or vasodilators for heart failure at entry into the trial. The majority of patients in the trial had a history of ischaemic heart disease. A history of myocardial infarction was present in 80% of patients, current angina pectoris in 34% and a history of hypertension in 37%. Patients who had a recent myocardial infarction (i.e. within the preceding 30 days) were not included in the SOLVD trials.
In patients with left ventricular ejection fractions of less than 35%, enalapril has been shown to retard the progression of heart failure, reduce hospitalisations for heart failure and reduce the risk of myocardial infarction. In addition, in patients who have significant symptoms of heart failure (New York Heart Association classes 2 to 4) and also left ventricular ejection fractions of less than 35%, enalapril has been shown to improve survival and reduce hospitalisations for unstable angina pectoris.

Mechanism of action.

How enalapril, or converting enzyme inhibitors in general, lower blood pressure is not entirely clear. The mechanism most favoured is inhibition of the angiotensin converting enzyme (ACE), a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the pressor substance angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion.
While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, which plays a major role in the regulation of blood pressure, Enalapril is antihypertensive even in patients with low renin hypertension. Enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide; however, the role that this plays in the therapeutic effect of enalapril remains to be elucidated.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril is approximately 60%. The oral bioavailability of enalaprilat is approximately 40%. The absorption of oral enalapril maleate is not influenced by the presence of food in the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar for the various doses in the recommended therapeutic range.

Distribution.

Protein binding is approximately 50%. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to angiotensin converting enzyme (ACE). In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration of enalapril maleate. The plasma concentration-time profile of enalaprilat was complex with several exponentials including a very prolonged terminal phase (t1/2 > 30 hours). The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril maleate is 11 hours.

Metabolism.

Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin converting enzyme inhibitor. The liver appears to be the main site for this conversion. Except for conversion to enalaprilat, there is no evidence for significant metabolism of Enalapril-PS.

Excretion.

Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril.

5.3 Preclinical Safety Data

Genotoxicity.

Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in in vivo cytogenic study using mouse bone marrow.

Carcinogenicity.

There was no evidence of a carcinogenic effect when enalapril was administered for 106 weeks to rats at doses of up to 90 mg/kg/day. Enalapril has also been administered for 94 weeks to male and female mice at doses up to 90 mg and 180 mg/kg/day, respectively, and showed no evidence of carcinogenicity.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Enalapril AN is indicated in the treatment of:
All grades of essential hypertension.
Renovascular hypertension.

Congestive heart failure.

Enalapril AN is indicated for the treatment of all degrees of symptomatic heart failure. In such patients it is recommended that Enalapril AN be administered together with a diuretic.

Left ventricular dysfunction.

All degrees of left ventricular dysfunction where the left ventricular ejection fraction is less than 35%, irrespective of the presence or severity of obvious symptoms of heart failure.

4.3 Contraindications

History of previous hypersensitivity to Enalapril AN or to any component of the formulation, and in patients with a history of angioneurotic oedema relating to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Enalapril should not be administered with aliskiren in patients with diabetes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Enalapril is contraindicated in combination with a neprilysin inhibitor (e.g. sacubitril). Do not administer enalapril within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

4.4 Special Warnings and Precautions for Use

Angioedema.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including enalapril maleate. In such cases enalapril should be promptly discontinued and the patient carefully observed until the swelling disappears. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.
Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.
Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, which may include subcutaneous adrenaline solution 1:1,000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly administered (See Section 4.8 Adverse Effects (Undesirable Effects)).
The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom free intervals. Angioedema may occur with or without urticaria.
Black patients receiving ACE inhibitors have been reported to have higher incidence of angioedema compared to non-blacks.
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.
Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk for angioedema (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Anaphylactoid reactions during hymenoptera desensitization.

Rarely, patients receiving ACE inhibitors during desensitization with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization.

Hypotension.

Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of enalapril use in severely salt/ volume depleted persons such as those treated vigorously with diuretics or patients on dialysis (See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.) In patients with heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotaemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs the patient should be placed in supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which usually can be given without difficulty once the blood pressure has increased after volume expansion.

