Consumer medicine information

Malean

Enalapril maleate

BRAND INFORMATION

Brand name

Malean

Active ingredient

Enalapril maleate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Malean.

SUMMARY CMI

MALEAN

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using MALEAN?

MALEAN contains the active ingredient enalapril maleate. MALEAN is used to lower high blood pressure, which doctors call hypertension. It is also used to treat heart failure.

For more information, see Section 1. Why am I using MALEAN? in the full CMI.

2. What should I know before I use MALEAN?

Do not use if you have ever had an allergic reaction to MALEAN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use MALEAN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MALEAN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MALEAN?

  • 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.

More instructions can be found in Section 4. How do I use MALEAN? in the full CMI.

5. What should I know while using MALEAN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using MALEAN.
  • Go to your doctor regularly for a check-up. Have your blood pressure checked when your doctor says, to make sure MALEAN is working.
  • If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up.
  • Make sure you drink enough water during exercise and hot weather when you are taking MALEAN, especially if you sweat a lot.
  • If you have excessive vomiting and/or diarrhoea while taking MALEAN, tell your doctor.
Things you should not do
  • Do not give MALEAN to anyone else, even if they have the same condition as you.
Driving or using machines
  • MALEAN may cause dizziness or light-headedness in some people. Make sure you know how you react to MALEAN before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed
Drinking alcohol
  • If you drink alcohol, dizziness or light-headedness may be worse.
Looking after your medicine
  • Keep it in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the blister pack until it is time to take them.

For more information, see Section 5. What should I know while using MALEAN? in the full CMI.

6. Are there any side effects?

Common side effects include headache, light-headedness or dizziness, fatigue, dry cough, mild stomach upsets and muscle cramps. Serious side effects include fast or irregular heartbeat, fainting, yellowing of the skin or eyes, skin rash, worrying or frequent infections, signs of dehydration or symptoms of as allergic reaction (i.e. swelling of the face or throat, hives, shortness of breath etc.).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

MALEAN

Active ingredient(s): enalapril maleate

Consumer Medicine Information (CMI)

This leaflet provides important information about using MALEAN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using MALEAN.

Where to find information in this leaflet:

1. Why am I using MALEAN?
2. What should I know before I use MALEAN?
3. What if I am taking other medicines?
4. How do I use MALEAN?
5. What should I know while using MALEAN?
6. Are there any side effects?
7. Product details

1. Why am I using MALEAN?

MALEAN contains the active ingredient enalapril maleate. MALEAN belongs to a group of medicines called Angiotensin Converting Enzyme (ACE) inhibitors.

MALEAN is used to lower high blood pressure, which doctors call hypertension. It is also used to treat heart failure.

One of the ways MALEAN helps lower blood pressure and treat heart failure is that it widens blood vessels. This means that blood is able to pass through them more easily and the heart doesn't have to pump as hard to move blood around the body. This also means that when you place extra demands on your heart, such as during exercise, the heart may cope better so you may not get short of breath as easily.

MALEAN is not addictive.

Hypertension:

Everyone has blood pressure. This pressure helps get your 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. MALEAN 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.

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

In many patients with heart failure who have no symptoms, MALEAN may help to stop the heart muscle from getting weaker. MALEAN 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 MALEAN, heart failure patients may have less chance of having a heart attack.

When used to treat heart failure, MALEAN 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.

2. What should I know before I use MALEAN?

Warnings

Do not use MALEAN if:

