Consumer medicine information

Auspril Tablets

Enalapril maleate

BRAND INFORMATION

Brand name

Auspril Tablets

Active ingredient

Enalapril maleate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Auspril Tablets.

What is in this leaflet

This leaflet answers some common questions about AUSPRIL tablets.

It does not contain all the available information about this medicine.

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 AUSPRIL against the benefits he/she expects it will have for you.

Ask your doctor or pharmacist if you have any concerns about taking this medicine.

Keep this leaflet with the medicine.

You may need to read it again.

What is AUSPRIL

The name of your medicine is AUSPRIL.

The active ingredient is called enalapril maleate.

Enalapril maleate belongs to a group of medicines called the Angiotensin Converting Enzyme (ACE) inhibitors, which are used for the treatment of hypertension and heart failure.

AUSPRIL is available as 5 mg, 10 mg and 20 mg tablets.

What AUSPRIL is used for

AUSPRIL lowers high blood pressure, a condition which doctors call "hypertension". It is also used to treat heart failure.

Hypertension (high blood pressure) is when your blood pressure stays at a high level than what is needed, even when you may be calm and relaxed.

There are usually no symptoms of hypertension. The only way you will know if you have the condition is to have your blood pressure checked by your doctor on a regular basis.

If high blood pressure is not treated, it can lead to serious health problems such as stroke, heart disease and kidney failure.

AUSPRIL will help to lower your blood pressure.

Heart failure is the condition where the heart muscle is unable to pump strongly enough blood to different tissues throughout the body.

Heart failure may start with no symptoms, but as the condition progresses, patients may feel short of breath or may get tired during activities such as walking. Some patients may wake up at night with a shortness of breath. In different parts of the body, fluid may also collect such as in the ankles and feet, causing them to swell.

AUSPRIL will help to treat heart failure, whether you have any symptoms or not.

In many patients with heart failure who have had symptoms, AUSPRIL may slow the progression of heart failure and reduce the need to go to hospital due to the heart failure. AUSPRIL may also help some of these patients live longer.

In many patients with heart failure who have had no symptoms, AUSPRIL may help to reduce the weakening heart muscle. The medicine 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 to stay at hospital due to heart failure.

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

When used to treat heart failure, AUSPRIL is usually used with other medicines called diuretics or fluid tablets. These medicines help the kidney to eliminate any excess fluids from the body.

How it works

One of the ways AUSPRIL helps lower blood pressure and treats heart failure is that it widens the blood vessels. This means that blood is able to pass more easily through the blood vessels, limiting its efforts in pumping blood around the body. This means that the heart is able to cope better when extra demands are placed on the heart.

Use AUSPRIL only as directed and consult a health care professional if pain or symptoms persist.

Your doctor may have prescribed AUSPRIL for another condition.

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

If you have any concerns, you should discuss this with your doctor.

AUSPRIL tablets are only available with a doctor's prescription.

This medicine is not addictive.

Before you take AUSPRIL

When you must not take it

Do not take AUSPRIL if you are allergic to:

  • Enalapril maleate or any other 'ACE inhibitors' used for high blood pressure or heart failure such as 'Amprace' (Another brand of enalapril maleate).
  • Any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction to AUSPRIL may include skin rash, itchiness, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain.

You must tell your doctor if:

  • You are pregnant or intend to become pregnant.
    AUSPRIL is rated in Australia as a Category D drug for the use in pregnancy. It is not recommended for use during pregnancy.
    If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
    When taken during the second and third trimesters, ACE inhibitors cause a range of abnormalities including renal dysfunction and oligohydramnios. These can be associated with fetal death in utero.
  • You are breast-feeding or intend to breast-feed.
    AUSPRIL is distributed in breast milk so it is not recommended for nursing mothers.
  • You are also taking an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic.

Do not take AUSPRIL if you have ever experienced excessive swelling of the face, lips, mouth, tongue, throat, hands or feet, for no apparent reason.

Taking AUSPRIL tablets could cause this problem to happen again.

Do not take AUSPRIL after the expiry date (EXP.) printed on the pack.

If you take this medicine after the expiry date has passed, it may have no effect at all, or worse, there may be an entirely unexpected effect.

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

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

Before you start to take it

You must tell your doctor if:

  1. You are allergic to any other medicines or any foods, dyes or preservatives.
  2. You have or have had any other medical conditions/ health problems, especially the following:
  • Kidney disease, or are undergoing dialysis
  • Heart problems
  • Diabetes
  • You are following a very low salt diet

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

Taking other medicines

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

Some of these medicines may interfere with AUSPRIL.