Neutropenia/ agranulocytosis.

Another ACE inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia/ neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded.
It is recommended that periodic haematological monitoring be considered in patients with diseases known to affect bone marrow function (e.g. renal dysfunction, collagen vascular disease) and/or who are taking concomitant therapy known to be associated with bone marrow depression.

Haemodialysis patients.

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Evaluation of the hypertensive patient should always include assessment of renal function (See Section 4.2 Dose and Method of Administration).

Aortic stenosis/ hypertrophic cardiomyopathy.

As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Hyperkalaemia.

(also See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Agents increasing serum potassium.)
Elevated serum potassium (greater than 5.7 mmol/L) was observed in approximately 1% of hypertensive patients in clinical trials. In most cases, these were isolated values, which resolved despite continued therapy. Hyperkalaemia was a cause of discontinuation of therapy in 0.28% of hypertensive patients. Risk factors for the development of hyperkalaemia may include renal insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and the concomitant use of potassium sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements and/or potassium containing salt substitutes, or drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole) which should be used cautiously, if at all, with Enalapril.
The use of potassium supplements, potassium sparing diuretics or potassium containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias.
If concomitant use of enalapril and any of the abovementioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Hypoglycaemia.

Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycaemia, especially during the first month of combined use (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Antidiabetics).

Surgery/ anaesthesia.

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Cough.

A persistent non-productive, ticklish cough has been reported in some patients undergoing treatment with enalapril and other ACE inhibiting drugs. The cough is often worse when lying down. The cough is more common in women (who account for about two-thirds of reported cases). The patients who cough may have increased bronchial reactivity compared to those who do not cough. It may disappear in some patients with continued use, or diminish or disappear if the dose of the drug is reduced.
In those in whom cough persists, the drug should be discontinued. The cough usually returns on rechallenge. No residual effects have been reported.

Use in renal impairment.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including enalapril, may be associated with oliguria and/or progressive azotaemia and rarely with acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20% of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required.

Use in the elderly.

No data available.

Paediatric use.

Enalapril AN has not been studied in children.

Effects on laboratory tests.

Serum electrolytes.

Hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use), hyponatraemia.

Creatinine, blood urea nitrogen.

In controlled clinical trials, minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2% of patients with essential hypertension treated with enalapril maleate alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (See Section 4.4 Special Warnings and Precautions for Use).

Haemoglobin and haematocrit.

Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.3 g % and 1.0 vol %, respectively) occur frequently in hypertensive patients treated with enalapril maleate but are rarely of clinical importance unless another cause of anaemia coexists. In clinical trials, less than 0.1% of patients discontinued therapy due to anaemia.

Other (causal relationship unknown).

In marketing experience, rare cases of pancreatitis, neutropenia, thrombocytopenia, agranulocytosis and bone marrow depression have been reported.
A few cases of haemolysis have been reported in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Liver function tests.

Elevations of hepatic enzymes and/or serum bilirubin have occurred.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Hypotension; patients on diuretic therapy.

Patients on diuretics and especially those in whom diuretic therapy was recently instituted may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimised by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least one hour after the initial dose (See Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Agents causing renin release.

The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (e.g. diuretics).

Other cardiovascular agents.

Enalapril has been used concomitantly with beta-adrenergic blocking agents, methyldopa, nitrates, calcium blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions.

Agents increasing serum potassium (also See Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia).

Enalapril may attenuate potassium loss caused by thiazide type diuretics. Potassium sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of enalapril maleate with these agents is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be also at increased risk for hyperkalaemia.

Antidiabetics.

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored for hypoglycaemia, especially during the first month of treatment with an ACE inhibitor.

Serum lithium.

As with other drugs that eliminate sodium, lithium clearance may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

Nonsteroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors.

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g. elderly patients or patients who are volume depleted, including those on diuretic therapy) who are being treated with NSAIDs, including selective cyclooxygenase-2 inhibitors, the coadministration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function. These effects are usually reversible, including possible renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly.
Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Dual blockade of the renin-angiotensin-aldosterone system.

It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, dual blockade of the renin-angiotensin-aldosterone system (with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors such as aliskiren) is associated with increased risks of hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) as compared to monotherapy. Dual blockade should be limited to individually defined cases with close monitoring of blood pressure, renal function and electrolytes. Do not co-administer aliskiren with enalapril in patients with diabetes. Avoid use of aliskiren with enalapril with renal impairment (GFR 60 mL/min).

Gold.

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.

Mammalian target of rapamycin (mTOR) inhibitors.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see Section 4.4 Special Warnings and Precautions for Use).

Neprilysin inhibitors.

Patients taking a concomitant neprilysin inhibitor (e.g. sacubitril) may be at increased risk for angioedema (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no adverse effects on reproductive performance in male and female rats treated with 10 to 90 mg/kg/day of enalapril.
(Category D)
Australian Definition of Pregnancy Category D: Drugs that have caused, are suspected to have caused - or may be expected to cause - an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
As with all ACE inhibitors, enalapril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with enalapril and avoided during the treatment. Enalapril is contraindicated during pregnancy (see Section 4.3 Contraindications). ACE inhibitors can cause foetal and neonatal morbidity and death when given to pregnant women. Several dozen cases have been reported in the world literature.
If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment.
If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
Data show that enalapril crosses the human placenta. Post marketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero. There have been reports of foetal hypotension, renal failure, hyperkalaemia, skull hypoplasia and death when ACE inhibitors have been used during the second and third trimesters of pregnancy.
A historical cohort study in over 29,000 infants born to non-diabetic mothers has shown 2.7 times higher risk for congenital malformations in infants exposed to any ACE inhibitor during first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02) respectively, compared to no exposure.
There is a potential risk of foetal hypotension, decreased birthweight and decreased renal perfusion or anuria in the foetus from in utero exposure to ACE inhibitors. Oligohydramnios in the mother has also been reported, presumably representing decreased renal function in the foetus. Oligohydramnios in this setting has been associated with foetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these were due to ACE inhibitor exposure. In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated with a potentially increased risk of birth defects.
Any neonate exposed to enalapril in utero should be observed closely for adequate urine output, blood pressure and hyperkalaemia. If required, appropriate medical measures should be initiated, including administration of fluids or dialysis to remove enalaprilat from the circulatory system.
The maternal and foetal toxicity occurred in some rabbits at doses of 1 mg/kg/day or more. Saline supplementation prevented the maternal and foetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day. Enalapril was not teratogenic in rabbits. There was no foetotoxicity or teratogenicity in rats treated with up to 200 mg/kg/day of enalapril. Foetotoxicity expressed as a decrease in average foetal weight occurred in rats given enalapril 1,200 mg/kg/day, but did not occur when these animals were supplemented with saline.
It is not known if enalapril is secreted in human milk. However, enalapril has been demonstrated to be secreted into the milk of lactating rats. In view of this and a lack of knowledge of the effects of enalapril on neonates, this product should not be used during lactation or else breastfeeding should be discontinued.

4.8 Adverse Effects (Undesirable Effects)

Enalapril maleate has been evaluated for safety in more than 10,000 patients, including over 1,000 patients treated for one year or more. Enalapril maleate has been found to be generally well tolerated in controlled clinical trials involving 2,677 patients.
The most frequent clinical adverse experiences in controlled trials were headache (4.8%), dizziness (4.6%) and fatigue (2.8%). For the most part, adverse experiences were mild and transient in nature. Discontinuation of therapy was required in 6.0% of patients. In clinical trials, the overall frequency of adverse experiences was not related to total daily dosage within the range of 10 to 40 mg. The overall percentage of patients treated with enalapril maleate reporting adverse experiences was comparable to placebo.
Adverse experiences occurring in greater than 1% of patients treated with enalapril maleate in controlled clinical trials are shown in Table 1 (See Table 1).
Clinical adverse experiences occurring since the drug was marketed or in 0.5 to 1.0% of patients in the controlled trials are listed below and, within each category, are in order of decreasing severity.
Adverse effects reported for enalapril include:
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); not known (cannot be estimated from the available data).

Blood and lymphatic system disorder.

Uncommon: anaemia (including aplastic and haemolytic).
Rare: neutropenia, decrease in haemoglobin, decrease in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases.

Cardiac disorders.

Common: Rhythm disturbances, angina pectoris, tachycardia, chest pain.
Uncommon: Palpitations, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Section 4.4 Special Warnings and Precautions for Use).

Endocrine disorders.

Not known: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Vascular disorders.

Common: Hypotension (including orthostatic hypotension).
Uncommon: Flushing, orthostatic hypotension.
Rare: Raynaud's phenomenon.

Gastrointestinal system disorders.

Very common: Nausea.
Common: Diarrhoea, abdominal pain.
Uncommon: Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer.
Rare: Stomatitis/ aphthous ulcerations, glossitis.

Hepatobiliary disorders.

Rare: Hepatic failure, hepatitis - either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice).

Metabolism and nutrition disorders.

Uncommon: Hypoglycaemia (in diabetic patients on oral antidiabetic agent or insulin - see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Psychiatric disorders.

Common: Depression.
Uncommon: Confusion, nervousness, insomnia.
Rare: Dream abnormality, sleep disorders, hallucinations.

Nervous system disorders.

Very common: Dizziness.
Common: Headache, syncope, taste alteration.
Uncommon: Confusion, Somnolence, paraesthesia, vertigo.

Eye disorders.

Very common: Blurred vision.

Ear and labyrinth disorders.

Uncommon: Tinnitus.

Renal and urinary disorders.

(See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Uncommon: Renal failure, renal dysfunction, proteinuria.
Rare: Oliguria.

Respiratory, thoracic and mediastinal disorders.

Very common: Cough.
Common: Dyspnoea.
Uncommon: Bronchospasm, rhinorrhoea, sore throat, hoarseness.
Rare: Pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Skin and subcutaneous tissue disorders.

Common: Rash, hypersensitivity/ angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx.
Uncommon: Pruritus, urticaria, alopecia, diaphoresis.
Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, pemphigus, erythroderma.
Not known: A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.

Musculoskeletal, connective tissue, and bone disorders.

Uncommon: Muscle cramps.

Reproductive system and breast disorders.

Uncommon: Impotence.
Rare: Gynecomastia.

General disorders and administration site conditions.

Very common: Asthenia.
Common: Fatigue, chest pain.
Uncommon: Malaise, fever, vasculitis, hyperhidrosis, photosensitivity.

Investigations.

Common: Hyperkalaemia, increases in serum creatinine.
Uncommon: Increases in blood urea, hyponatraemia.
Rare: Elevations of liver enzymes, elevations of serum bilirubin.
A symptom complex has been reported which may include fever, serositis, myalgia and arthralgia/arthritis; an elevated erythrocyte sedimentation rate (ESR), eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur. These symptoms have disappeared after discontinuation of therapy.

Angioedema.

Angioedema has been reported in patients receiving enalapril maleate (0.2%). Angioedema associated with laryngeal oedema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalapril should be discontinued and appropriate therapy instituted immediately (See Section 4.4 Special Warnings and Precautions for Use). In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including enalapril.

Hypotension.

Combining the results of clinical trials in patients with hypertension or congestive heart failure, hypotension (including postural hypotension, and other orthostatic effects) was reported in 2.3% of patients following the initial dose of enalapril or during extended therapy. In the hypertensive patients, hypotension occurred in 0.9% and syncope occurred in 0.5% of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.1% of hypertensive patients (See Section 4.4 Special Warnings and Precautions for Use).

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

Dosage.

Essential hypertension.

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of Enalapril-PS. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with Enalapril AN to reduce the likelihood of hypotension. (See Section 4.4 Special Warnings and Precautions for Use.) If the patient's blood pressure is not controlled with Enalapril AN alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued an initial dose of 2.5 mg (break the 5 mg tablet) should be used under medical supervision for at least one hour to determine whether excess hypotension will occur (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The recommended initial dose in patients not on diuretics is 5 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 to 40 mg/day administered in a single dose or two divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice-daily administration should be considered. If blood pressure is not controlled with Enalapril AN alone, a diuretic may be added.
Concomitant administration of Enalapril AN with potassium supplements, potassium salt substitutes or potassium sparing diuretics may lead to increases of serum potassium (see Section 4.4 Special Warnings and Precautions for Use).
To date there is insufficient experience with Enalapril AN in the treatment of accelerated or malignant hypertension. Enalapril-PS, therefore, is not recommended in such situations.

Renovascular hypertension.

Since blood pressure and renal function in such patients may be particularly sensitive to ACE inhibition, therapy should be initiated with a lower starting dose (e.g. 5 mg or less). The dosage should then be adjusted according to the needs of the patient. Most patients may be expected to respond to 20 mg taken once daily. For patients with hypertension who have been treated recently with diuretics, caution is recommended (see below).

Congestive heart failure.

Therapy with Enalapril AN must be started under close medical supervision.
Blood pressure and renal function should be monitored closely both before and after starting treatment with Enalapril AN (see Section 4.4 Special Warnings and Precautions for Use) because severe hypotension and (more rarely) consequent renal failure have been reported.
Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/ volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment.
The initial dose of enalapril in patients with congestive heart failure (especially renally impaired or sodium and/or volume depleted patients) should be lower (2.5 mg or less), and it should be administered under close medical supervision to determine the initial effect on the blood pressure. The appearance of hypotension after the initial dose of Enalapril AN does not imply that hypotension will recur during chronic therapy with Enalapril AN and does not preclude continued use of the drug.
In the absence of, or after effective management of, symptomatic hypotension following initiation of therapy with Enalapril AN in congestive heart failure, the dose should be gradually increased, depending on the patient's response, to the usual maintenance dose (10 to 20 mg) given in a single or divided dose. This dose titration may be performed over a two to four week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure. In clinical trials in which mortality and morbidity was reduced, dosage was divided in two doses.

Left ventricular dysfunction without symptoms of overt heart failure.

In the SOLVD-Prevention trial, the initial dose was 2.5 mg twice daily and titrated as described for congestive heart failure, above, to the usual maintenance dose of 20 mg in two divided doses.

Method of administration.

For oral administration.

Dosage adjustment in:

Renal impairment.

The usual dose of enalapril is recommended for patients with a creatinine clearance > 30 mL/minute (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance less than or equal to 30 mL/minute (serum creatinine greater than or equal to 3 mg/dL), the first dose is 2.5 mg once daily. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

Normal renal function.

In patients with creatinine clearance > 80 mL/minute, the initial dose is 5 mg/day.

Mild impairment.

Creatinine clearance less than or equal to 80 to > 30 mL/minute, the initial dose is 5 mg/day.

Moderate to severe impairment.

Creatinine clearance less than or equal to 30 mL/minute, the initial dose is 2.5 mg/day.

Dialysis patients.

2.5 mg on dialysis days. Dosage on nondialysis days should be adjusted depending on the blood pressure response.

Elderly (over 65 years).

The starting dose should be 2.5 mg. Some elderly patients may be more responsive to Enalapril AN than younger patients.

4.7 Effects on Ability to Drive and Use Machines

When driving vehicles or operating machines it should be taken into account that occasionally, dizziness or weariness may occur.

4.9 Overdose

Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension, beginning approximately six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor, which can be treated, if necessary, by intravenous infusion of normal saline solution.
Several hypertensive patients in clinical studies have received as much as 80 mg of enalaprilat intravenously over a 15-minute period. No adverse effects, other than those associated with recommended dosages, were observed. Enalaprilat may be removed from the general circulation by haemodialysis.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium bicarbonate, lactose monohydrate, maize starch, purified talc, magnesium stearate, hyprolose (5 mg only); iron oxide red (10 and 20 mg only) and iron oxide yellow (20 mg only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25 °C. Protect from light and moisture.

6.5 Nature and Contents of Container

Enalapril AN 5 mg, 10 mg and 20 mg (AUST R 188552, AUST R 188553, and AUST R 188554 respectively) are packed in aluminium/aluminium blisters of 30's.

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