  • you are allergic to enalapril, or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include skin rash, itchiness, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain. Always check the ingredients to make sure you can use this medicine.
  • 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.
    If you have had an allergic reaction to an ACE inhibitor before, you may be allergic to MALEAN.
  • you have a 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.
  • you are taking a medicine containing a neprilysin inhibitor (e.g., sacubitril). Do not take MALEAN for at least 36 hours before or after you take sacubitril/valsartan, a medicine containing a neprilysin inhibitor.
  • you are pregnant or breast-feeding.
  • the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have any other medical conditions especially the following:
    - kidney disease, or are undergoing dialysis
    - diabetes
    - heart problems
  • have recently suffered from excessive vomiting or diarrhoea
  • are following a very low salt diet
  • are taking potassium supplements, potassium-sparing agents, potassium-containing salt substitutes or other drugs that may increase serum potassium (e.g., trimethoprim-containing products)
  • have had an allergy to any other medicines or any other substances, such as foods, preservatives or dyes
  • suffer from low blood pressure (you may notice this as faintness or dizziness, especially when standing)
  • are scheduled for surgery and anaesthesia (even at the dentist office), as there may be a sudden fall in blood pressure associated with anaesthesia
  • are taking a medicine containing a neprilysin inhibitor (e.g., sacubitril)
  • are taking a medicine containing vildagliptin
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

MALEAN should not be used during pregnancy or while 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.

3. What if I am taking other medicines?

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

Some medicines may interfere with MALEAN and affect how it works.

Medicines that may increase the effect of MALEAN or the risk of side effects include:

  • other blood pressure medicines
  • diuretic tablets - also called fluid or water tablets
  • potassium tablets
  • potassium-containing salt substitutes
  • potassium-sparing agents (e.g. spironolactone, eplerenone, triamterene, amiloride)
  • other drugs that may increase serum potassium (e.g., trimethoprim-containing products)
  • arthritis medicines including gold therapy
  • mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or a medicine containing a neprilysin inhibitor (e.g., sacubitril) or vildagliptin as coadministration with MALEAN could increase the risk for an allergic reaction called angioedema.

Medicines that may reduce the effect of MALEAN include:

  • non-steroidal anti-inflammatory medicines (NSAIDs or Coxibs/COX-2 inhibitors), used to relieve pain, swelling and other symptoms of inflammation

Medicines that may be affected when taken with MALEAN include:

  • 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 MALEAN

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MALEAN.

4. How do I use MALEAN?

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 MALEAN only when prescribed by your doctor.
  • Follow the instructions provided and use MALEAN until your doctor tells you to stop. MALEAN helps control your high blood pressure and helps improve your heart failure, but does not cure it. Therefore MALEAN must be taken every day.

For high blood pressure:

  • For most patients, the usual starting dose is 5 mg 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 40 mg each day.

For heart failure:

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

When to take MALEAN

  • MALEAN should be taken 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.
  • It does not matter if you take MALEAN before or after food.

How to take MALEAN

  • Swallow MALEAN with a glass of water.

If you forget to take MALEAN

MALEAN should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking your tablet(s) 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.

  • If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you use too much MALEAN

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

If you think that you have used too much MALEAN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using MALEAN?

Things you should do

  • Have your blood pressure checked when your doctor says, to make sure MALEAN is working.
  • 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 plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking MALEAN.
    Your blood pressure may drop suddenly.
  • Make sure you drink enough water during exercise and hot weather when you are taking MALEAN, especially if you sweat a lot.
    If you do not drink enough water while taking MALEAN, 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 MALEAN, 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.

Call your doctor straight away if you:

  • become pregnant while taking MALEAN
  • feel any light-headedness or dizziness after you take your first dose of MALEAN or if your dose is increased. This is especially important if you are taking MALEAN for heart failure.

Remind any doctor, dentist or pharmacist you visit that you are using MALEAN.

Things you should not do

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

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 smoking or at least cut down.
  • Weight - your doctor may suggest losing some weight to help lower your blood pressure and help lessen the amount of work your heart has to do. Some people may need a dietician's help to lose weight.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MALEAN affects you.

MALEAN 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 MALEAN before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol, dizziness or light-headedness may be worse.