These include:

  • Cardiovascular drugs, used to treat heart problems
  • Diuretic tablets - also called fluid or water tablets
  • Lithium, a medicine used to treat mood swings and some types of depression
  • Potassium tablets
  • Potassium-containing salt substitutes
  • Non-steroidal anti-inflammatory medicines used to relieve pain, swelling, and other symptoms of inflammation

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

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

In the future, before you start to take any other medicine, tell your doctor or pharmacist that you are taking AUSPRIL.

How to take AUSPRIL

Follow your doctor's instructions carefully, as they may differ from the information contained in this leaflet.

If you do not understand the instructions in this leaflet, 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 upon your condition and whether you are taking other medicines.

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.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

How to take it

Swallow AUSPRIL tablets with a glass of water or other liquid.

It does not matter if you take the tablets before or after food.

When to take it

Take your tablets at about the same time each day. This will have the best effect. It will also help you remember when to take them.

How long to take it

AUSPRIL helps control your high blood pressure and helps improve your heart failure, but it does not cure it. THEREFORE, your tablets must be taken every day.

Continue taking AUSPRIL tablets as long as your doctor recommends it.

If you forget to take it

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

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

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

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

If you are unsure about whether to take your next dose, speak to your doctor or pharmacist.

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

If you take too much (Overdose) 

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

If you take too much AUSPRIL, you may have the following symptoms: light-headedness or dizziness or faintness.

While you are using it

Things you must do

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

Use your medicine exactly as directed or as your doctor has prescribed.

Tell your doctor if you feel it is not helping your condition.

Have your blood pressure checked when your doctor tells you to, to make sure AUSPRIL is working for you.

Tell your doctor immediately if you are feeling any light-headedness, dizziness, or faintness while you are taking this medicine.

Get up slowly when getting out of bed or standing up if you feel light-headed, dizzy or faint.

Tell your doctor immediately if you become pregnant while you are taking AUSPRIL.

Tell your doctor and pharmacist that you are taking AUSPRIL, if you are about to be started on any new medication.

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

Drink enough water during exercise and in hot weather when you are taking AUSPRIL, especially if you sweat a lot.

If you start to have excessive vomiting and/or diarrhea occurring while you are taking this medicine, tell your doctor immediately.

Visit your doctor regularly. Your doctor needs to check your progress and see whether you need to stop taking AUSPRIL.

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

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

Things you must not do

Do not take any other medicines while you are taking AUSPRIL without first telling your doctor.

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

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

AUSPRIL 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 this medicine 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 become worse.

Below are some suggested self-help measures that may help improve your condition.

Talk to your doctor or pharmacist about these measures and for any more information you may need.

  • 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 a good exercise. Before you start any exercise, ask your doctor for the most suitable program for you.
  • Salt - your doctor may advise you to monitor 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 reduce your intake.
  • Weight - your doctor may suggest you to lose some weight, so that you are able to help lower your blood pressure. 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 AUSPRIL.

It helps most people with high blood pressure and heart failure, but it may have unwanted side effects in some people.

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.

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

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

  • light-headedness or dizziness due to low blood pressure
  • depression, dream abnormality or hallucinations
  • headache
  • fatigue
  • dry cough
  • mild stomach upsets such as feeling sick, diarrhoea, or stomach pains
  • muscle cramps

These side effects are usually mild, but may become serious.

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

  • changes in the way your heart beats, for example, if you notice it is 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

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

Serious side effects are rare.

If any of the following occur, stop taking AUSPRIL and tell your doctor immediately or go to casualty 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 swellings 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.

All of these side effects are rare.

Some people may get other side effects when taking AUSPRIL.

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

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using it

Storage

Keep your tablets in the blister pack until it is time to take them.

Keep AUSPRIL in a cool dry place where the temperature stays below 25°C and protect it from light and moisture.

Keep it where young children cannot reach it.

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

Do not store AUSPRIL or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on windowsills.

Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

AUSPRIL tablets (oral) are available in three different strengths and each of them has a different appearance:

AUSPRIL 5 mg tablets:
White to off-white barrel-shaped tablet, embossed with EL 'bisect' 5 on one side and the Arrow logo, ">" on the other side.

AUSPRIL 10 mg tablets:
Salmon barrel-shaped tablet, embossed with EL 'bisect' 10 on one side and the Arrow logo, ">" on the other side.

AUSPRIL 20 mg tablets:
Peach barrel-shaped tablet, embossed with EL 'bisect' 20 on one side and the Arrow logo, ">" on the other side.

Ingredients

Active ingredient:

  • Enalapril maleate

Inactive ingredients: AUSPRIL 5 mg, 10 mg and 20 mg tablets contain:

  • lactose
  • sodium bicarbonate
  • starch-maize
  • starch-pregelatinised maize
  • magnesium stearate
  • croscarmellose sodium
  • iron oxide red (10 mg and 20 mg)
  • iron oxide yellow (10 mg)

AUSPRIL does NOT contain gluten, sucrose, tartrazine or any other azo dyes.

BRAND INFORMATION

Brand name

Auspril Tablets

Active ingredient

Enalapril maleate

Schedule

S4

 

Name of the medicine

Enalapril maleate.

Excipients

Sodium bicarbonate, lactose, maize starch, pregelatinised maize starch, magnesium stearate. Auspril 10 and 20 mg tablets also contain croscarmellose sodium, iron oxide red CI77491 and iron oxide yellow.

Description

Chemical name: (S)-1-[N-[1-(ethoxycarbonyl) -3-phenylpropyl]-L-alanyl] -L-proline, (Z)-2-butenedioate salt (1:1). It lacks a sulfhydryl group. Molecular formula: C20H28N2O5.C4H4O4. MW: 492.53. CAS: 76095-16-4. Enalapril maleate is a white to off white crystalline powder. It is sparingly soluble in water, soluble in ethanol and freely soluble in methanol and dimethylformamide. Enalapril maleate is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Enalapril maleate is the ethyl ester of the parent diacid, enalaprilat.

Pharmacology

Actions.

How enalapril, or converting enzyme inhibitors in general, lower blood pressure is not entirely clear. The mechanism most favoured is the 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.
Enalapril maleate is a prodrug 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.

Pharmacokinetics

Absorption.

Following oral administration, enalapril is rapidly absorbed and then hydrolysed to enalaprilat, which is a specific, long acting, ACE inhibitor.

Metabolism and excretion.

Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of oral enalapril is approximately 60%. The oral bioavailability of enalaprilat is approximately 40%. Protein binding is approximately 50%. There is limited information on the distribution of enalapril into the central nervous system (CNS), however, it appears to poorly cross the blood brain barrier. Enalaprilat appears to not distribute into the CNS. Enalapril maleate crosses the placenta. Enalapril and enalaprilat are distributed into milk in trace amounts.
Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent ACE inhibitor. The onset of action of enalapril is one hour. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of the drug. 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 the 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 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 (t½ > 30 hours). The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril is 11 hours. However, its half-life is increased in renal failure. 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.

Pharmacodynamics.

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 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 the 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 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.
In a multicentre, placebo controlled clinical trial (SOLVD), 2569 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 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.

Indications

Hypertension.

All grades of essential hypertension. Renovascular hypertension.

Congestive heart failure.

All degrees of symptomatic heart failure. In such patients, it is recommended that Auspril 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.

Contraindications

History of previous hypersensitivity to Auspril or to any component of the formulation.
History of angioneurotic oedema relating to previous treatment with an ACE inhibitor.
Hereditary or idiopathic angioedema.
Pregnancy (see Precautions, Use in pregnancy).

Precautions

Angioedema.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including Auspril. In such cases, Auspril should be promptly discontinued and the patient carefully observed until the swelling disappears. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal. 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 to 0.5 mL) and/or measures to ensure a patent airway should be promptly administered. (See Adverse 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 nonblacks.

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 Interactions with Other Medicines and Adverse Effects.)
In patients with heart failure, with or without 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 myocardial infarction or cerebrovascular accident.
If hypotension occurs the patient should be placed in a 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.

Impaired renal function.

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 Auspril, 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 Auspril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Auspril and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function. (See Dosage and 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.

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, diabetes mellitus and the concomitant use of potassium sparing diuretics, potassium supplements and/or potassium containing salt substitutes, which should be used cautiously, if at all, with Auspril. (See Interactions with Other Medicines.)

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.

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 nonproductive, 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.

Carcinogenicity and mutagenicity.

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 and 180 mg/kg/day, respectively, and showed no evidence of carcinogenicity. 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 Escherichia 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. There were no adverse effects on reproductive performance in male and female rats treated with 10 to 90 mg/kg/day of enalapril.

Use in pregnancy.

(Category D)
As with all ACE inhibitors, Auspril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Auspril and avoided during the 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.
A historical cohort study in over 29,000 infants born to nondiabetic 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.
When taken during the second and third trimesters, ACE inhibitors cause a range of abnormalities including renal dysfunction and oligohydramnios. These can be associated with foetal death in utero.
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 enalapril up to 200 mg/kg/day. 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.

Use in lactation.

It is not known if Auspril is secreted in human milk. However, Auspril 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.

Use in children.

Auspril has not been studied in children.

Interactions

Combination use of angiotensin converting enzyme 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 (nonsteroidal anti-inflammatory drug (NSAID) or cyclooxygenase (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.

Hypotensive 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 Precautions and Dosage and Administration.)

Agents causing renin release.

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

Other cardiovascular agents.

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

Agents increasing serum potassium.

Auspril may attenuate potassium loss caused by thiazide type diuretics. Potassium sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Sympathomimetics.

Concurrent use of these agents may cause a reduction in the effects of the ACE inhibitors. Therefore, the patient must be carefully monitored so that the desired effect is being achieved.

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.

Bone marrow depressants.

Concurrent use with the ACE inhibitor may increase the risk of fatal neutropenia and agranulocytosis developing.

Nonsteroidal anti-inflammatory drugs.

Concurrent use may lead to the reduction of antihypertensive effects of ACE inhibitors. In some patients with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function. These effects are usually reversible.

Adverse Effects

Enalapril maleate has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. Enalapril maleate 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%), 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% 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.
Clinical adverse experiences occurring since the drug was marketed or in 0.5 to 1% of patients in the controlled trials are listed below.

Cardiovascular effects.

Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Precautions), syncope, orthostatic hypotension, palpitations, chest pain, rhythm disturbances, angina pectoris, Raynaud's phenomenon, atrial fibrillation.

Gastrointestinal effects.

Ileus, pancreatitis, hepatitis or cholestatic jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.

Nervous system/ psychiatric effects.

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

Renal effects.

Renal failure, oliguria, renal dysfunction (see Precautions and Dosage and Administration).

Respiratory effects.

Bronchospasm, asthma, dyspnoea, rhinorrhoea, sore throat, hoarseness, nasal congestion, upper respiratory infection, pulmonary infiltrates.

Other effects.

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 erythrocyte sedimentation rate (ESR), eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur. These symptoms have disappeared after discontinuation of therapy. Dermatological and hypersensitivity reactions such as exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster and erythema multiforme have been rarely reported in patients receiving enalapril 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 maleate should be discontinued and appropriate therapy instituted immediately. (See Precautions.)

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 Precautions.)

Clinical laboratory test findings.

Serum electrolytes.

Hyperkalaemia (see Precautions) and 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. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see Precautions).

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 and 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 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 liver enzymes and/or serum bilirubin have occurred.

Dosage and Administration

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of Auspril. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with Auspril to reduce the likelihood of hypotension. (See Precautions.) If the patient's blood pressure is not controlled with Auspril alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued, an initial dose of 2.5 mg should be used under medical supervision for at least one hour to determine whether excess hypotension will occur. (See Precautions and Interactions with Other Medicines.)
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 Auspril alone, a diuretic may be added.
Concomitant administration of Auspril with potassium supplements, potassium salt substitutes or potassium sparing diuretics may lead to increases of serum potassium (see Precautions).
To date, there is insufficient experience with Auspril in the treatment of accelerated or malignant hypertension. Auspril, therefore, is not recommended in such situations.

Dosage in the elderly (> 65 years).

The starting dose should be 2.5 mg. Some elderly patients may be more responsive to Auspril 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). 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 Auspril must be started under close medical supervision.
Blood pressure and renal function should be monitored closely both before and after starting treatment with Auspril (see Precautions) 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 Auspril 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 Auspril does not imply that hypotension will recur during chronic therapy with Auspril 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 Auspril 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 above (see 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/minute (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≤ 30 mL/minute (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.

Normal renal function.

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

Mild impairment.

Creatinine clearance ≤ 80 and > 30 mL/minute, the initial dose is 5 mg/day.

Moderate to severe impairment.

Creatinine clearance ≤ 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.

Overdosage

Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension which can be treated, if necessary, by intravenous infusion of normal saline solution. Renal dysfunction, including acute renal failure; hyperkalaemia; and hyponatremia may also occur. 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. Treatment of enalapril overdosage is supportive and symptomatic. For acute oral overdosage, gastric lavage or the administration of activated charcoal may be performed to prevent further gastrointestinal absorption of the drug. Enalaprilat may be removed from the general circulation by haemodialysis.

Presentation

Tablets (barrel shaped, embossed with EL bisect tablet strength on one side and Arrow logo (>) on reverse), 5 mg (white to off white, marked 5), 10 mg (salmon, marked 10), 20 mg (peach, marked 20): 30’s (blister pack).

Storage

Store below 25°C. Protect from moisture.

Poison Schedule

S4.