Consumer medicine information

Quinapril Generic health

Quinapril

BRAND INFORMATION

Brand name

Quinapril Generic Health

Active ingredient

Quinapril

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Quinapril Generic health.

What is in this leaflet

This leaflet answers some common questions about Quinapril generic health.

It does not contain all the available information.

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

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

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

Keep this leaflet with your Quinapril generic health tablets. You may need to read it again.

What Quinapril generic health is used for

Quinapril generic health is used to lower high blood pressure (hypertension). It is also used to treat heart failure.

Hypertension

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

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems, including stroke, heart disease and kidney failure.

Heart Failure

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 short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet.

How Quinapril generic health works

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

Quinapril generic health belongs to a group of medicines calledangiotensin converting enzyme (ACE) inhibitors.

Your doctor may have prescribed Quinapril generic health for another reason.

Ask your doctor if you have any questions about why Quinapril generic health has been prescribed for you.

Quinapril generic health is not addictive.

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

Use in Children

The safety and effectiveness of Quinapril generic health in children have not been established.

Before you take Quinapril generic health

When you must not take it

Do not take Quinapril generic health if:

  • you have an allergy to Quinapril generic health or any other medicine containing quinapril, or any of the ingredients listed at the end of this leaflet;
  • you have taken any other 'ACE inhibitor' medicine before, which caused your face, lips, tongue, throat, hands or feet to swell up, or made it hard for you to breathe;
  • you or your family have a history of swelling of the face, lips, tongue, throat, hands or feet for no apparent reason.

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

If you have had an allergic reaction to an ACE inhibitor before, you may be allergic to Quinapril generic health.

Use of ACE inhibitors have been associated with Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent low blood sodium levels.

Your doctor may also wish to do a blood test to monitor your sodium levels to ensure they are within normal limits. In the elderly and other at risk patients, sodium levels may be monitored more frequently.

Do not take Quinapril generic health if:

  • you have kidney problems or a condition called 'renal artery stenosis’.
  • you have regular dialysis for blood filtration.

You may experience an allergic reaction.

Do not take Accupril if you are currently taking a blood pressure lowering medicine containing aliskiren or with medicines known as angiotensin receptor blockers (ARB) or other ACE inhibitors and you have the following conditions:

  • diabetes;
  • kidney problems;
  • high levels of potassium in your blood;
  • congestive heart failure.

You may experience severe side effects.

Do not take Quinapril generic health if you are pregnant or breastfeeding. Quinapril generic health may enter your womb or it may pass into the breast milk and there is the possibility that your baby may be affected.

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

If you are not sure whether you should start taking Quinapril generic health, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to:

  • any other medicines;
  • any other substances, such as foods, preservatives or dyes.

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

  • kidney problems, or are having dialysis;
  • liver problems;
  • heart problems;
  • low blood pressure, which you may notice as dizziness or light-headedness
  • diabetes;
  • high levels of potassium in your blood.

You must also tell your doctor if you:

  • are following a very low salt diet;
  • are about to receive desensitisation therapy for an allergy;
  • are about to undergo dialysis or lipoprotein apheresis;
  • 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 Quinapril generic health.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

  • all prescription medicines;
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by Quinapril generic health or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • other medicines used to treat high blood pressure;
  • other medicines that work in a similar fashion to ACE inhibitors, such as Angiotensin Receptor Blockers (these are used to treat high blood pressure and/or heart failure);
  • diuretics, also known as fluid or water tablets;
  • non-steroidal anti-inflammatory drugs (NSAIDs) or Cox 2 inhibiting medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis;
  • potassium supplements or potassium-containing salt substitutes;
  • lithium, a medicine used to treat mood swings and some types of depression;
  • tetracycline antibiotics;
  • trimethoprim or trimethoprim/ sulfamethoxazole, medicines used to treat bacterial infections.

Tell your doctor if you are taking any of the following blood pressure lowering medicines:

  • angiotensin II receptor blocker (ARB);
  • aliskiren.

For some patients, Quinapril generic health should not be taken in combination with these medicines.

Your doctor may check your kidney function, blood pressure and the amount of electrolytes (eg. potassium) in your blood at regular intervals.

Tell your doctor if you are taking any of the following medicines:

  • mTOR inhibitors (eg. temsirolimus), used in the treatment of kidney cancer;
  • DPP-IV inhibitors (eg. vildagliptin), used in the treatment of diabetes;
  • NEP inhibitors (eg. sacubitril/ valsartan), used in the treatment of congestive heart failure.

Taking Accupril in combination with these medicines may increase your risk of having an allergic reaction.

If you are not sure if you are taking any of the medicines mentioned in this leaflet, check with your doctor or pharmacist.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking Quinapril generic health.

How to take Quinapril generic health

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

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

How much to take

Your doctor or pharmacist will tell you how many tablets you will need to take each day. This depends on your condition and whether or not you are taking any other medicines.

For high blood pressure

For most patients, not on diuretics, the usual starting dose is 5 mg to 10 mg taken once a day. The dose may need to be increased depending on your blood pressure at an interval of 4 weeks. Most patients take between 10 mg and 40 mg each day.

This dose may be taken once a day or divided into two equal doses per day (one in the morning and one at night).

For heart failure

The usual starting dose is 5 mg taken once a day. In most patients, effective doses are between 10 mg and 20 mg a day.

Your doctor will advise whether the dose is to be taken as a single dose or as two separate doses (one in the morning and one at night).

How to take it

Swallow Quinapril generic health tablets whole with a full glass of water.

Do not chew the tablets.

When to take it

Take Quinapril generic health at about the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

Take Quinapril generic health before meals.

Food with a high fat content may interfere with the absorption of Quinapril generic health.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Quinapril generic health helps control your condition, but does not cure it. It is important to keep taking your medicine every day even if you feel well.

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 it as soon as you remember and then go back to taking your medicine 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 not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Australian Poisons Information Centre (telephone 13 11 26), or the New Zealand National Poisons Information Centre (telephone 0800 POISON or 0800 764 766), or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Quinapril generic health.

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

If you take too much Quinapril generic health, you may feel light-headed, dizzy or you may faint.

While you are taking Quinapril generic health

Things you must do

If you are about to be started on any new medicine, remind your doctor, dentist or pharmacist that you are taking Quinapril generic health.

Make sure you drink enough water during exercise and hot weather when you are taking Quinapril generic health, especially if you sweat a lot. If you do not drink enough water while taking Quinapril generic health, you may feel faint, light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.

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

Tell your doctor immediately if you feel light-headed or dizzy after taking your first dose of Quinapril generic health, or when your dose is increased. This is especially important if you are taking Quinapril generic health for heart failure.

If you are going to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking Quinapril generic health. Your blood pressure may drop suddenly.

If you become pregnant while taking Quinapril generic health, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking Quinapril generic health. Quinapril generic health may interfere with the results of some tests as it can result in sodium blood levels that are lower than the normal limits.

Have your blood pressure checked when your doctor says, to make sure Quinapril generic health is working.

Go to your doctor regularly for a check-up. Your doctor may occasionally do a blood test to check your potassium levels and see how your kidneys are working.

Things you must not do

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

Do not take Quinapril generic health to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking Quinapril generic health, or change the dosage, without checking with your doctor.

Things to be careful of

If you feel light-headed, dizzy or faint 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 Quinapril generic health affects you. As with other ACE inhibitor medicines, Quinapril generic health may cause dizziness, light-headedness or tiredness in some people. Make sure you know how you react to Quinapril generic health before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

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

Some self-help measures suggested below may help your condition.

Talk to your doctor or pharmacist about these measures and for more information.

Alcohol

Your doctor may advise you to limit your alcohol intake.

Weight

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

Diet

Eat a healthy diet which includes plenty of fresh vegetables, fruit, bread (preferably wholegrain), cereals and fish. Also eat less sugar and fat (especially saturated fat) which includes sausages, fatty meats, full cream dairy products, biscuits, cakes, pastries, chocolates, chips and coconut. Monounsaturated and polyunsaturated fats from olive oil, canola oil, avocado and nuts are beneficial in small quantities.

Salt

Your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake, you should avoid using salt in cooking or at the table and avoid cooked or processed foods containing high sodium (salt) levels.

Exercise

Regular exercise, maintained over the long term, helps to reduce blood pressure and helps get the heart fitter. Regular exercise also improves your blood cholesterol levels, helps reduce your weight and stress levels, and improves your sleep, mood and ability to concentrate. However, it is important not to overdo it. Before starting any exercise, ask your doctor about the best kind of programme for you.

Smoking

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

Ask your doctor or pharmacist for further information and advice.

Side effects

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

Quinapril generic health helps most people with high blood pressure and heart failure, but it may have unwanted side effects in a few people.

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

It can be difficult to tell whether side effects are the result of taking Quinapril generic health, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

If you are over 65 years of age you may have an increased chance of getting side effects.

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

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

Tell your doctor if…

Ask your doctor or pharmacist for advice if you notice any of the following and they worry you:

  • feeling light-headed, dizzy or faint;
  • dry cough;
  • headache;
  • feeling sick (nausea) or vomiting;
  • stomach pain;
  • diarrhoea;
  • constipation;
  • unusual tiredness or weakness;
  • fatigue;
  • feeling drowsy or sleepy during the day;
  • hair loss or thinning;
  • dry mouth or throat;
  • taste disturbances or loss of taste;
  • confusion or nervousness;
  • back pain;
  • rash;
  • difficulty in getting or maintaining an erection.

These side effects are usually mild. All side effects should be reported to a health professional.

Tell your doctor as soon as possible if…

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, raised or red skin rash;
  • signs of worrying or frequent infections such as fever, severe chills, sore throat or mouth ulcers;
  • aching, tender or weak joints or muscles not caused by exercise;
  • feelings of deep sadness and unworthiness (depression);
  • severe upper stomach pain, often with nausea and vomiting;
  • passing little or no urine;
  • bleeding or bruising more easily than normal.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Go to hospital if…

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;
  • fast or irregular heartbeat;
  • shortness of breath or tightness in the chest;
  • sudden onset of stomach pains or cramps with or without nausea or vomiting;
  • severe flaking or peeling of the skin;
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals;
  • chest pain.

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

Stop taking Quinapril generic health and tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice the following:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing.

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

Other side effects not listed above may also occur in some people.

After taking Quinapril generic health

Storage

Keep your tablets in the box until it is time to take them. If you take the tablets out of the box they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store Quinapril generic health or any other medicine in the bathroom or near a sink.

Do not leave it on a windowsill or in the car on hot days. Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

Quinapril generic health 5 mg are yellow coloured, oval shaped, film-coated tablets debossed with ‘5’ on one side and scoreline on the other side.

Quinapril generic health 10 mg are yellow coloured, capsule shaped, film-coated tablets debossed with ‘10’ on one side and scoreline on the other side.

Quinapril generic health 20 mg are yellow coloured, circular, film-coated tablets debossed with ‘20’ on one side and scoreline on the other side.

A box of Quinapril generic health contains 30 tablets.

Ingredients

Active ingredient

Quinapril generic health 5 mg tablets contain 5 mg quinapril (as hydrochloride).

Quinapril generic health 10 mg tablets contain 10 mg quinapril (as hydrochloride).

Quinapril generic health 20 mg tablets contain 20 mg quinapril (as hydrochloride).

Other ingredients

  • magnesium carbonate hydrate;
  • calcium sulfate dihydrate;
  • colloidal anhydrous silica;
  • crospovidone;
  • povidone;
  • magnesium stearate.

The tablet film-coating (OPADRY AMB complete film coating system 80W52110 Yellow (PI 12212)) contains the following ingredients:

  • polyvinyl alcohol;
  • titanium dioxide;
  • talc;
  • lecithin;
  • iron oxide yellow;
  • xanthan gum.

Quinapril generic health does not contain sucrose, gluten, tartrazine or any other azo dyes.

Australian Registration Numbers

Quinapril generic health 5 mg:
AUST R 133199.

Quinapril generic health 10 mg:
AUST R 133200.

Quinapril generic health 20 mg:
AUST R 133201.

Sponsor

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia

E-mail: [email protected]
Telephone: +61 3 9809 7900
Website: www.generichealth.com.au

This leaflet was prepared in July 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Quinapril Generic Health

Active ingredient

Quinapril

Schedule

S4

 

1 Name of Medicine

Quinapril hydrochloride.

2 Qualitative and Quantitative Composition

Quinapril Generic Health tablets contains 5 mg, 10 mg or 20 mg quinapril (as hydrochloride).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Quinapril Generic Health 5 mg tablet.

Yellow coloured, oval shaped, film-coated tablets debossed with '5' on one side and score line on the other side.

Quinapril Generic Health 10 mg tablet.

Yellow coloured, capsule shaped, film-coated tablets debossed with '10' on one side and score line on the other side.

Quinapril Generic Health 20 mg tablet.

Yellow coloured, circular, film-coated tablets debossed with '20' on one side and score line on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Quinapril hydrochloride tablets are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. Sufficient data have not been provided to support the use of quinapril tablets in renovascular hypertension.

Congestive heart failure.

Quinapril hydrochloride tablets are indicated as an adjunctive treatment of mild to moderate congestive heart failure when given concomitantly with a diuretic and/or cardiac glycoside.

4.2 Dose and Method of Administration

Quinapril Generic Health tablets should preferably be taken before meals as food with a high fat content may diminish the rate and extent of absorption of the drug.

Hypertension.

Monotherapy.

The recommended initial dosage of quinapril hydrochloride tablets in patients not on diuretics is 5 mg to 10 mg once daily. Dosage should be adjusted according to blood pressure response measured at peak (2-6 hours after dosing) and trough (predosing). Generally, dosage adjustments should be made at intervals of at least 4 weeks. Most patients have required dosages of 10 mg to 40 mg/day, given as a single dose or in two equally 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 may be warranted. When a dose of 20 mg/day is reached without adequate response, a diuretic may be added (e.g. hydrochlorothiazide 12.5 mg or 25 mg) or if the dose is increased, optimal control may require twice daily medication.

Concomitant diuretics.

If blood pressure is not adequately controlled with quinapril hydrochloride tablet monotherapy, a diuretic may be added. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of quinapril hydrochloride tablets. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with quinapril hydrochloride tablets (see Section 4.4 Special Warnings and Precautions for Use). Then, if blood pressure is not controlled with quinapril hydrochloride tablets alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 2.5 mg to 5 mg quinapril hydrochloride tablets should be used with careful medical supervision for several hours and until blood pressure has stabilised. The dosage should subsequently be titrated (as described above) to the optimal response (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Renal impairment.

Kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are shown in Table 1.
Patients should subsequently have their dosage titrated (as described above) to the optimal response.

Elderly (> 65 years).

The recommended initial dosage of quinapril hydrochloride tablets in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response.

Congestive heart failure.

Quinapril hydrochloride tablet is indicated as an adjunctive therapy with diuretics and/or cardiac glycosides. The recommended initial dosage in patients with congestive heart failure is a single 5 mg dose following which the patient should be monitored closely for symptomatic hypotension. If the initial dose of quinapril hydrochloride tablet is well tolerated, patients may be titrated slowly at weekly intervals given as a divided dose twice a day up to 20 mg/day. Those patients who have received 10 mg twice daily during 1 month with satisfactory response may be transferred to 20 mg once daily. Few patients may require 40 mg/day given in two doses. Titration to higher doses should cease after an effective dose is reached or undesirable hypotension, or orthostasis, or azotaemia prohibits reaching this dose (see Section 4.4 Special Warnings and Precautions for Use). Patients can normally be maintained effectively on doses of 10 mg to 20 mg/day given as 1 or 2 doses. Quinapril hydrochloride tablets should always be given with concomitant diuretic and/or cardiac glycoside therapy.
Following the initial dose of quinapril hydrochloride tablets, the patient should be observed under medical supervision for at least 2 hours for the presence of hypotension or orthostasis and, if present, until blood pressure stabilises. The appearance of hypotension, orthostasis, or azotaemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretics.

Dosage adjustment in patients with heart failure and renal impairment or hyponatraemia.

Pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function in patients with heart failure and renal impairment. The recommended initial dose of quinapril hydrochloride tablet is 5 mg in patients with creatinine clearance above 30 mL/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 mL/min. There is insufficient data for dosage recommendation in patients with creatinine clearance less than 10 mL/min (see Section 4.2 Dose and Method of Administration, Congestive heart failure; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.3 Contraindications

Quinapril hydrochloride tablets are contraindicated in:
patients who are hypersensitive to quinapril or any of the other ingredients in the tablet;
patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor;
combination with sacubitril/valsartan due to the increased risk of angioedema;
severe renal artery stenosis;
patients haemodialysed using high flux polyacrylonitrile ('AN69') membranes (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactoid reaction during haemodialysis);
pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Women who intend to become pregnant, or of childbearing potential unless on an effective contraceptive and highly unlikely to conceive.
Do not administer quinapril hydrochloride in combination with aliskiren in:
patients with diabetes;
patients with moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m2);
patients with hyperkalaemia (> 5 mmol/L);
congestive heart failure patients who are hypotensive.
Do not administer quinapril hydrochloride in combination with angiotensin receptor blockers or other ACE inhibitors in:
diabetic patients with end organ damage;
patients with moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m2);
patients with hyperkalaemia (> 5 mmol/L);
congestive heart failure patients who are hypotensive.

4.4 Special Warnings and Precautions for Use

Angioedema.

Since 1984, severe life-threatening angioedema has been reported with most of the ACE inhibitors. The overall incidence with some of the ACE inhibitors is approximately 0.1% to 0.2%. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually the angioedema is non-pitting oedema of the skin, mucous membrane or subcutaneous tissue.
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. Angioedema may occur with or without urticaria.
Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors. In such cases the product should be promptly discontinued and the patient carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal oedema can be fatal or near fatal. There seems to be no difference in the incidence of angioedema in patients of either sex or in those with heart failure or hypertension. In the majority of reported cases the symptoms occurred during the first week of therapy.
In USA studies, black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-black patients. It should also be noted that in controlled clinical trials conducted in Europe and North America, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-black patients.
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) or concomitant DPP-IV inhibitor (e.g. vildagliptin) therapy or a neutral endopeptidase inhibitor may be at increased risk for angioedema. Caution should be used when starting an mTOR inhibitor or a DPP-IV inhibitor or a neutral endopeptidase inhibitor (see Section 4.3 Contraindications) in a patient already taking an ACE inhibitor.

Intestinal angioedema.

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 there has been no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
There are reports where switching to another ACE inhibitor was followed by recurrence of oedema and others where it was not. Because of the potential severity of this rare event, another ACE inhibitor should not be used in patients with a history of angioedema to a drug of this class (see Section 4.3 Contraindications). Where involvement of tongue, glottis or larynx is likely to cause airway obstruction, appropriate therapy, including adrenaline and oxygen administration, should be carried out promptly or the patient hospitalised. Medical therapy of progressive angioedema should be aggressive. Failing a rapid response, oral/ nasal intubation or securing an airway by surgical means (e.g. cricothyrotomy or tracheostomy) may be necessary followed by mechanical ventilation. Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.

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 patients with impaired renal function, in salt/ volume depleted patients such as patients with renovascular hypertension, vomiting or diarrhoea, those treated vigorously with diuretics, 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)). In patients with severe congestive heart failure with or without associated renal insufficiency, excessive hypotension has been observed. This may be associated with syncope, neurological deficits, oliguria and/or progressive azotaemia, but rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started at low doses under very close supervision. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dosage is increased, or diuretic therapy is commenced or 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. In all high risk patients, it is advisable to initiate treatment at lower dosages than those usually recommended for uncomplicated patients.
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 already receiving a diuretic when quinapril is initiated can develop symptomatic hypotension. In these patients it is important, if possible, to stop the diuretic for 2 to 3 days before starting quinapril hydrochloride tablets. If blood pressure is not controlled with quinapril hydrochloride tablets alone, the diuretic should be resumed. If it is not possible to withdraw diuretic therapy, begin quinapril hydrochloride tablets at a low initial dose.

Anaphylactoid reactions during desensitisation.

Patients receiving ACE inhibitors during desensitising treatment with hymenoptera venom have sustained life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld, but they have reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during LDL apheresis.

Patients undergoing low-density lipoprotein apheresis with dextran-sulfate absorption when treated concomitantly with an ACE inhibitor, have reported anaphylactoid reactions.

Anaphylactoid reactions during haemodialysis.

Clinical evidence has shown that patients haemodialysed using certain high-flux membranes (such as polyacrylonitrile membranes) are likely to experience anaphylactoid reactions with concomitant ACE inhibitor treatment. This combination should therefore not be used (see Section 4.3 Contraindications). The use of either alternative antihypertensive drugs, or alternative membranes for haemodialysis is recommended (e.g. cuprophane or polysulphone PSF).

Foetal/neonatal morbidity and mortality.

See Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy.

Cough.

Cough has been reported with the use of ACE inhibitors, including quinapril. Characteristically, the cough is persistent dry, non-productive, and resolves after discontinuation of therapy. The frequency of reports has been increasing since cough was first recognised as a side effect of ACE inhibitor therapy. In various studies, the incidence of cough varies between 2% to 15% depending on the drug, dosage and duration of use. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
The cough is often worse when lying down or at night, and has been reported more frequently 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. The observed higher frequency of this side effect in non-smokers may be due to a higher level of tolerance in smokers to cough.
The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins which accumulate because of ACE inhibition. Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor; the reaction may recur but this is not invariably the case. A change to another class of drug may be required in severe cases.

Hypoglycaemia and diabetes.

ACE inhibitors have been associated with hypoglycaemia in diabetic patients on insulin or oral hypoglycaemic agents; closer monitoring of diabetic patients may be required.

Hyperkalaemia.

ACE inhibitors decrease the formation of angiotensin II, which results in decreased production of aldosterone and an increase in serum potassium levels (> 5.5 mEq/L). Hyperkalaemia is more likely in patients with some degree of renal impairment, those taking concomitant potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs known to raise serum potassium levels. Diabetics and elderly patients particularly, 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 serum electrolytes (including potassium, sodium and urea) measured from time to time (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). This is more important in patients taking diuretics. When administered concomitantly, quinapril may reduce the hypokalaemia induced by thiazide diuretics.

Hyponatraemia and syndrome of inappropriate anti-diuretic hormone (SIADH).

Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatraemia has been observed in some patients treated with other ACE inhibitors. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.

Neutropenia/agranulocytosis.

Agranulocytosis and bone marrow depression (including leucopenia/ 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 periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease, renal disease (serum creatinine ≥ 180 micromol/L) and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive.

Dermatological reactions.

Dermatological reactions characterised by maculopapular pruritic rashes and sometimes photosensitivity have been reported rarely with ACE inhibitors. Rare and sometimes severe skin reactions (e.g. lichenoid eruptions, psoriasis, pemphigus-like rash, rosacea, Stevens-Johnson syndrome) have also been reported. A causal relationship is difficult to assess.
A cutaneous reaction to one ACE inhibitor may not occur with another drug of the same class. There have, however, been reports of cross-reactivity.

Taste disturbance (dysgeusia).

The incidence of taste disturbance was reported to be high (up to 12.5%) with high doses of one ACE inhibitor, but the overall incidence for the class is probably low (< 0.5%). However, the relevant data are scarce and difficult to interpret.
Taste disturbance has been described as a suppression of taste or a metallic sensation in the mouth. The dysgeusia usually occurs in the first few weeks of treatment and may disappear within 1 to 3 months despite continued treatment.

Surgery/anaesthesia.

In patients undergoing major surgery or who require anaesthesia, hypotension due to anaesthetic agents may be greater in patients receiving ACE inhibitors because of interference with compensatory mechanisms associated with the renin-angiotensin system. If perioperative hypotension occurs, volume expansion would be required.

Valvular stenosis.

Patients with aortic stenosis are at a particular risk of decreased coronary perfusion and hypotension when treated with vasodilators. Vasodilators may tend to drop diastolic pressure, and hence coronary perfusion pressure, without producing the concomitant reduction in myocardial oxygen demand that normally accompanies vasodilatation. The true clinical importance of this concern is uncertain. Nevertheless, ACE inhibitors should be avoided in such patients.

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

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

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

As a consequence of inhibiting the RAAS, hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals with congestive heart failure, especially if combining medicinal products that affect this system. Dual blockade of the RAAS with ACE-inhibitors, angiotensin receptor blockers or a direct renin inhibitor such as aliskiren, is associated with an increased risk of developing these conditions compared to monotherapy. Routine combination therapy with RAAS acting agents is not recommended and should be limited to individually defined cases with close monitoring of blood pressure, renal function and electrolyte levels (see Section 4.3 Contraindications).

Use in hepatic impairment.

Hepatitis or hepatic failure have been rarely seen in clinical trials with quinapril, however, hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug. In patients with hepatic impairment from alcoholic cirrhosis, it has been shown that the half-life of quinapril was doubled in comparison to age matched controlled volunteers. This indicates that liver metabolism is an important facet of quinapril metabolism. There was no alteration in the half-life of quinaprilat probably because renal excretion is its principal method of removal. The plasma quinaprilat levels were, however, lower than matched controls. The results suggested that not only the rate but also the extent of the conversion of quinapril to quinaprilat were impaired. Particularly in patients with severe hepatic insufficiency there may be a reduction in efficacy of quinapril due to failure of conversion to the active metabolite.
Quinapril when combined with a diuretic should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Use in renal impairment.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including quinapril hydrochloride tablets, may be associated with oliguria and/or progressive azotaemia and rarely acute renal failure and/or death (see Section 4.8 Adverse Effects (Undesirable Effects)).
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in 20% of patients. These increases were usually reversible upon discontinuation of the ACE inhibitor. ACE inhibitors should not be used in patients with known or suspected renal artery stenosis (see Section 4.3 Contraindications). When an ACE inhibitor is given to a patient with stenosis of the renal artery supplying a solitary kidney or with bilateral renal artery stenosis, acute renal insufficiency may occur. ACE inhibition may also cause a decrease in renal function in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces the pressure in the afferent glomerular arteriole, and transglomerular hydrostatic pressure is then maintained by angiotensin II-induced constriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration pressure falls and renal failure may result. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors.
The half-life of quinaprilat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of < 60 mL/min require a lower initial dosage of quinapril (see Section 4.2 Dose and Method of Administration). These patients' dosage should be titrated upwards based upon therapeutic response, and renal function should be closely monitored although initial studies do not indicate that quinapril produces further deterioration in renal function.
In people with a creatinine clearance < 40 mL/min/1.73 m2, quinaprilat did accumulate but not as much as would be suggested by the increased half-life (2.2-12 hours) implying that alternative methods of removal become important.
Some hypertensive or heart failure patients with no apparent pre-existing renovascular disease have developed increases in blood urea nitrogen and serum creatinine, which is usually minor and transient. This is more likely to occur in patients with pre-existing renal impairment or in those on diuretics. Dosage reduction of the ACE inhibitor and/or discontinuation of the diuretic may be required.
Evaluation of hypertensive patients should always include assessment of renal function (see Section 4.2 Dose and Method of Administration). If a deterioration in renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by another and in these patients usage of another class of antihypertensive agent would be preferable. Patients with unilateral renal artery disease present a special problem as deterioration of renal function may not be apparent from measurement of blood urea and serum creatinine.
Some ACE inhibitors have been associated with the occurrence of proteinuria (up to 0.7%) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium-sparing diuretics or high doses of other diuretics, limited cardiac reserve, or treatment with a nonsteroidal anti-inflammatory drug. Evaluation of hypertensive patients should always include assessment of renal function (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Elderly patients exhibited increased area under the plasma concentration time curve (AUC) and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself. In controlled and uncontrolled studies of quinapril hydrochloride tablets where 918 (21%) patients were 65 years and older, no overall differences in effectiveness or safety were observed between older and younger patients. However, greater sensitivity of some older individual patients cannot be ruled out.

Paediatric use.

The safety and effectiveness of quinapril hydrochloride tablets in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant diuretic therapy.

When a diuretic is added to the therapy of a patient receiving an ACE inhibitor, the antihypertensive effect is usually additive. Patients on diuretics, especially those on recently instituted diuretic therapy or in those with intravascular volume depletion, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with quinapril hydrochloride tablets. The possibility of hypotensive effects with quinapril hydrochloride tablets may be minimised by discontinuing the diuretic and ensuring adequate hydration and salt intake prior to initiation of treatment with quinapril hydrochloride tablets. If it is not possible to discontinue the diuretic, the starting dose of quinapril hydrochloride tablets should be reduced and the patient closely observed for several hours following the initial dose of the ACE inhibitor and until the blood pressure has stabilised (see Section 4.2 Dose and Method of Administration).

Agents increasing serum potassium.

Quinapril hydrochloride tablets can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. The concomitant therapy of an ACE inhibitor with a potassium-sparing diuretic (e.g. spironolactone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes, or other drugs known to raised serum potassium levels can increase the risk of hyperkalaemia. Therefore if coadministration is indicated they should be used with caution and patient's serum potassium should be monitored frequently. In patients who are elderly or have compromised renal function, co-administration of an ACE inhibitor with sulfamethoxazole/trimethoprim has been associated with severe hyperkalaemia, which is thought to be due to trimethoprim. Quinapril and trimethoprim-containing products should therefore be co-administered with caution and with appropriate monitoring of serum potassium.

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

Dual blockade of the RAAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalaemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on quinapril hydrochloride and other agents that affect the RAAS (see Section 4.4 Special Warnings and Precautions for Use).
Do not administer quinapril in combination with aliskiren in patients with diabetes, in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2), in patients with hyperkalaemia (> 5 mmol/L) or in congestive heart failure patients who are hypotensive (see Section 4.3 Contraindications).
Do not administer quinapril in combination with angiotensin receptor blockers or other ACE inhibitors in diabetic patients with end organ damage, in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2), in patients with hyperkalaemia (> 5 mmol/L) or in congestive heart failure patients who are hypotensive (see Section 4.3 Contraindications).

Tetracycline and other drugs that interact with magnesium.

Simultaneous administration of tetracycline with quinapril hydrochloride tablets reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in quinapril hydrochloride tablets. This interaction should be considered if coprescribing quinapril hydrochloride tablets and tetracycline or other drugs that interact with magnesium.

Lithium.

Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. 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.

Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors).

Nonsteroidal anti-inflammatory drugs with prostaglandin synthetase inhibitory properties (e.g. indomethacin) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including quinapril, may be attenuated by NSAIDs.

Other drugs known to cause angioedema.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) or concomitant DPP-IV inhibitor (e.g. vildagliptin) therapy or a neutral endopeptidase inhibitor may be at increased risk for angioedema. Caution should be used when starting an mTOR inhibitor or a DPP-IV inhibitor or a neutral endopeptidase inhibitor (see Section 4.3 Contraindications) in a patient already taking an ACE inhibitor.

Agents affecting sympathetic activity.

Agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neurone blocking agents) may be used with caution. Beta-adrenergic blocking drugs will increase the antihypertensive effect of ACE inhibitors, and therefore the patient will need to be closely supervised.

Other agents.

Drug interaction studies of quinapril hydrochloride tablets with other agents showed:
Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril hydrochloride tablet.
The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril hydrochloride tablet coadministration twice daily.
Quinapril hydrochloride tablet treatment did not affect the pharmacokinetics of digoxin.
No pharmacokinetic interaction was observed when single doses of quinapril hydrochloride tablet and hydrochlorothiazide were administered concomitantly.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no adverse effects on fertility or reproduction in rats at oral doses up to 100 mg/kg/day.
(Category D)1
As with all ACE inhibitors, quinapril tablets are contraindicated in pregnancy (see Section 4.3 Contraindications). Pregnancy should be excluded before starting treatment with quinapril tablets 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.
When pregnancy is detected, the ACE inhibitor should be discontinued as soon as possible and arrangements for further care should be made.
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.
Post-marketing experience with all ACE inhibitors suggest that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus.
ACE inhibitors have been associated with foetal death in utero. Adverse events appear to be most likely in the second and third trimesters.
Infants exposed to ACE inhibitors during pregnancy may be at an increased risk for malformations of the cardiovascular system and central nervous system. There have also been reports of prematurity, hypotension, renal system disorders (including renal failure), skull hypoplasia, oligohydramnios, limb contractures, craniofacial deformities, hypoplastic lung development, intrauterine growth retardation, patent ductus arteriosus, foetal death and/or death in the newborn in association with the maternal use of ACE inhibitors.
Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia. If such complications occur, attention should be directed toward support for blood pressure and renal perfusion. Haemodialysis and peritoneal dialysis have little effect on the elimination of quinapril or quinaprilat.
1 Australian categorisation definition of: Category D.
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
 ACE inhibitors, including quinapril, are secreted in human milk to a limited extent. Because of the potential for serious reactions in nursing infants, quinapril hydrochloride tablets should not be given to a nursing mother.

4.7 Effects on Ability to Drive and Use Machines

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating quinapril hydrochloride tablet therapy.

4.8 Adverse Effects (Undesirable Effects)

Hypertension.

Quinapril hydrochloride tablets have been evaluated for safety in 4,960 subjects and patients and was well tolerated. Of these, 3,203 patients including 655 elderly patients, participated in controlled clinical trials. Quinapril hydrochloride tablets have been evaluated for long-term safety in over 1,400 patients treated for 1 year or more.
Adverse experiences were usually mild and transient in nature. Discontinuation of therapy because of adverse events was required in 4.7% of patients in placebo controlled hypertension trials.
Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 1,563 patients in placebo controlled hypertension trials who were treated with quinapril hydrochloride tablets are shown in Table 2.

Heart failure.

Quinapril hydrochloride tablets have been evaluated for safety in 1,222 quinapril hydrochloride tablet-treated patients. Of these, 632 patients participated in controlled trials. In placebo controlled trials, discontinuation of therapy because of adverse events was required in 6.8% of patients with congestive heart failure.
Adverse experience probably or possibly related or of unknown relationship to therapy occurring in 1% or more of the 585 patients in placebo controlled congestive heart failure trials who were treated with quinapril hydrochloride tablets are shown in Table 3.

Hypertension and/or heart failure.

Clinical adverse experiences probably, possibly or definitely related, or of uncertain relationship to therapy occurring in 0.5% to ≤ 1.0% (except as noted) of the patients with congestive heart failure or hypertension treated with quinapril hydrochloride tablets (with or without concomitant diuretic) in controlled or uncontrolled trials (n = 4,847) and less frequent, clinically significant events seen in clinical trials or postmarketing experience listed by body system include those in Table 4. See Table 5.

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

No specific information is available on the treatment of overdosage with quinapril.

Signs and symptoms.

The most likely clinical manifestation would be symptoms attributable to severe hypotension. Survival has been reported in a 24 year old male who presented with acute renal failure after intentionally ingesting 150 mg to 200 mg quinapril. The patient recovered without haemodialysis.

Treatment of overdosage.

Treatment is symptomatic and supportive, consistent with established medical care. Hypotension would normally be treated by intravenous volume expansion, such as an infusion of normal saline. Persistent hypotension should be treated by established procedures. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available and such determinations have, in any event, no established role in the management of quinapril overdose.
No data are available to suggest that physiological manoeuvres (e.g. manoeuvres to change the pH of the urine) that might accelerate elimination of quinapril and its metabolites would be effective.
Haemodialysis and peritoneal dialysis have little effect on the elimination of quinapril or quinaprilat.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Quinapril is deesterified to the principal metabolite, quinaprilat, which is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, noradrenaline or adrenaline. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril hydrochloride tablets alone resulted in mean increases in potassium of 0.07 mmol/L (see Section 4.4 Special Warnings and Precautions for Use). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).
Quinapril hydrochloride tablets have been shown to be effective in the treatment of congestive heart failure and hypertension. While the principal mechanism of antihypertensive effect is thought to be through the renin angiotensin aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator. Bradykinin acts on bradykinin receptors in the vascular endothelium to promote the release of the vasodilators such as nitric oxide and prostacyclin. Whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated.
ACE inhibitors, including quinapril, may enhance insulin sensitivity.

Endothelial dysfunction.

Endothelial dysfunction is associated with hypertension and heart failure and is considered an important pathophysiological mechanism in cardiovascular disease. Quinapril has been shown to improve endothelium-dependent vasomotor function by mechanisms leading to increased availability of nitric oxide. The clinical significance of improving endothelial function has not yet been established.
In patients with chronic heart failure (NYHA function class III) (n = 40), intra-arterial infusion of quinaprilat 1.6 microgram/min (n = 15) significantly increased endothelium mediated flow-dependent dilation (FDD) in the radial artery by > 40% (change in FDD: quinapril = 10.2 ± 0.6% versus control = 6.9 ± 0.6%; p < 0.01). In a six month placebo-controlled trial (n = 105), normotensive patients, with and without a history of hypertension, who were free of left ventricular dysfunction and severe dyslipidaemia and who required percutaneous coronary artery revascularisation, were treated with quinapril 40 mg daily (n = 51). There was an endothelium-dependent reduction of acetylcholine induced intra-arterial vasoconstriction of the coronary arteries (4.5 ± 3.0% and 12.1 ± 3.0% at 10-6 and 10-4 mol/L respectively; overall p = 0.002) (TREND study). Flow-mediated vasodilation (FMD) of the brachial artery was significantly increased to 9.1% from a baseline of 7.3% (change in FMD: 1.8 ± 1.0%; p < 0.02) in patients with coronary artery disease treated with quinapril 20 mg daily (n = 56) for 8 weeks in a partial-block, cross-over, blinded study of 80 patients comparing the effect of four anti-hypertensives on brachial flow-mediated vasodilation (BANFF study).

Clinical effects.

Single doses of 20 mg of quinapril hydrochloride tablets provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20 mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 mg to 80 mg.

Hypertension.

Administration of 10 mg to 40 mg quinapril hydrochloride tablets to patients with essential hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. Achievement of maximum blood pressure lowering effects may require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained throughout the 24 hour dosing interval and continue during long-term therapy with no evidence of tolerance.
Haemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction.
Use of quinapril tablets with a thiazide diuretic gives a blood pressure lowering effect greater than that seen with either agent alone.
In patients with hypertension, quinapril hydrochloride tablets 10 mg to 40 mg were similar in effectiveness to captopril, enalapril, propranolol and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (≥ 65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients.

Heart failure.

When compared with placebo therapy, quinapril hydrochloride tablet administration to patients with congestive heart failure in most controlled studies has prolonged exercise time only modestly, or not at all. On the other hand, the cessation of quinapril hydrochloride tablet therapy in patients stabilised on this therapy together with diuretic therapy has been shown to result in progressive clinical deterioration in the control of heart failure. While some short-term placebo-controlled studies have demonstrated significant improvements in NYHA functional class with quinapril hydrochloride tablet therapy, other studies have not. In longer-term but controlled studies, more consistent improvements in NYHA functional class with quinapril hydrochloride tablet therapy have been demonstrated. There is a lack of data to support an improved prognosis in congestive heart failure. The effects of quinapril on long-term mortality in heart failure have not been evaluated.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

The pharmacokinetics of quinapril and quinaprilat are linear over a single dose range of 5 mg to 80 mg doses and 40 mg to 160 mg in multiple daily doses.

Absorption.

Following oral administration, peak plasma quinapril concentrations are observed within 1 hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25% to 30%) when quinapril hydrochloride tablets are administered during a high fat meal.

Distribution.

Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.

Metabolism.

Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of quinapril hydrochloride tablets, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose.

Excretion.

Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose. It has an apparent elimination half-life in plasma of approximately 2 hours representing the clearance of the free quinaprilat from the plasma and a prolonged terminal phase with a half-life of 25 hours thought to reflect the slow release of quinaprilat from ACE.

Renal impairment.

In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic haemodialysis or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. A study in 20 patients with renal impairment (creatinine clearance 12 to 119 mL/min/1.73 m2) showed alterations in both quinapril and quinaprilat pharmacokinetics. The Cmax and AUC for quinapril were greater in patients with renal impairment and the elimination half-life tended to be longer. However, these changes were small and probably not clinically important. The pharmacokinetic data for quinaprilat were markedly different. Cmax, AUC and the elimination half-life all increased as renal impairment became greater. When the creatinine clearance was below 40 mL/min/1.73 m2, trough levels of quinaprilat were markedly increased. The elimination half-life increased from 2 to 4 hours as creatinine clearance fell from 120 to 40 mL/min/1.73 m2 and increased further to 12 to 14 hours when creatinine was 12 mL/min/1.73 m2. Thus, if a person has a creatinine clearance below 40 mL/min/1.73 m2, then it is likely that quinaprilat will accumulate and quinapril therapy should be started at a low dose and gradually titrated upward. If creatinine clearance is greater than 40 mL/min/1.73 m2, quinapril and quinaprilat are unlikely to accumulate.

Hepatic impairment.

The elimination half-life of quinapril was found to have doubled in patients with hepatic impairment from alcoholic cirrhosis when compared to age-matched healthy volunteers. This indicates that liver metabolism is an important facet of quinapril metabolism. There was no alteration in the elimination half-life of quinaprilat probably because renal excretion is its principal route of elimination. The plasma quinaprilat levels, were, however, lower than in matched controls. These results suggested that not only the rate but the extent of the conversion of quinapril to quinaprilat was impaired. Particularly in patients with severe hepatic insufficiency there may be a reduction in efficacy of quinapril due to failure of conversion to the active metabolite. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

Cardiac impairment.

The presence of mild to moderate congestive heart failure per se appears to have minimal effect on the pharmacokinetics of quinaprilat, except in so far that congestive heart failure may be associated with renal failure. Dosing of quinapril in patients with congestive heart failure should be based on their renal function.

Elderly patients.

Elimination of quinaprilat is reduced in elderly patients (≥ 65 years); this reduction is attributable to a decrease in renal function (see Section 4.2 Dose and Method of Administration) and not to age itself.
Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.

5.3 Preclinical Safety Data

Genotoxicity.

Neither quinapril nor quinaprilat are mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicological studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleous test with mice, in vitro chromosome aberration with V79 cultured lung cells and an in vivo cytogenetic study with rat bone marrow.

Carcinogenicity.

At least one other ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential of ACE inhibitors to cause this effect in man is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when it does occur, it is considered to be benign.
Quinapril was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day for 104 weeks. Female rats given the highest dose level have an increased incidence of mesenteric lymph node haemangiomas and skin/ subcutaneous lipomas.

6 Pharmaceutical Particulars

6.1 List of Excipients

Quinapril Generic Health tablets also contain magnesium carbonate hydrate, calcium sulfate dihydrate, colloidal anhydrous silica, crospovidone, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, lecithin, iron oxide yellow, and xanthan gum.

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.

6.5 Nature and Contents of Container

Quinapril Generic Health tablets available in Al/Al blister pack of 30 tablets.
Not all strengths are currently marketed in Australia.

Australian registration numbers.

Quinapril Generic Health 5 mg tablets: AUST R 133199.
Quinapril Generic Health 10 mg tablets: AUST R 133200.
Quinapril Generic Health 20 mg tablets: AUST R 133201.

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

Quinapril tablets contain the hydrochloride salt of quinapril the ethyl ester of a nonsulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. The drug molecule contains three chiral centres but is present as the pure S-S-S-stereoisomer.

Chemical structure.


Chemical Name: 3-isoquinolinecarboxylic acid, 2-[2-[[1-(ethoxycarbonyl)- 3-phenylpropyl]amino]-1-oxopropyl]- 1,2,3,4-tetrahydro monohydrochloride, [3S-[2[R*(R*)],3R*]]; or (S)-2-[(S)-N- [(S)-1-carboxy-3-phenylpropyl]alanyl]- 1,2,3,4-tetrahydro- 3-isoquinolinecarboxylic acid, 1-ethyl ester, monohydrochloride.
Molecular Formula: C25H30N2O5.HCl.
Molecular Weight: 475.0.

CAS number.

82586-55-8.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes