Consumer medicine information

Prilace

Ramipril

BRAND INFORMATION

Brand name

Prilace

Active ingredient

Ramipril

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Prilace.

What is in this leaflet

This leaflet answers some common questions about PRILACE.

It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking PRILACE against the benefits they expect it will have for you.

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

Keep this leaflet with your medicine. You may need to read it again.

What PRILACE is used for

PRILACE contains ramipril, which belongs to a group of medicines called angiotensin-converting enzyme (ACE) inhibitors.

PRILACE is used to treat:

  • high blood pressure (hypertension)
  • some heart conditions such as heart failure after a heart attack
  • kidney problems in some patients.

PRILACE is also used to reduce the risk of cardiovascular problems and complications in patients aged 55 years or more with heart or blood vessel disease, or diabetes.

Hypertension
PRILACE is used to lower high blood pressure (hypertension). Everyone has blood pressure. This pressure helps circulating your blood around your body. Your blood pressure is different at different times of the day and can be affected by how busy or worried you are. You would have hypertension 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 you have hypertension is to have your blood pressure checked on a regular basis. If hypertension is not treated, it can lead to serious health problems, including stroke, heart disease and kidney failure.

Heart failure after a heart attack
PRILACE may be used after a heart attack. A heart attack occurs when one of the major blood vessels supplying blood to your heart becomes blocked. This means that your heart muscle cannot receive the oxygen it needs and becomes damaged. This may lead to further problems, such as heart failure, irregular heart rhythms and blood clots.

Heart failure means that the heart muscle is weak and 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. 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 at night with difficulty breathing. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet.

Kidney problems
PRILACE may be used to treat some kidney problems. Some conditions, such as diabetes and hypertension, can lead to kidney problems. These problems develop slowly over several years. Good control of your blood sugar and blood pressure are important in keeping your kidneys healthy, but may not always prevent kidney damage from occurring.

Prevention of cardiovascular problems and complications PRILACE may be used to reduce the risk of some cardiovascular problems and complications in patients aged 55 or more who have:

  • coronary artery disease (heart disease caused by poor blood flow in the blood vessels of the heart)
  • peripheral vascular disease (poor circulation in the hands or feet)
  • stroke.

PRILACE may also be used to reduce the risk of cardiovascular problems and complications in diabetic patients aged 55 years or more who have:

  • high blood pressure
  • high cholesterol levels
  • kidney problems
  • previous blood vessel disease
  • and are current smokers.

How PRILACE works

PRILACE works by widening the blood vessels, which reduces the pressure in the vessels, making it easier for your heart to pump blood around your body. This helps increasing the supply of oxygen to your heart, so that when you place extra demands on your heart, such as during exercise, your heart may cope better and you may not get short of breath as easily.

By increasing the supply of oxygen to your heart, your heart does not have to work as hard and it is under less stress, which may reduce the risk of further damage occurring to it following a heart attack.

PRILACE also improves blood flow to the small blood vessels found in the kidneys, in which helps the kidneys to work more efficiently. This in turn can help to slow down the progression of kidney damage that might result from having diabetes or high blood pressure.

Ask your doctor if you have any questions about why PRILACE has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

Before you take it

When you must not take it

Do not take PRILACE if you are allergic to ramipril, or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include skin rash, itching, difficulty breathing, swelling of the face, lips or tongues, abdominal pain, muscle or joint pain.

Do not take PRILACE if you have previously taken any other ACE inhibitor medicines that caused your face, lips, tongue or throat to swell, 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 PRILACE.

Do not take PRILACE if you or your family have a history of swelling of the face, lips, tongue, throat, intestines, hands or feet for no apparent reason.

Do not take PRILACE if you have a kidney problem known as renal artery stenosis.

Do not take PRILACE if you have problems or conditions affecting the flow of blood in and out of your heart such as aortic or valvular stenosis.

Do not take PRILACE if you are pregnant or intend to become pregnant. PRILACE may affect your developing baby if you take it during pregnancy.

Do not take PRILACE if you are breastfeeding. PRILACE may pass into breast milk and affect your breast-fed baby.

Do not take PRILACE if you undergo dialysis using certain high-flux membranes.

Do not take PRILACE if you have low blood pressure.

Do not take PRILACE if the expiry date (Exp.) printed on the pack has passed.

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

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

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have or have had any other medical conditions including:

  • kidney problems, or having dialysis (note that your doctor may give you PRILACE because of your kidney problems)
  • liver problems
  • heart problems (note that your doctor may give you PRILACE because of your heart problems)
  • diabetes (note that your doctor may give you PRILACE because of your diabetic problem)
  • low blood pressure, which you may notice as dizziness or light-headedness
  • low white blood cell counts
  • high level of potassium in your blood
  • systemic lupus erythematosus, scleroderma or other auto-immune conditions.

Tell you doctor if you have a family history of swelling of the face, lips, tongue, throat, intestines, hands or feet.

Tell your doctor if you:

  • follow a very low or very high salt diet
  • are dehydrated, or have had a recent bout of vomiting or diarrhoea
  • are about to have surgery or a general anaesthetic
  • plan to become pregnant or breastfeed.

If you have not told your doctor about any of the above, tell them before you start taking PRILACE.

Taking other medicines

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

Some medicines may be affected by PRILACE, or may affect how well it works. These include:

  • other medicines used to treat high blood pressure
  • diuretics, also known as fluid or water tablets
  • anti-inflammatory drugs (e.g. non-steroidal anti-inflammatory drugs, COX-2 inhibitors) used to relieve pain, inflammation, swelling and other symptoms including arthritis
  • potassium supplements or potassium-containing salt substitutes
  • lithium, a medicine used to treat mood swings and some types of depression
  • insulin and tablets used to treat diabetes
  • heparin
  • general anaesthetic
  • medicines that may affect blood cells, such as allopurinol, procainamide, corticosteroids, immunosuppressants, or medicines used to treat cancer
  • medicines for appetite control, asthma (high doses of corticosteroids), colds, coughs or sinus problems, particularly when PRILACE is used to control high blood pressure.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor can tell you what to do if you are taking any of these medicines.

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

How to take it

How much to take

Your doctor will decide how many tablets or capsules you will need to take each day. This depends on the condition being treated and whether or not you are taking any other medicines. Some patients may need a lower starting dose.

The usual dose of PRILACE is:

  • for high blood pressure, 2.5 mg to 10 mg per day
  • for heart failure, 5 mg to 10 mg per day
  • for kidney problems, 1.25 mg to 5 mg per day
  • for cardiovascular risk, 2.5 mg to 10 mg per day.

Depending on your response, your doctor may adjust the dose.

If two tablets are prescribed, your doctor may want you to take them either together or at different times. This will depend on the condition being treated and how you respond to PRILACE.

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

How to take it

PRILACE should be swallowed with plenty of fluid. It can be taken before or after meals.

PRILACE capsules should be swallowed whole.

When to take it

Take PRILACE at about the same time of each day. Taking your tablets or capsules at about the same time of each day will have the best effect. It will also help you to remember when to take it.

How long to take it

Continue taking PRILACE for as long as your doctor tells you. PRILACE helps control your condition but does not cure it. Thus, you must take it every day.

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 the missed dose as soon as you remember and then go back to taking your tablets or capsules as you would normally.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much PRILACE.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much PRILACE, you may feel dizzy, light-headed, weak or you may faint. You may also experience slow heartbeat.

While you are taking it

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are taking PRILACE.

Before starting any new medicine, tell your doctor or pharmacist that you are taking PRILACE.

Tell your doctor if you feel light-headed or dizzy after taking your first dose of PRILACE or when your dose is increased.

Tell your doctor immediately if you become pregnant or intend to become pregnant while taking PRILACE.

Make sure you drink enough water during exercise and in hot weather when you are taking PRILACE, especially if you sweat a lot. If you do not drink enough water while taking PRILACE on hot days or during exercising, you may feel dizzy, light-headed or sick. This is because your blood pressure has dropped too much.

If you continue to feel unwell, tell your doctor.

Tell your doctor if you have excess vomiting or diarrhoea while taking PRILACE. You may lose too much water and salt, and your blood pressure may drop too much.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking PRILACE. Your blood pressure may drop suddenly during anaesthesia.

If you are about to have any blood tests, tell your doctor that you are taking PRILACE. PRILACE may interfere with the results of some tests.

Go to your doctor regularly for a check-up. Have your blood pressure checked regularly either by your doctor or as instructed. This is to make sure PRILACE is working for your conditions. Also, your doctor may occasionally do a blood test to check your potassium level and see how your kidneys are working.

Things you must not do

Do not stop taking PRILACE or lower or increase the dosage, without checking with your doctor.

Do not use PRILACE to treat any other conditions unless your doctor tells you to.

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

Things to be careful of

If you feel light-headed or dizzy when getting out of bed or standing up, get up slowly. 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 continues or gets worse, talk to your doctor.

Be careful driving or operating machinery until you know how PRILACE affects you. This medicine may cause dizziness, light-headedness, tiredness or drowsiness in some people. Make sure you know how you react to PRILACE before you drive, operate machinery or do anything that could be dangerous if you are dizzy or light-headed. If these occur, do not drive or operate machinery.

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

Things that may help 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.
  • Smoking - your doctor may advise you to stop smoking or at least cut down.
  • Exercise - regular exercise helps reduce blood pressure and helps get the heart fitter, but it is important not to overdo it. Walking is a good exercise, but try to find a route that is reasonably flat. Before starting any exercise, ask your doctor for a program that best suits you.
  • Weight - your doctor may suggest you to lose some weight, so to help lower your blood pressure and lessen the amount of work your heart has to do. Some people may need a dietician’s help to lose weight.
  • Diet - eat a healthy low-fat diet that includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also, eat less fat and sugar.
  • Salt - your doctor may advise you to watch the amount of salt in your diet. To reduce salt intake, you can avoid or minimise using salt in cooking or at the table.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PRILACE. Like all medicines, PRILACE may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

  • feeling dizzy, light-headed, faint
  • dry cough
  • headache
  • nausea (feeling sick), vomiting
  • stomach pain
  • diarrhoea
  • unusual tiredness, weakness
  • ringing or buzzing in the ears
  • forgetfulness
  • confusion.

These side effects are usually mild.

Tell your doctor as soon as possible if you notice any of the following:

  • disturbed vision
  • symptoms of sunburn (such as redness, itching, swelling, blistering), which may occur more quickly than normal
  • itchy or raised skin rash, hives or nettlerash
  • yellowing of the skin and/or eyes
  • fast or irregular heartbeat
  • shortness of breath or tightness in the chest
  • severe upper stomach pain, often with nausea and vomiting
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • passing little or no urine, or more urine than is normal for you
  • signs of anaemia such as tiredness, being short of breath and looking pale
  • numbness, tingling and colour change (white, blue then red) in the fingers or toes when exposed to the cold
  • bleeding or bruising more easily than normal.

These side effects are rare but serious. You may need medical attention.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • fainting within a few hours of taking a dose
  • chest pain
  • severe dizziness and confusion with visual disturbances and speech problems
  • swelling of the face, lips, mouth, tongue or throat, which may cause difficulty in swallowing or breathing
  • pink or red itchy spots on the skin, which may blister and progress to form raised, red, pale-centred marks
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals.

These are very serious side effects and require immediate attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

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

After taking it

Storage

Keep PRILACE where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep PRILACE in the pack until it is time to take them. If you take the medicine out of the pack, it may not keep as well.

Keep PRILACE in a cool dry place, protected from light, where the temperature stays below 25°C.

Do not store PRILACE or any other medicines in the bathroom or near a sink. Do not leave PRILACE in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking PRILACE, or the tablets or capsules have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

PRILACE is available in four strengths:

  • 1.25 mg tablet: white to off-white, oval-shaped tablet marked “RP 1” on one side
  • 2.5 mg tablet: white to off-white, oval-shaped tablet marked “RP 2” on one side and scoreline on other side
  • 5 mg tablet: white to off-white, oval-shaped tablet marked “RP 5” on one side and scoreline on other side
  • 10 mg capsule: white and blue opaque capsules, with “RP 10” printed in black.

PRILACE is available in blister packs of 30 tablets or capsules.

Ingredients

PRILACE tablets contain either 1.25 mg, 2.5 mg or 5 mg of the active ingredient ramipril. The tablets also contain:

  • sodium bicarbonate
  • calcium sulfate
  • pregelatinised maize starch
  • sodium stearylfumarate.

PRILACE capsules contain 10 mg of the active ingredient ramipril. The capsules also contain pregelatinised maize starch. The capsule shells are size#4 Hard Gelatin Capsules White Op/ Blue Op with black printing ink.

PRILACE tablets and capsules do not contain gluten, sucrose, tartrazine or any azo dyes.

PRILACE capsules may contain traces of sulfites.

Sponsor

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

www.arrotex.com.au

Australian registration numbers:

PRILACE 1.25 mg: AUST R 121854

PRILACE 2.5 mg: AUST R 121855

PRILACE 5 mg: AUST R 121856

PRILACE 10 mg: AUST R 133085.

This leaflet was revised in December 2022.

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Prilace

Active ingredient

Ramipril

Schedule

S4

 

1 Name of Medicine

Ramipril.

2 Qualitative and Quantitative Composition

Prilace tablets come in four strengths and contain 1.25 mg, 2.5 mg, 5 mg and 10 mg* of ramipril.
Prilace capsules contain 10 mg of ramipril.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Prilace 1.25 mg tablets are white to off-white, oval-shaped tablet marked "RP 1" on one side.
Prilace 2.5 mg tablets are white to off-white, oval-shaped tablet marked "RP 2" on one side and scoreline on other side.
Prilace 5 mg tablets are white to off-white, oval-shaped tablet marked "RP 5" on one side and scoreline on other side.
Prilace 10 mg tablets are white to off-white, oval-shaped tablet marked "RP 10" on one side and scoreline on other side.
Prilace 10 mg capsules are white and blue opaque capsule with "RP 10" printed in black.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypertension. Data are currently not available to support the use of ramipril in renovascular hypertension.
Post-myocardial infarction heart failure.
Prevention of progressive renal failure in patients with persistent proteinuria in excess of 1 g/day.
Reducing the risk of myocardial infarction, stroke, cardiovascular death or the need for revascularisation procedures in patients 55 years of age or more who have clinical evidence of coronary artery disease, stroke or peripheral vascular disease.
Reducing the risk of myocardial infarction, stroke, cardiovascular death or revascularisation procedures in diabetic patients 55 years or more with one or more of the following risk factors: systolic blood pressure > 160 mmHg or diastolic blood pressure > 90 mmHg (or on antihypertensive treatment); total cholesterol > 5.2 mmol/L or HDL cholesterol < 0.9 mmol/L; current smoker; known microalbuminuria; any evidence of previous vascular disease.

4.2 Dose and Method of Administration

Prilace tablets and capsules should be swallowed with a generous amount of fluid, with or without food. Prilace capsules should be swallowed whole.

Hypertension.

The recommended initial dosage for patients not receiving a diuretic is Prilace 2.5 mg once a day. Depending upon the patient's response, the dosage may then be increased at intervals of two to three weeks, first to 5 mg and then to a maximum of 10 mg once daily. If blood pressure is not controlled with Prilace alone, a diuretic can be added (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Potassium supplements and potassium sparing diuretics).
Occasionally, in patients already taking diuretics, an undesirable large drop in blood pressure may occur after the first dose of Prilace. If possible, therefore, treatment with the diuretic should be discontinued two to three days before starting treatment with Prilace. If this is not possible, initial treatment with Prilace should start at a dose of 1.25 mg once daily and then be adjusted to the patient's needs.
An initial dose of 1.25 mg should also be considered in patients in whom fluid or salt depletion has not been completely corrected or in patients for whom a hypotensive reaction would constitute a particular risk (e.g. with relevant stenosis of coronary vessels or of those supplying the brain).

Postmyocardial infarction heart failure.

The recommended initial dose is Prilace 5 mg daily, divided into two doses of 2.5 mg each, one in the morning and one in the evening. If the patient does not tolerate this initial dosage, it is recommended that 1.25 mg be given twice daily for two days. In either event, depending on the patient's response, the dose may then be increased. It is recommended that the dose, if increased, be doubled at intervals of one to three days. The maximum permitted daily dose is ramipril 10 mg to be given in divided doses. Treatment should be started in hospital when the patient is haemodynamically stable, preferably between two and ten days after acute myocardial infarction.
Treatment should be reviewed after 15 months with the consideration of withdrawing ACE inhibitor treatment from patients who are haemodynamically stable with no symptoms or signs of heart failure.
Sufficient experience is still lacking in the treatment of patients with severe heart failure (NYHA class IV) immediately after myocardial infarction.

Progressive renal failure in patients with persistent proteinuria in excess of 1 g/day.

The recommended initial dose is Prilace 1.25 mg once daily. This should be doubled at intervals of two to three weeks, depending on how the drug is tolerated. There are no efficacy data regarding doses above 5 mg/day in patients with nephropathy.
In hypertensive patients, a target diastolic blood pressure of < 90 mmHg should be pursued.
In patients pretreated with a diuretic, consideration must be given to discontinuing the diuretic for at least two to three days or longer (depending on the duration of action) or at least consideration should be given to reducing the dose before initiating Prilace.

Patients at increased cardiovascular risk.

The recommended initial dose is Prilace 2.5 mg once daily. Depending on the tolerability, the dose should be doubled after one week of treatment and, after three weeks, should be increased to 10 mg.
The usual maintenance dose is Prilace 10 mg daily.

Impaired renal function.

In hypertensive patients with creatinine clearance levels of 50 mL/minute and above (serum creatinine < 1.5 mg/dL), a dosage adjustment is not required. Also, see Section 4.2 Dose and Method of Administration, Progressive renal failure in patients with persistent proteinuria in excess of 1 g/day above.
For patients with creatinine clearance levels between 20 and 50 mL/minute (serum creatinine between 1.5 and 3 mg/dL), the recommended initial dose is Prilace 1.25 mg once daily. This should be doubled at intervals of two to three weeks depending on how the drug is tolerated.
Particular care should be exercised in patients with impaired renal function who are to be treated for heart failure post-myocardial infarction, as such patients may be susceptible to hypotension. Patients with impaired renal function treated for heart failure post-myocardial infarction have not been studied systematically.

Impaired hepatic function.

In patients with impaired hepatic function, the metabolism of ramipril, and therefore, the formation of the bioactive metabolite ramiprilat, is delayed due to diminished activity of the esterases in the liver, resulting in elevated plasma ramipril levels. Treatment with ramipril should, therefore, be initiated under close medical supervision and should not exceed 2.5 mg daily.

Use in the elderly.

The recommended starting dose is 1.25 mg once daily, which can then be increased according to the individual patient's blood pressure response.

4.3 Contraindications

Hypersensitivity to ramipril, or to any other ACE inhibitor, or to any of the excipients; history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor; haemodynamically relevant renal artery stenosis either bilateral or unilateral in the single kidney.
As with all vasodilators, ACE inhibitors should not be used in patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of aortic or mitral valve). Hypotensive or haemodynamically unstable patients; pregnancy; lactation; renal failure (see Section 4.4 Special Warnings and Precautions for Use).
Extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, such as dialysis or haemofiltration with high flux dialyser membranes. Life threatening anaphylactoid hypersensitivity reactions, sometimes progressing to shock, have been described in the course of dialysis with high flux membranes (e.g. polyacrylonitrile membranes such as AN69) during ACE inhibitor therapy. This combination must be avoided, either by using other medical products to control high blood pressure or cardiac insufficiency or by using other membranes during dialysis.
Similar reactions have been seen in patients undergoing low density lipoprotein aphaeresis with dextran sulphate during ACE inhibitor therapy.
Ramipril must not be used with aliskiren containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance < 60 mL/min).
Ramipril must not be used with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
Ramipril must not be used concomitantly with sacubitril/valsartan therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Do not initiate ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until ramipril is eliminated from the body.

4.4 Special Warnings and Precautions for Use

Angioedema - head, neck or extremities.

Ramipril is contraindicated in patients with a history of angioedema. Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors. If angioedema occurs, the product 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 should resolve without treatment, although antihistamines may be useful in relieving symptoms. Laryngeal oedema, however, can be fatal, thus where there is angioedema involving swelling of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, e.g. subcutaneous adrenaline solution 1:1,000 (0.3 to 0.5 mL), should be promptly administered (see Section 4.8 Adverse Effects (Undesirable Effects)). Hospitalisation of the patient is advisable with observation for at least 12 to 24 hours and discharge only upon complete resolution of the symptoms.
Angioedema may occur with or without urticaria. The onset of angioedema associated with the use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom free intervals.
Medical therapy of progressive angioedema should be aggressive. Failing a rapid response, mechanical methods to secure an airway should be undertaken before massive oedema complicates oral or nasal intubation or surgical procedures (e.g. cricothyrotomy or tracheostomy). Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.

Angioedema - intestinal.

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, facial angioedema also occurred. The intestinal angioedema symptoms resolved after stopping the ACE inhibitor.
An increased risk of angioedema is possible with concomitant use of other drugs which may cause angioedema (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hypotension.

Hypotension may occur in patients commencing treatment with ACE inhibitors. Excessive hypotension is rarely seen in uncomplicated hypertensive patients but is a possible consequence of use in severely salt/ volume depleted persons, e.g. patients with renovascular hypertension, those treated vigorously with diuretics, after severe diarrhoea or patients undergoing dialysis (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)). It is recommended that dehydration, hypovolaemia or salt depletion be corrected before initiating treatment. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed with ACE inhibitors. This may be associated with syncope, neurological deficit, oliguria and/or progressive azotaemia, but rarely with acute renal failure and/or death. If ramipril is to be used in such patients for treatment of hypertension, therapy should be started under very close supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dosage, with or without a diuretic, is increased. In patients with heart failure, correcting dehydration, hypovolaemia or salt depletion must be carefully weighed against the risk of volume overload.
For this reason also, in patients treated with ramipril after a myocardial infarction, treatment should not be initiated until the patient is haemodynamically stable (see Section 4.2 Dose and Method of Administration).
Similar consideration 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. In all high risk patients, it is advisable to initiate treatment at lower dosages than those usually recommended for uncomplicated patients.
In order to assess the extent of an acute fall in blood pressure and where necessary to take corrective action, blood pressure should be measured repeatedly after the first dose of ramipril, after a dosage increase of ramipril, after the first dose of an additional diuretic and after any dosage increase of the diuretic. This should be done until blood pressure has satisfactorily stabilised.
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.

Patients with hyperstimulated renin angiotensin system.

In the treatment of patients with a hyperstimulated renin angiotensin system, particular caution must be exercised. Such patients are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or for the first time at an increased dose. Initial doses or initial dose increases must be accompanied by close blood pressure monitoring until such time as no further acute reduction in blood pressure is to be anticipated, for example:
in patients with severe, and particularly with malignant hypertension. The initial phase of treatment requires special medical supervision;
in patients with heart failure, particularly if severe, or if treated with other substances having antihypertensive potential. If heart failure is severe, the initial phase of treatment requires special medical supervision;
in patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve). The initial phase of treatment requires special medical supervision;
in patients with haemodynamically relevant renal artery stenosis. The initial phase of treatment requires special medical supervision. Discontinuation of diuretic therapy may be required;
in patients pretreated with diuretics. Where discontinuing use or reducing the dose of the diuretic is not possible, the initial phase of treatment requires special medical supervision;
in patients in whom fluid or salt depletion exist or may develop (as a result of insufficient fluid or salt intake, or as a result of, e.g. diarrhea, vomiting or excessive sweating in cases where salt and fluid replacement is inadequate).
Generally, it is recommended that dehydration, hypovolemia or salt depletion be corrected before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed against the risk of volume overload). When these conditions have become clinically relevant, treatment with ramipril must only be started or continued if appropriate steps are taken concurrently to prevent an excessive fall in blood pressure and deterioration of renal function.

Dual blockade of the renin angiotensin aldosterone system (RAAS).

Dual blockade of the renin angiotensin aldosterone system by combining ramipril with an angiotensin II receptor antagonist (AIIRA) or with aliskiren is not recommended since there are increased risks of hypotension, hypokalemia and changes in renal function. The use of ramipril in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (creatinine clearance < 60 mL/min) (see Section 4.3 Contraindications).
The use of ramipril in combination with AIIRA is contraindicated in patients with diabetic nephropathy.

Monitoring of renal function.

It is recommended that renal function be monitored, particularly in the initial weeks of treatment with an ACE inhibitor. Particularly careful monitoring is required in patients with:
heart failure;
renovascular disease, including patients with haemodynamically relevant unilateral renal artery stenosis. In the latter patient group, even a small increase in serum creatinine may be indicative of unilateral loss of renal function;
impairment of renal function;
kidney transplant.

Electrolyte monitoring.

It is recommended that serum potassium and serum sodium be monitored regularly. More frequent monitoring of serum potassium is necessary in patients with impaired renal function.

Patients at particular risk from a pronounced reduction in blood pressure.

In patients who would be at particular risk from an undesirably pronounced reduction in blood pressure (e.g. patients with haemodynamically relevant stenosis of the coronary arteries or of the blood vessels supplying the brain), the initial phase of treatment requires special medical supervision.

Neutropenia/ agranulocytosis.

Agranulocytosis and bone marrow depression (including leucopenia or neutropenia) have been reported with ACE inhibitors. These have mostly occurred in patients with pre-existing impaired renal function, collagen vascular disease, immunosuppressant therapy or a combination of these complicating factors. Most episodes of leucopenia and neutropenia have been single, transient occurrences without any associated clinical symptoms. In addition, data to establish a causal relationship are currently lacking.
It is recommended that white blood cell counts be monitored to permit detection of a possible leucopenia, particularly in the initial phase of treatment. More frequent monitoring is advised in the initial phase of treatment and in patients with collagen vascular disease, renal disease (serum creatinine greater than or equal to 180 micromol/L) and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive.

Cough.

A persistent dry (nonproductive) irritating cough has been reported with most ACE inhibitors in use. The frequency of reports has been increasing since cough was first recognised as a side effect of ACE inhibition. In various studies, the incidence of cough varies between 2% and 15% depending upon the drug, dosage and duration of use.
The cough is often worse when lying down or at night. The cough is more common in women (who account for two-thirds of the reported cases). Patients who cough may have increased bronchial reactivity compared to those who do not cough. The observed higher frequency of this complication in nonsmokers may be due to higher level of tolerance to cough by smokers.
The mechanism of this adverse reaction is not clear but it is most likely to be secondary to the effects of converting enzyme inhibitor on kinins (bradykinin and/or prostaglandin) resulting in stimulation of pulmonary cough reflex.
Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor. The reaction may recur on rechallenge with another ACE inhibitor but this is not invariably the case. A change in antihypertensive regimen may be required in severe cases. NSAIDs (e.g. sulindac) have been reported to be effective in relieving coughing induced by ACE inhibitors. In patients with mild hypertension or patients likely to be treated with other antihypertensive agents, it is unlikely that risks of prescribing an NSAID will outweigh the benefit of relieving cough.

Hyperkalaemia.

Because the ACE inhibitors decrease the formation of angiotensin II, which results in decreased production of aldosterone, increase in serum potassium levels (> 5.5 mEq/L) is not unexpected with this class of drugs. Hyperkalaemia is more likely in patients with some degree of renal impairment, those treated with potassium sparing diuretics or potassium supplements and/or consuming potassium containing salt substitutes. Diabetic patients, and particularly elderly diabetic patients, may be at increased risk of hyperkalaemia. In some patients, hyponatraemia may coexist with hyperkalaemia. It is recommended that patients undergoing ACE inhibitor treatment should have measurement of serum electrolytes (including potassium, sodium and urea) regularly. This is more important in patients taking diuretics.

Dermatological reactions.

Dermatological reactions characterised by maculopapular pruritic rashes and sometimes photosensitivity have been reported with another ACE inhibitor. Rare and sometimes severe skin reactions (lichenoid eruptions, psoriasis, pemphigus-like rash, rosacea, Stevens-Johnson syndrome, etc.) have been reported. A causal relationship is difficult to assess.
Patients who developed a cutaneous adverse event with one ACE inhibitor may be free of reaction when switched to another drug of the same class, but there are also reports of cross reactivity.

Taste disturbances (dysgeusia).

Taste disturbances were reported to be high (up to 12.5%) with high doses of another ACE inhibitor. The actual incidence of taste disturbance is probably low (< 0.5%) but data in this respect are scarce and difficult to interpret.
Taste disturbances with ACE inhibitors are described as suppression of taste or a metallic sensation in the mouth or sometimes there may be taste reduction or even complete loss of taste. The dysgeusia occurs usually in the first weeks of treatment and usually disappears within one to three months of treatment.

Surgery/ anaesthesia.

In patients undergoing major surgery or anaesthesia who are being treated with agents that produce hypotension, ACE inhibitors 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.

Use in hepatic impairment.

As ramipril is a prodrug metabolised in the liver to its active moiety, particular caution and close monitoring should be applied to patients with impaired liver function. The metabolism of the parent compound and, therefore, the formation of the bioactive metabolite ramiprilat may be diminished; resulting in markedly elevated plasma levels of the parent compound (due to the reduced activity of the esterases in the liver) (see Section 4.2 Dose and Method of Administration). Patients in whom severe liver cirrhosis with oedema and/or ascites is present, the renin angiotensin system may be significantly activated; therefore, particular caution must be exercised in treating these patients.

Use in renal impairment.

Ramipril can prevent progressive renal failure in patients with persistent proteinuria in excess of 1 g/day. The nephroprotective effect of ramipril was observed to be more evident at doses greater than 1.25 mg in a small post hoc analysis which examined changes in serum creatinine and GFR (rather than changes in the rate of decline of GFR) after three months treatment with ramipril. This effect could depend upon the selective availability at the renal tissue site and on the patient's sodium status. These studies also indicate that, in renally impaired patients, higher doses of ramipril did not represent a higher risk than did lower doses of ramipril.
As a consequence of inhibition of the renin angiotensin aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin angiotensin aldosterone system, treatment with ACE inhibitors, including ramipril, may be associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.
In patients after renal transplantation, there is a risk of renal impairment.
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 are usually reversible upon discontinuation of ACE inhibitor treatment and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Patients with unilateral renal artery disease present a special problem as deterioration of function may not be apparent from measurement of blood urea nitrogen and serum creatinine. Even a small increase in serum creatinine may be indicative of unilateral loss of renal function.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine which are usually minor and transient, especially when ramipril has been given concomitantly with a diuretic in patients with pre-existing renal impairment. Dosage reduction of ramipril and/or discontinuation of the diuretic may be required. Additionally, in patients with renal insufficiency, serum potassium should be monitored more frequently as there is a risk of hyperkalaemia.
There is insufficient experience in the use of ramipril in patients with severe renal impairment (i.e. creatinine clearance less than 20 mL/minute/1.73 m2 body surface area).
Ramipril is not suitable for the treatment of patients requiring haemodialysis for endstage renal failure since only negligible amounts are dialysable.
Evaluation of the hypertensive patient or patient with heart failure should always include assessment of renal function (see Section 4.2 Dose and Method of Administration). If deterioration in renal function has occurred after treatment with one ACE inhibitor, it is likely to be precipitated by another and in these patients other classes of antihypertensive agent should be preferred.

Use in the elderly.

In clinical trials, no overall difference in effectiveness or safety has been observed between patients over 65 years and younger patients. However, since both liver and kidney function may decline with age, the starting dose of ramipril should be reduced to 1.25 mg daily. Some elderly patients may be particularly responsive to ACE inhibitors. Evaluation of renal function at the beginning of treatment is recommended.

Paediatric use.

The safety and effectiveness of ramipril have not been established in children.

Effects on laboratory tests.

The serum sodium level may decrease. Since ramipril leads to a decrease in aldosterone secretion, elevation of serum potassium may occur. Therefore, potassium sparing diuretics or potassium supplements should be avoided. Increases in serum bilirubin and/or liver enzymes have been observed. Mild to severe decreases in haemoglobin (also due to haemolytic anaemia), red blood cells, platelets and white blood cells have been observed with ACE inhibitors (see Section 4.4 Special Warnings and Precautions for Use, Neutropenia/ agranulocytosis). Eosinophilia has also been seen. Raised titres of antinuclear antibodies have been observed with other ACE inhibitors.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Sacubitril/valsartan.

The concomitant use of ACE inhibitors with sacubitril/valsartan therapy is contraindicated as this increases the risk of angioedema (see Section 4.3 Contraindications).

Extracorporeal treatments.

Extracorporeal treatments leading to contact of blood with negative charged surfaces must be avoided, such as dialysis or haemofiltration with high flux dialyser membranes.

Aliskiren containing medicines.

The combination of ramipril with aliskiren containing medicines is contraindicated in patients with diabetes mellitus or with moderate to severe renal impairment (creatinine clearance < 60 mL/min) and is not recommended in other patients (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Angiotensin II receptor antagonists (AIIRAs).

The use of ramipril in combination with an AIIRA is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Antihypertensive drugs.

Possible potentiation of the antihypertensive effect must be anticipated when ramipril is administered concurrently with other antihypertensive agents and other substances with antihypertensive potential (e.g. nitrates, tricyclic antidepressants, anaesthetics). Regular monitoring of serum sodium is recommended in patients undergoing concurrent diuretic therapy.

Vasopressor sympathomimetics.

The antihypertensive effect of ramipril may be reduced by concurrent administration of vasopressor sympathomimetics. Close monitoring of blood pressure is particularly recommended.

Diuretics.

Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimised by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, the starting dose should be reduced (see Section 4.2 Dose and Method of Administration). Regular monitoring of serum sodium is necessary in patients undergoing concurrent diuretic therapy.

Potassium supplements and potassium sparing diuretics.

Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium sparing diuretics (spironolactone, amiloride, triamterene and others) or potassium supplements can increase the risk of hyperkalaemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently.

Lithium.

Excretion of lithium may be reduced by ACE inhibitors. Increased serum lithium levels and symptoms of lithium toxicity (e.g. cardiotoxic and neurotoxic effects) have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Nonsteroidal anti-inflammatory drugs.

As with other ACE inhibitors, a decrease in the antihypertensive effects of ramipril in patients taking NSAIDs (e.g. aspirin, phenylbutazone, indomethacin) or COX-2 inhibitors (e.g. celecoxib, meloxicam) is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function and an increase in serum potassium.

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 [nonsteroidal anti-inflammatory drugs (NSAIDs) 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.

Anaesthetics.

General anaesthetics or anaesthetics with an antihypertensive action may cause the blood pressure to drop further in patients taking ramipril. Appropriate counter measures, such as increasing the blood volume or, if necessary, administering angiotensin II, should be taken before or during surgery.

Antidiabetic agents.

ACE inhibitors may reduce insulin resistance. The possibility of an increased blood sugar reduction must be considered in patients treated concurrently with ramipril and antidiabetic agents such as insulin and sulfonylurea derivatives. Particularly close blood glucose monitoring is, therefore, recommended in the initial phase of coadministration.

Vildagliptin.

An increased incidence of angioedema was found in patients taking ACE inhibitors and vildagliptin.

Heparin.

A rise in serum potassium concentration is possible when ramipril and heparin are administered concurrently.

Alcohol.

Concomitant administration with alcohol may lead to increased vasodilation. Ramipril may potentiate the effect of alcohol.

Desensitisation therapy.

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom is increased under ACE inhibition. It is assumed that this effect may also occur in connection with other allergens.

Other.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents and other substances that may change the blood picture; the likelihood of blood picture changes is increased when ramipril is administered with these substances.
A high intake of dietary salt may decrease the effects of antihypertensive medication.

mTOR inhibitors (e.g. temsirolimus).

An increased incidence of angioedema was observed in patients taking ACE inhibitors and mTOR inhibitors (mammalian target of rapamycin inhibitors).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
As with all ACE inhibitors, Prilace should not be taken during pregnancy. Pregnancy must be excluded before starting treatment with Prilace and avoided during the treatment. Otherwise there is risk of harm to the foetus.
If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced with 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 ramipril in pregnant women. However, data show that ramipril crosses the human placenta. Postmarketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the fetus. ACE inhibitors have also been associated with fetal death in utero.
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 1st 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 with no exposure.
When ACE inhibitors have been used during the second and third trimesters of pregnancy, there have been reports of neonatal hypotension, renal failure, skull hypoplasia and death.
Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios has been associated with fetal limb contractures, craniofacial malformations, hypoplastic lung development and intrauterine growth retardation. Prematurity and patent ductus arteriosus have been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure or to the mother's underlying disease.
 Ingestion of ramipril 10 mg as a single dose resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, there is evidence that ramiprilat is excreted in rat milk, hence ramipril should not be given to breastfeeding mothers. If treatment with ramipril is necessary during lactation, the patient should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

The antihypertensive effect in individual cases may be symptomatic. Some adverse effects (e.g. some symptoms of reduction in blood pressure such as lightheadedness, dizziness) may impair the patient's ability to concentrate and react. Treatment with any blood pressure lowering agent may, therefore, affect the ability to drive, cross the road safely or operate machinery, especially at the start of treatment or when changing over from other preparations, or during concomitant use of alcohol.

4.8 Adverse Effects (Undesirable Effects)

Ramipril has been evaluated for safety in over 4,000 patients with hypertension. The frequency of adverse reactions associated with ramipril was low in clinical trials. Generally, adverse reactions are mild and transient, and do not require discontinuation of therapy. The most frequently reported adverse reactions are nausea, dizziness and headache. Cough has been reported in clinical trials with an incidence between less than 2% and up to 5.5%.
In placebo controlled trials, however, there was an excess of upper respiratory infection and flu syndrome in the ramipril group. As these studies were carried out before the relationship of cough to ACE inhibitors was recognised, some of these events may represent ramipril induced cough.
When used to treat nephropathy, the risks of ramipril therapy are no greater than when it is used to treat hypertension.
Similarly, the information available from the HOPE study in 9,200 patients does not reveal any increased risk of treatment with ramipril 10 mg in high risk cardiovascular patients or in diabetics.
The following lists adverse events reported in clinical trials with an incidence of greater than 2% (more common) and those with an incidence of equal to or less than 2% (less common).

More common reactions.

Cardiovascular.

Symptomatic hypotension characterised by dizziness, weakness, nausea, headache, palpitations, tiredness, lightheadedness, impaired reactions or tinnitus may occur, particularly at initiation of treatment or after increasing the dose of ramipril (see Section 4.4 Special Warnings and Precautions for Use). Orthostatic blood pressure decreased (disturbed orthostatic regulation), syncope.

Gastrointestinal.

Nausea, vomiting, abdominal pain and diarrhoea may occur, but these reactions are often transient. Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia.

Dermatological.

Apparent hypersensitivity reactions (manifested by dermatitis, pruritus or rash, with or without fever) (see Section 4.4 Special Warnings and Precautions for Use).

Cough.

A persistent, dry (nonproductive) cough has been reported with ramipril as with other ACE inhibitors. Bronchitis, sinusitis, dyspnoea.

Musculoskeletal and connective tissue disorder.

Muscle spasms (muscle cramps), myalgia.

Metabolism and nutrition disorders.

Blood potassium increased.

General disorders and administration site conditions.

Chest pain, fatigue.

Less common reactions.

Cardiovascular.

Peripheral oedema, flushing and disturbed orthostatic regulation may be observed. Isolated cases of syncope, angina pectoris, arrhythmias, chest pain, palpitations, tachycardia, myocardial ischaemia and myocardial infarction have been observed. Exacerbation of perfusion disturbances due to vascular stenosis. Cerebral ischaemia leading to transient ischaemic attacks or stroke. Vasculitis.

Renal.

Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking ramipril, particularly when ramipril was given concomitantly with a diuretic (see Section 4.4 Special Warnings and Precautions for Use). Impairment of renal function (isolated cases progressing to acute renal failure) may develop. Deterioration of pre-existing proteinuria (although ACE inhibitors usually reduce proteinuria) or an increase in urinary output may occur.

Angioedema.

In very rare cases, angioedema, including fatal angioedema, has occurred during therapy with ACE inhibitors, including ramipril. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with ramipril must be discontinued and appropriate therapy started immediately (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal.

Abdominal or gastric pain (sometimes with enzyme changes suggesting pancreatitis), pancreatitis (cases of fatal outcome have been exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, anorexia, decreased appetite, constipation, dry mouth, dyspepsia, dysphagia, gastroenteritis, nausea, increased salivation, taste or smell disturbances and aneusia (loss of taste), dysgeusia (taste disturbances).

Hepatobilliary disorder.

Hepatic enzymes and/or bilirubin conjugated increased.

Dermatological (mucosal and cutaneous).

Reactions such as conjunctivitis, urticaria, pruritus, alopecia, onycholysis, precipitation and/or intensification of Raynaud's phenomenon and sweating have been observed (see Section 4.4 Special Warnings and Precautions for Use).

Neurological and psychiatric.

Amnesia, confusion, convulsions, depressed mood, depression, disorders of balance, hearing loss, headache (not causally related to reduction in blood pressure), insomnia, loss of appetite, nervousness, anxiety, neuralgia, neuropathy, paraesthesia, restlessness, somnolence, tinnitus, tremor, vertigo and vision disturbances including blurred vision.

Blood and lymphatic system disorders.

Eosinophilia.

Respiratory, thoracic and mediastinal disorders.

Bronchospasm including aggravated asthma, nasal congestion.

Reproductive system and breast disorders.

Impotence and reduced libido (as generally possible in unusually low blood pressure and as possible consequence of other adverse effects).

Musculoskeletal and connective tissue disorders.

Arthralgia.

General disorders and administration site conditions.

Pyrexia (fever).

Other reactions.

Rarely, cholestatic jaundice, liver damage (including acute liver failure), have been reported. Also, photosensitivity reactions and purpura have occurred. The likelihood and the severity of anaphylactic and anaphylactoid reactions may be increased while taking ACE inhibitors. This must be considered when desensitisation is performed. Isolated cases of agranulocytosis, pancytopenia or bone marrow depression or failure may occur.

Blood and lymphatic system disorders.

Decreased white blood cell count (including neutropenia or agranulocytosis), red blood cell count, haemoglobin and platelet count, haemolytic anaemia.

Nervous system disorders.

Balance disorder, cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired (impaired reactions), burning sensation, parosmia (smell disturbances).

Ear and labyrinth disorders.

Hearing impairment.

Gastrointestinal disorders.

Glossitis, aphthous stomatitis (inflammatory reactions of the oral cavity).

Skin and subcutaneous tissue disorders.

Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema alopecia.

Endocrine disorders.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders.

Blood sodium decreased.

Vascular disorders.

Hypoperfusion (exacerbation of perfusion disturbances), Raynaud's phenomenon.

General disorders and administration site conditions.

Asthenia (weakness).

Immune system disorders.

Anaphylactic or anaphylactoid reactions (severe anaphylactic and anaphylactoid reactions to insect venom is increased under ACE inhibition), antinuclear antibody increased.

Hepatobiliary disorders.

Hepatocellular damage, acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Reproductive system and breast disorders.

Gynaecomastia.

Psychiatric disorders.

Confusional state, disturbance in attention.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

In cases of overdose, the following may occur: excessive peripheral vasodilation, severe hypotension, shock, bradycardia, electrolyte disturbances, and renal failure. Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital.

Treatment.

The treatment given depends on how and when the drug was taken and on the type and severity of symptoms. Steps must be taken to eliminate ramipril which has not yet been absorbed (e.g. administration of adsorbants during the first 30 minutes if possible). Vital and organ functions must be monitored under intensive care conditions and safeguarded if necessary. In case of hypotension, administration of α1-adrenergic agonists should be considered in addition to volume and salt substitution.
No experience is available concerning the efficacy of forced diuresis, altering urine pH, haemofiltration or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or haemofiltration is considered, consideration must be given to the fact that ramipril is contraindicated with certain high flux filtration membranes and with dextran sulphate LDL apheresis (see Section 4.3 Contraindications).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Single doses of ramipril 2.5 to 20 mg produce approximately 60 to 80% inhibition of ACE activity four hours after dosing with approximately 40 to 60% inhibition after 24 hours. Multiple oral doses of ramipril 2.0 mg or more cause plasma ACE activity to fall by more than 90% four hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.

Mechanism of action.

Ramipril is a prodrug which, after absorption from the gastrointestinal tract, is hydrolysed in the liver to form the active moiety, ramiprilat. Ramipril and ramiprilat inhibit angiotensin converting enzyme (ACE) which is identical to kininase II. This converting enzyme (ACE) is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex, thus inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.
Kininase II is one of the enzymes responsible for the degradation of bradykinin, a potent vasodepressor peptide. The inhibition of kininase II activity by ramipril prevents the degradation of bradykinin, thus leading to increased levels of this potent vasodepressor substance. While the mechanism through which ramipril lowers blood pressure is believed to be primarily suppression of the renin angiotensin aldosterone system, it has an antihypertensive effect even in patients with low renin hypertension. Although ramipril was antihypertensive in all races studied, black hypertensive patients (usually a low renin hypertensive population) had a smaller average response to monotherapy than nonblack patients.
The nephroprotective effects of ramipril are in addition to its antihypertensive action. These effects are a result of its beneficial effects on glomerular permeability, which reduces protein filtration (an intrinsically toxic biological process) and thus contributes to its antiproteinuria effects.

Clinical trials.

Hypertension.

Administration of ramipril to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt and/or volume depleted (see Section 4.4 Special Warnings and Precautions for Use). Use of ramipril in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.
In single dose studies, doses of ramipril 5 to 20 mg lowered blood pressure within one to two hours, with peak reductions achieved three to six hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer-term (four to twelve weeks) controlled studies, once daily doses of 2.5 to 10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak versus trough effect, the trough effect represented about 50 to 60% of the peak response.
In most trials, the antihypertensive effect of ramipril increased during the first several weeks of repeated measurements. The antihypertensive effect of ramipril has been shown to continue during long-term therapy for at least two years. Abrupt withdrawal of ramipril has not resulted in a rapid increase in blood pressure.
Interaction studies of ramipril and thiazides have been carried out. Limited experience in controlled and uncontrolled trials combining ramipril with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin angiotensin system.

Myocardial infarction.

The efficacy of ramipril has been established in a study of 2,000 patients with myocardial infarction who showed clinical signs of heart failure (Acute Infarct Ramipril Efficacy study). Treatment with ramipril resulted in a significant improvement in survival and clinical outcomes. Over an average follow-up period of 15 months, ramipril reduced all cause mortality by 6% compared to placebo (risk reduction 27%, p = 0.002) and reduced the risk of secondary outcomes including progression to severe or resistant heart failure, reinfarction, stroke or death (in the absence of any prior validated event) by 19% (p = 0.008). These results are based on intention to treat analysis and are, therefore, likely to be conservative in terms of potential benefit of ramipril. A subsidiary analysis showed that the benefit of ramipril, in terms of survival, was evident as early as one month into treatment. The difference in mortality in the two groups at 30 days represented a risk reduction for the ramipril group over placebo of 29% (p = 0.053).

Nondiabetic nephropathy.

In overt, mostly nondiabetic (13% diabetic subjects included) nephropathy, the pivotal Ramipril Efficacy In Nephropathy (REIN) study (n = 166) has demonstrated statistically significant decreases in the rate of progression of renal insufficiency and the development of endstage renal failure. The populations studied in this placebo controlled trial included normotensive patients, patients with uncontrolled mild to moderate hypertension (diastolic blood pressure > 90 mmHg) and patients with controlled mild to moderate hypertension. For those with uncontrolled hypertension, the target blood pressure was predefined (diastolic blood pressure < 90 mmHg) and, if this was not achieved with study medication (ramipril or placebo) alone, additional antihypertensives were added. The improvements observed are more dramatic with poorer (elevated) baseline proteinuria (greater than or equal to 3 g/24 hours) but are also observed at lower baseline proteinuria (> 1 and < 3 g/24 hours). At this level of proteinuria, subgroup analysis in the REIN study indicated that only patients with worse (lower) GFR (< 45 mL/minute/1.73 m2) received statistically significant benefits in endstage renal failure. The results of the REIN study are summarised in Table 1.
The improvement in these key endpoints was observed to increase with time, to be maintained long term and to apply to both hypertensive and nonhypertensive patients. A delay of approximately three months was seen prior to detection of the beneficial effects of ramipril, suggesting the value of early treatment.

Diabetic nephropathy.

Studies in overt diabetic nephropathy, particularly the angiotensin converting enzyme II (ACE II) study have demonstrated that both low and high dose ramipril therapy can retard proteinuria and maintain renal health (maintain GFR, creatinine levels and creatinine clearance). The ACE II study, which was an open label follow-up to the ACE I study with captopril, investigated the effect of intensive (target mean arterial pressure (MAP) ≤ 92 mmHg; n = 63) versus moderate (target MAP ≥ 100 to ≤ 107 mmHg; n = 66) blood pressure control with ramipril on renal function. While the study observed no significant differences between these moderate and intensive blood pressure control groups, there was no observed deterioration of renal function in this high risk population throughout the two year study (no statistically significant change in serum creatinine or creatinine and a significant improvement in proteinuria). The trial, therefore, demonstrates the benefit of ramipril in maintaining the renal health of diabetic patients. These results are presented in Table 2.

Patients with an increased cardiovascular risk.

The placebo controlled HOPE study with once daily ramipril was conducted in patients with an increased cardiovascular risk attributable to either vascular diseases (such as manifest coronary heart disease, a history of stroke or a history of peripheral vascular disease) or to diabetes mellitus plus at least one additional risk factor (such as microalbuminuria, hypertension, elevated total cholesterol levels, low high density lipoprotein cholesterol levels or smoking). Importantly, patient exclusion criteria included MI or stroke within four weeks of the start of the study, heart failure or low ejection fraction (< 0.40). Ramipril was administered adjunctive to standard therapy (e.g. in addition to aspirin, cholesterol lowering agents, other antihypertensives, oral antidiabetic agents) and on a preventative basis to over 9,200 such patients. Patients were initiated on ramipril 2.5 mg for one week which was then titrated firstly to ramipril 5 mg for three weeks and then to ramipril 10 mg. The results of the HOPE study in terms of the primary composite endpoint and its components (CV death, MI or stroke) for the whole population (ITT - intention to treat) and for those patients with diabetes are presented in Table 3.
The results of the HOPE study in terms of the prespecified secondary endpoints for the whole population (intention to treat) are presented in Table 4.
The results of the HOPE study in terms of the prespecified secondary endpoints for those patients with diabetes are presented in Table 5.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50 to 60% and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.
Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose proportional. The 24 hour area under the curve (AUC) for ramiprilat, however, is dose proportional over the 2.5 to 20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28 and 44%, respectively, when oral ramipril 5 mg was compared with the same dose of ramipril given intravenously.

Distribution.

Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE and kininase II, has a half-life of two to four hours.
Because of its potent binding to and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9 to 18 hours. The terminal elimination phase has a prolonged half-life (> 50 hours) and probably represents the binding/ dissociation kinetics of the ramiprilat/ ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5 to 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13 to 17 hours.
After once daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ramipril, especially at low doses (2.5 mg), but the difference is clinically insignificant.

Metabolism.

Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached two to four hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%. Ramipril is almost completely metabolised to ramiprilat, which has about six times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester. After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine and about 40% is found in the faeces. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

Excretion.

The urinary excretion of ramipril, ramiprilat and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance less than 40 mL/minute/1.73 m2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations (see Section 4.2 Dose and Method of Administration).

Impaired liver function.

In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about threefold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No evidence of a carcinogenic effect was found when ramipril was given to rats (up to 500 mg/kg/day for 24 months) or to mice (up to 1,000 mg/kg/day for 18 months).
An increased incidence of oxyphilic cells in the renal tubules and oxyphilic microadenomas was observed in rats treated for 24 months with ramipril (3.2 to 500 mg/kg/day). Data from historical control animals showed that the spontaneous occurrence of oxyphilic cells in rat kidney is age related, is higher in males and reaches a level similar to that seen in the ramipril treated group. There is no evidence in humans that the occurrence of oxyphilic cells is age related. Moreover, progression of oxyphilic cells to neoplasia (oncocytoma) is rare and, when it occurs, is considered to be benign. Whether this finding in rats represents any potential risk to humans is, therefore, unclear.

Fibromuscular pad formation.

In several repeated dose studies in rats, especially male animals treated with ramipril (3.2 to 500 mg/kg bodyweight/day) showed an increased incidence of so called fibromuscular pad formation in the basal region of the gastric mucosa. The findings suggest an increased connective tissue formation and also partly increased formation of smooth muscle (lamina muscularis mucosae) due to a predominantly round cell inflammatory reaction. In all studies (1 to 24 month, carcinogenicity) the changes were always of the same type and no tendency of proliferation was obvious. Thus, it seems to be rather a reactive process with circumscribed scar tissue formation. The changes in the rat stomach mucosa could not be reproduced in other species (i.e. mouse, dog, rabbit, monkey).
This lesion was also observed when rats were treated with a relatively high dose (90 mg/kg/day for 3 to 6 months) of another ACE inhibitor. In the light of the available data, fibromuscular pad formation in the rat would not appear to present a serious risk in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Prilace tablets contain sodium bicarbonate, calcium sulfate, pregelatinised maize starch and sodium stearylfumarate.
The tablets are gluten free.
Prilace capsules contain pregelatinised maize starch. The capsule shells are size #4 Hard Gelatin Capsules G41CSRR0238 White Op/Blue Op with black printing ink (TekPrint SW-9008 or SW-9009).
The capsules are gluten free.

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

Prilace 1.25 mg, 2.5 mg, 5 mg and 10 mg* tablets are available in blister packs of 30's.
Prilace 10 mg capsules are available in blister packs and bottles* of 30's.
* Currently not marketed.

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

Ramipril is a white to almost white, crystalline powder soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°C and 112°C.

Chemical structure.

The chemical name for ramipril is (2S,3aS,6aS)-1-[(S)-N-[(S)-1-carboxy)-3- phenylpropyl]alanyl]octahydro cyclopenta[b]pyrrole-2- carboxylic acid, 1-ethyl ester. Its structural formula is:
Its empiric formula is C23H32N2O5, and its molecular weight is 416.5.
Ramipril is a 2-aza-bicyclo[3.3.0]- octane-3-carboxylic acid derivative. It has five chiral centres with an S-configuration in all five asymmetric carbon atoms.

CAS number.

87333-19-5.

7 Medicine Schedule (Poisons Standard)

Prescription Medicine (Schedule 4).

Summary Table of Changes