Looking after your medicine

  • MALEAN tablets should be kept in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack and store them in another container they will not keep well and they may become soft and crumbly.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Heart and circulation-related:
  • light-headedness or dizziness because blood pressure is too low
Respiratory-related:
  • dry cough
Gastrointestinal-related:
  • mild stomach upsets such as feeling sick, diarrhoea, or stomach pains
Muscle/skeleton-related:
  • muscle cramps
General conditions:
  • headache
  • fatigue
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction:
  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • swelling of the hands, feet, or ankles
Skin-related:
  • pinkish, itchy swellings on the skin, also called hives or nettlerash
Heart and circulation-related:
  • chest pain, angina
  • collapse, numbness or weakness of arms or legs
Respiratory-related:
  • wheeziness due to tightness in the chest
Stop taking MALEAN, call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Serious side effects

Heart and circulation-related:
  • changes in the way your heart beats, for example, if you notice it beating faster
  • fainting
Gastrointestinal-related:
  • yellowing of the skin and eyes, also called jaundice
  • fainting
Skin-related:
  • itchy skin rash or other skin problems
  • signs of worrying or frequent infections such as fever, severe chills, sore throat or mouth ulcers
Kidney-related:
  • passing less urine than is normal for you
General conditions:
  • 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.
Tell your doctor immediately if you notice any of these serious side effects.
You may need urgent medical attention.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What MALEAN contains

Active ingredient
(main ingredient)		enalapril maleate 5, 10 or 20 mg per tablet
Other ingredients
(inactive ingredients)
  • maleic acid
  • lactose monohydrate
  • hypromellose
  • croscarmellose sodium
  • sodium stearylfumarate
Potential allergens
  • contains sugars as lactose.

Do not take this medicine if you are allergic to any of these ingredients.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

What MALEAN looks like

5 mg tablets

White to off white, round, flat-face bevelled edge tablets break line on one side and “5” debossed on the other side. AUST R 196512.

10 mg tablets

White to off white, round, flat-face bevelled edge tablets with break line on one side and “10” debossed on the other side. AUST R 196485.

20 mg tablets

White to off white, round, flat-face bevelled edge tablets with break line one side and “20” debossed on the other side. AUST R 196489.

Available in blister packs of 30.

Who distributes MALEAN

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC3121
Australia
www.arrotex.com.au

This leaflet was prepared in March 2025.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

Malean

Active ingredient

Enalapril maleate

Schedule

S4

 

1 Name of Medicine

Enalapril maleate.

2 Qualitative and Quantitative Composition

Enalapril maleate is a white or almost white crystalline powder with a molecular weight of 492.5, a melting point of about 144°C, and a pKa of 3 and 5.4. It is sparingly soluble in water, freely soluble in methanol, practically insoluble in methylene chloride. It dissolves in dilute solutions of alkali hydroxides.
Malean 5 mg tablets contain 5 mg Enalapril maleate.
Malean 10 mg tablets contain 10 mg Enalapril maleate.
Malean 20 mg tablets contain 20 mg Enalapril maleate.

List of excipients with known effect.

Contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Malean 5 mg tablets are white to off white, round, flat-face beveled edge tablets with breakline on one side and "5" embossing on the other side.
Malean 10 mg tablets are white to off white, round, flat-face beveled edge tablets with breakline on one side "10" embossing on the other side.
Malean 20 mg tablets are white to off white, round, flat-face beveled edge tablets with breakline on one side and "20" embossing on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Malean is indicated in the treatment of: all grades of essential hypertension; renovascular hypertension.

Congestive heart failure.

Malean is indicated for the treatment of all degrees of symptomatic heart failure. In such patients, it is recommended that Malean 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.

4.2 Dose and Method of Administration

Essential hypertension.

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of Malean. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with Malean 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 Malean 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 per 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 Malean alone, a diuretic may be added.
Concomitant administration of Malean 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 Malean in the treatment of accelerated or malignant hypertension. Malean, therefore, is not recommended in such situations.

Dosage in the elderly (over 65 years).

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

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). 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 next paragraph).

Congestive heart failure.

Therapy with Malean must be started under close medical supervision.
Blood pressure and renal function should be monitored closely both before and after starting treatment with Malean (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 Malean 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 Malean does not imply that hypotension will recur during chronic therapy with Malean 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 Malean in congestive heart failure, the dose should be gradually increased, depending on the patient's response, to the usual maintenance dose (10-20 mg) given in a single or divided dose. This dose titration may be performed over a 2 to 4 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 above (see Section 4.2 Dose and Method of Administration, Congestive heart failure), to the usual maintenance dose of 20 mg in two divided doses.

Dosage adjustment in renal impairment.

The usual dose of enalapril is recommended for patients with a creatinine clearance > 30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance < 30 mL/min (serum creatinine > 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. See Table 1.

4.3 Contraindications

1. History of previous hypersensitivity to Malean 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.
2. Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
3. Malean should not be administered with aliskiren in patients with diabetes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
4. Malean is contraindicated in combination with a neprilysin inhibitor (e.g. sacubitril). Do not administer Malean 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

General.

Angioedema.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. 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 1:1000 (0.3 mL 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 of angioedema.
Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk of angioedema (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients receiving concomitant ACE inhibitor and vildagliptin may be at increased risk for angioedema (see 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 or dietary salt restriction or those suffering from diarrhea or vomiting. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)). 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 angiotensin converting enzyme 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 haematologic monitoring be considered in patients with diseases known to affect bone marrow function (e.g. renal dysfunction, collagen vascular disease, etc) and/or who are taking concomitant therapy known to be associated with bone marrow depression.

Hemodialysis 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 one percent 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 percent of hypertensive patients. Risk factors for the development of hyperkalaemia may include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements and/or potassium-containing salt substitutes, or other drugs that may increase serum potassium (e.g. trimethoprim-containing products), 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 above-mentioned 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 commoner 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 angiotensin converting enzyme 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 percent 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.

See Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Paediatric use.

Enalapril has not been studied in children.

Effects on laboratory tests.

No data available.
Laboratory test findings.

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 percent of patients with essential hypertension treated with enalapril 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 percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with enalapril but are rarely of clinical importance unless another cause of anaemia coexists. In clinical trials, less than 0.1 percent 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 G6PD deficiency.

Liver function tests.

Elevations of liver 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. Risk factors for the development of hyperkalemia include renal insufficiency and diabetes mellitus. Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes, or other drugs that may increase serum potassium (e.g. trimethoprim-containing products), which may lead to significant increases in serum potassium. Therefore, if concomitant use of enalapril with potassium-sparing diuretics, potassium supplements, or potassium containing salt substitutes is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

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 which eliminate sodium, lithium clearance may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

Non-steroidal anti-inflammatory drugs 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 non-steroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, 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.

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 (RAAS) with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with a higher frequency of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g. by adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function.
Closely monitor blood pressure, renal function, and electrolytes in patients on Malean and other agents that affect the RAAS. Do not coadminister aliskiren with Malean in patients with diabetes. Avoid use of aliskiren with Malean in patients 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).

Vildagliptin.

Patients taking concomitant vildagliptin may be at increased risk for angioedema (see 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)
As with all ACE inhibitors, enalapril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with enalapril and avoided during treatment.
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.
There are no adequate and well-controlled studies of enalapril in pregnant women. Data, however, show that enalapril crosses the human placenta. Post marketing experience with all ACE inhibitors suggest 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 the 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 birth weight 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 fetus and may result in limb contractures, craniofacial deformations and hypoplastic lung development. 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 fetotoxicty of teratogenicity in rats treated with up to 200 mg/kg/day of enalapril. Fetotoxicity expressed as a decrease in average fetal weight occurred in rats given 1200 mg/kg/day of enalapril, 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 breast feeding should be discontinued.

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. (See Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Enalapril has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. Enalapril has been found to be generally well tolerated in controlled clinical trials involving 2677 patients.
The most frequent clinical adverse experiences in controlled trials were: headache (4.8 percent), dizziness (4.6 percent) and fatigue (2.8 percent). For the most part, adverse experiences were mild and transient in nature. Discontinuation of therapy was required in 6.0 percent 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 reporting adverse experiences was comparable to placebo.
Adverse experiences occurring in greater than one percent of patients treated with enalapril in controlled clinical trials are shown in Table 2.
Clinical adverse experiences occurring since the drug was marketed or in 0.5 to 1.0 percent of patients in the controlled trials are listed below and, within each category, are in order of decreasing severity.

Cardiovascular.

Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Section 4.4 Special Warnings and Precautions for Use, Hypotension), syncope, orthostatic hypotension, palpitations, chest pain, rhythm disturbances, angina pectoris, Raynaud's phenomenon.

Endocrine.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Gastrointestinal system.

Ileus, pancreatitis, hepatic failure, hepatitis either hepatocellular or cholestatic jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.

Metabolic.

Cases of hypoglycaemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Nervous system/psychiatric.

Depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, dream abnormality.

Renal.

Renal failure, oliguria, renal dysfunction. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration.)

Respiratory.

Bronchospasm/asthma, pulmonary infiltrates, dyspnoea, rhinorrhoea, sore throat and hoarseness.

Skin.

Diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, pruritus, urticaria, alopecia.

Other.

Vasculitis, muscle cramps, hyperhidrosis, impotence, pruritus, asthenia, photosensitivity, alopecia, flushing, taste alteration, tinnitus, glossitis, blurred vision, urticaria.
A symptom complex has been reported which may include fever, serositis, myalgia and arthralgia/arthritis; an elevated ESR, a positive ANA, eosinophilia and leukocytosis. 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 (0.2 percent). 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 effect) was reported in 2.3 percent of patients following the initial dose of enalapril or during extended therapy. In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent 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 https://www.tga.gov.au/reporting-problems.

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 fifteen 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 Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Enalapril maleate is a pro-drug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. The liver appears to be the main site for this conversion.
Administration of enalapril 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 2 to 4 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 4 to 6 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 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 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 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.

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 which 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.

In a multicentre, placebo-controlled clinical trial (SOLVD), 2,569 patients with all degrees of symptomatic heart failure and ejection fraction ≤ 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 ≤ 35% and no history of symptomatic heart failure were randomised to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 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 2-4) and also left ventricular ejection fractions of less than 35%, enalapril has been shown to improve survival and reduce hospitalisations for unstable angina pectoris.

5.2 Pharmacokinetic Properties

Absorption and distribution.

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%. Protein binding is approximately 50%. The absorption of oral enalapril 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.

Metabolism.

Following absorption, oral enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril.

Excretion.

Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. Except for conversion to enalaprilat, there is no evidence for significant metabolism 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. The plasma concentration time profile of enalaprilat was complex with several exponentials including a very prolonged terminal phase (t1/2 > 30 hr). The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril is 11 hours.

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 an 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 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Malean Tablets (5 mg, 10 mg and 20 mg) contain the following excipients; maleic acid, lactose monohydrate, hypromellose, croscarmellose sodium, sodium stearylfumarate.

6.2 Incompatibilities

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

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

Malean 5 mg tablets are packaged in blister packs of 30.
Malean 10 mg tablets are packaged in blister packs of 30.
Malean 20 mg tablets are packaged in blister packs of 30.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Enalapril (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Following oral administration, enalapril is rapidly absorbed and then hydrolysed to enalaprilat, which is a specific, long-acting, angiotensin converting enzyme inhibitor.
Malean tablets contain the maleate salt of enalapril, the ethyl ester of the parent diacid, enalaprilat. Enalapril maleate is chemically described as (2S)-1-[(2S)-2-[[(1S)-1- (Ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]pyrrolidine-2-carboxylic acid, (Z)-2- butenedioate salt (1:1). It lacks a sulphydryl group. Its empirical formula is C20H28N2O5.C4H4O4. It has a molecular weight of 492.53.

Chemical structure.


CAS number.

CAS reference number [76095-16-4].

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes