Consumer medicine information

Accuretic

Quinapril; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Accuretic

Active ingredient

Quinapril; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Accuretic.

SUMMARY CMI

Accuretic®

Consumer Medicine Information (CMI) summary

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

1. Why am I using Accuretic?

Accuretic contains the active ingredients quinapril hydrochloride and hydrochlorothiazide. Accuretic is used to lower high blood pressure (hypertension).

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

2. What should I know before I use Accuretic?

Do not use if you have ever had an allergic reaction to Accuretic, any sulfonamide or sulfur medicines or any of the ingredients listed at the end of the CMI.

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

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

3. What if I am taking other medicines?

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

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

4. How do I use Accuretic?

For most patients, the usual starting dose is one Accuretic 10 mg/12.5 mg tablet a day. The dose may need to be increased to one Accuretic 20 mg/12.5 mg tablet a day, then two Accuretic 10 mg/12.5 mg tablets a day if necessary.

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

5. What should I know while using Accuretic?

Things you should do

  • Remind any doctor, dentist or pharmacist you visit that you are using Accuretic.
  • Make sure you drink enough water during exercise and hot weather, especially if you sweat a lot.
  • Tell your doctor if you have excess vomiting and/or diarrhoea while taking Accuretic.
  • Tell your doctor immediately if you feel light-headed or dizzy after taking your first dose of Accuretic, or when your dose is increased.
  • Have your blood pressure checked when your doctor says, to make sure Accuretic is working.
  • Regularly check your skin for any new or suspicious skin lesions.

Things you should not do

  • Do not stop using this medicine, or change the dosage, without checking with your doctor.

Driving or using machines

  • Be careful driving or operating machinery until you know how Accuretic affects you.

Drinking alcohol

  • If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Drinking alcohol may make these symptoms worse. If it does, reduce your consumption of alcohol.
  • Your doctor may advise you to limit your alcohol intake.

Looking after your medicine

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

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

6. Are there any side effects?

Side effects include feeling light-headed, dizzy or faint, dry cough, headache, nausea or vomiting, stomach pain, diarrhoea, constipation, tiredness or weakness, fatigue, sleepiness or drowsiness, impotence, runny or blocked nose, sneezing, loss of taste, confusion, restlessness, back pain, indigestion, sore throat, rash. For more serious side effects and further information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Accuretic® (ack-u-ret-tic)

Active ingredient(s): quinapril hydrochloride and hydrochlorothiazide (quin-a-pril hi-dro-clor-ride and hi-dro-clor-o-thigh-a-zide)


Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Accuretic?

Accuretic contains the active ingredients quinapril hydrochloride and hydrochlorothiazide. Accuretic is a combination of a medicine called angiotensin converting enzyme (ACE) inhibitor and a diuretic "water tablet".

Accuretic 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.

Accuretic works by:

  • widening your blood vessels, which reduces pressure in the vessels, making it easier for your heart to pump blood around your body.
  • making your kidneys pass more water and salt and retain more potassium. This helps reduce high blood pressure.

2. What should I know before I use Accuretic?

Warnings

Do not use Accuretic if:

  1. you are allergic to quinapril hydrochloride or hydrochlorothiazide, any sulfonamide or sulfur medicines, or any of the ingredients listed at the end of this leaflet
    One of the active ingredients of Accuretic, hydrochlorothiazide, is a sulfur-containing medicine (a sulfonamide). Therefore, if you are allergic to sulfur medicines, such as some antibiotics, you are likely to be allergic to Accuretic. Check with your doctor or pharmacist if you are not sure whether you are allergic to sulfur medicines.
    Symptoms of an allergic reaction to Accuretic may include skin rash, itchiness, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain.
    Always check the ingredients to make sure you can use this medicine
  2. 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
    If you have had an allergic reaction to an ACE inhibitor before, you may be allergic to Accuretic.
  3. you or your family have a history of swelling of the face, lips, tongue, throat, hands or feet for no apparent reason
  4. you have kidney problems or a condition called 'renal artery stenosis'
  5. you have regular dialysis for blood filtration
  6. 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.
  7. you are currently taking a neutral endopeptidase inhibitor, used to treat high blood pressure or heart failure
    Taking Accuretic with a neutral endopeptidase inhibitor (e.g. sacubitril/ valsartan combination) increases your risk of angioedma, rapid swelling of your face, lips, mouth, tongue or throat and may result in difficulty in swallowing or breathing.
  8. you are pregnant or breastfeeding
    Accuretic may enter your womb or it may pass into the breast milk and there is the possibility that your baby may be affected.
  9. the expiry date printed on the pack has passed or if the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have any allergies to any other medicines, foods, preservatives or dyes
    have any other 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
    - gout
    - high cholesterol
    - Systemic Lupus Erythematosus (SLE), scleroderma or other autoimmune diseases
    - non-melanoma skin cancer
    - psoriasis (red patches on your skin) or worsening of already existing psoriasis.
  • have previously had trouble breathing, fever, or low blood pressure after taking hydrochlorothiazide
  • 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
  • take any medicines for any other condition.

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

Pregnancy and breastfeeding

If you become pregnant while taking Accuretic, tell your doctor immediately.

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

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

Children

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

3. What if I am taking other medicines?

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

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

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)
  • digoxin, a medicine used to treat heart failure
  • neutral endopeptidase inhibitor (e.g. sacubitril/valsartan combination), a medicine used to treat high blood pressure or heart failure.
  • other 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
  • allopurinol, a medicine used to treat gout
  • 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
  • any other antibiotics and medicines to treat infections
  • steroid medicines such as cortisone, prednisone
  • insulin and tablets used to treat diabetes
  • barbiturates, used to treat epilepsy, such as phenobarbitone
  • strong pain killers such as codeine, morphine, dextropropoxyphene
  • cholestyramine and colestipol, used to treat high cholesterol
  • medicines used to relax muscles before and during surgery
  • medicines used in emergency situations such as adrenaline.

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

  • angiotensin II receptor blocker (ARB)
  • aliskiren.
    For some patients, Accuretic should not be taken in combination with these medicines.
    Your doctor may check your kidney function, blood pressure and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.

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

  • mTOR inhibitors (e.g. temsirolimus), used in the treatment of kidney cancer
  • DPP-IV inhibitors (e.g. vildagliptin), used in the treatment of diabetes.
    Taking Accuretic in combination with these medicines may increase your risk of having an allergic reaction.

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

4. How do I use Accuretic?

How much to take

  • for most patients, the usual starting dose is one Accuretic 10 mg/12.5 mg tablet a day
  • the dose may need to be increased to one Accuretic 20 mg/12.5 mg tablet a day, then two Accuretic 10 mg/12.5 mg tablets a day if necessary
  • most patients take between 10 mg/12.5 mg to 20 mg/12.5 mg daily
  • each dose may be taken once a day
  • follow the instructions provided and use Accuretic until your doctor tells you to stop.

When to take Accuretic

  • take Accuretic at about the same time each day, with or without food
    Taking it at the same time each day will have the best effect. It will also help you remember when to take the tablets.
    It does not matter whether you take it with or without food.

How to take Accuretic

  • swallow the tablets whole with a full glass of water
  • do not chew the tablets.

If you forget to use Accuretic

Accuretic should be used regularly at the same time each day.

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 you missed.

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

If you use too much Accuretic

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

You should immediately:

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

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

5. What should I know while using Accuretic?

Things you should do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking Accuretic.

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

If you do not drink enough water while taking Accuretic, 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 and/or diarrhoea while taking Accuretic, or you have any of the following symptoms:

  • dry mouth, thirst
  • weakness, tiredness, drowsiness
  • muscle pains or cramps
  • fast heart beat
  • passing less urine than normal.

You may be dehydrated because you are losing too much water.

If you are going to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking Accuretic.

Your blood pressure may drop suddenly.

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

Accuretic may interfere with the results of some tests.

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

Regularly check your skin for any new or suspicious skin lesions. It has been observed that one of the ingredients in Accuretic may increase the risk of non-melanoma skin cancer if used at a high dose, or for an extended period.

Limit sun exposure and use adequate sun protection to minimise risk.

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.

Call your doctor straight away if you feel light-headed or dizzy after taking your first dose of Accuretic, or when your dose is increased.

Things you should not do

  • do not stop using this medicine suddenly, or change the dosage, without checking with you doctor
  • do not give your medicine to anyone else, even if they have the same condition as you
  • do not take Accuretic to treat any other complaints unless your doctor or pharmacist tells you to.

Things that would be helpful for your blood pressure

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.

Driving or using machines

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

As with other medicines in this class, Accuretic may cause dizziness, light-headedness or tiredness in some people. Make sure you know how you react to Accuretic 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.

Drinking alcohol

Be careful if you feel light-headed, dizzy or faint when getting out of bed or standing up. It is suggested you 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.

Drinking alcohol may make these symptoms worse. If it does, reduce your consumption of alcohol.

Looking after your medicine

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

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

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

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

Do not use this medicine after the expiry date.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

6. Are there any side effects?

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

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

Mild side effects

Mild side effects

What to do

  • feeling light-headed, dizzy or faint
  • dry cough
  • headache
  • feeling sick (nausea) or vomiting
  • stomach pain
  • diarrhoea
  • constipation
  • unusual tiredness or weakness, fatigue
  • sleepiness or drowsiness
  • difficulty in getting or maintaining an erection (impotence)
  • runny or blocked nose, or sneezing
  • taste disturbances or loss of taste
  • confusion or nervousness
  • restlessness
  • back pain
  • indigestion
  • sore throat and discomfort when swallowing
  • rash

Speak to your doctor if you have any of these mild side effects and they worry you.

Serious side effects

Serious side effects

What to do

  • eye pain, vision problems
  • blurred vision or yellow vision
  • itchy or raised skin rash, hives or nettle rash
  • muscle cramps
  • symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly than normal
  • signs of anaemia such as tiredness, being short of breath and looking pale
  • tingling or numbness in the hands, feet or ankles
  • severe upper stomach pain, often with nausea and vomiting
  • 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
  • passing little or no urine
  • swelling of the hands, feet or ankles
  • bleeding or bruising more easily than normal
  • yellowing of the skin and/or eyes
  • new or suspicious skin lesions

Call your doctor as soon as possible if you notice any of these serious side effects.

More serious side effects

What to do

  • fainting within a few hours of taking a dose
  • fast or irregular heart beat
  • shortness of breath or tightness in the chest
  • sudden or general weakness, or weakness in the arms or legs
  • sudden onset of stomach pains or cramps with or without nausea or vomiting
  • pink or red itchy spots on the skin which may blister and progress to form raised, red, pale-centered marks
  • severe flaking or peeling of the skin
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • severe skin reaction which starts with painful red areas, then large blisters and ends with peeling of layers of skin. This may be accompanied by fever and chills, aching muscles and generally feeling unwell
  • chest pain
  • loss of vision; may be temporary or more gradual

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these more serious side effects.

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

Stop taking Accuretic as well

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

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

Reporting side effects

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

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

7. Product details

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

What Accuretic contains

Active ingredients

(main ingredient)

Accuretic 10 mg/12.5 mg - 10 mg quinapril hydrochloride and 12.5 mg hydrochlorothiazide per tablet

Accuretic 20 mg/12.5 mg - 20 mg quinapril hydrochloride and 12.5 mg hydrochlorothiazide per tablet

Other ingredients

(inactive ingredients)

crospovidone

lactose monohydrate

magnesium carbonate hydrate

magnesium stearate

povidone

candelilla wax

Opadry Pink OY-S-6937

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

What Accuretic looks like

Accuretic 10 mg/12.5 mg - pink, oval, biconvex, film-coated tablets, scored on both sides
AUST R 81930

Accuretic 20 mg/12.5 mg - pink, triangular, biconvex, film-coated tablets, scored on one side
AUST R 81931

A box of Accuretic contains 30 tablets.

Who distributes Accuretic

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedicalinformation.com.au

This leaflet was prepared in July 2022.

© Pfizer Australia Pty Ltd 2022

®Registered Trade Mark

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Accuretic

Active ingredient

Quinapril; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Quinapril hydrochloride and hydrochlorothiazide.

2 Qualitative and Quantitative Composition

Accuretic is a fixed-combination tablet that combines an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a diuretic, hydrochlorothiazide (HCTZ). Accuretic is available in two tablet strengths.
Accuretic 10/12.5 containing quinapril 10 mg/ hydrochlorothiazide 12.5 mg.
Accuretic 20/12.5 containing quinapril 20 mg/ hydrochlorothiazide 12.5 mg.

Excipient(s) with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablet.

Accuretic 10/12.5 tablets.

Pink, oval, biconvex, film-coated tablets, scored on both sides. Each tablet contains 10 mg of quinapril and 12.5 mg of hydrochlorothiazide.

Accuretic 20/12.5 tablets.

Pink, triangular, biconvex, film-coated tablets, scored on one side. Each tablet contains 20 mg of quinapril and 12.5 mg of hydrochlorothiazide.

4 Clinical Particulars

4.1 Therapeutic Indications

Accuretic is indicated for the treatment of hypertension. Treatment should not be initiated with these fixed dose combinations.

4.2 Dose and Method of Administration

Patients not currently receiving a diuretic.

For patients not currently receiving a diuretic, whether or not they have been receiving quinapril monotherapy, the recommended initial dosage of Accuretic is one Accuretic 10/12.5 tablet once daily, taken with or without food. If blood pressure is not adequately controlled, the dose may be increased to one Accuretic 20/12.5 tablet once daily and then to two Accuretic 10/12.5 tablets once daily if necessary. Further dose increases are not expected to produce any additional reduction in blood pressure.
The score lines on Accuretic 10/12.5 tablets allow the tablets to be halved for the administration of a low starting dose in patients who are already taking a diuretic (see below). The score line on Accuretic 20/12.5 tablets is for identification purposes only. Accuretic 20/12.5 should not be prescribed as half tablets.

Patients currently receiving a diuretic or who are volume or salt depleted.

Patients who are volume or salt depleted should be adequately hydrated before starting Accuretic.
In patients who are currently being treated with a diuretic, the diuretic should be discontinued 2 to 3 days before starting treatment with one Accuretic 10/12.5 tablet once daily. Once blood pressure has stabilised, the dose of Accuretic may be titrated as usual.
If the diuretic cannot be discontinued, quinapril should be added at an initial dose of 2.5 to 5 mg once daily to minimise the potential for hypotension, and patients changed to Accuretic when they reach doses equivalent to those provided by the combination tablets. Alternatively, patients may be started on Accuretic at a dose of 5/6.25 (half a 10/12.5 tablet) once daily, then titrated upwards. In either case, the first dose should be given under medical supervision and patients observed until blood pressure has stabilised because of the risk of hypotension.

Use in renal impairment.

Dosage modification is not required in patients with mild to moderate renal impairment (creatinine clearance 30-60 mL/min). Accuretic is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min).
When concomitant diuretic therapy is required in such patients, a loop diuretic rather than a thiazide diuretic is preferred for use with quinapril.

4.3 Contraindications

Accuretic is contraindicated in:
Patients who are hypersensitive to either quinapril hydrochloride and/or hydrochlorothiazide, or any of the other ingredients in the tablet.
Patients with a history of hereditary and/or idiopathic angioedema or angioedema related to previous treatment with ACE inhibitors.
Combination with sacubitril/valsartan due to the increased risk of angioedema (see Section 4.4 Special Warnings and Precautions for Use, Angioedema; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other drugs known to cause angioedema).
Severe renal artery stenosis.
Due to the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide derived drugs.
Patients haemodialysed using high flux polyacrylonitrile ('AN69') membranes (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactoid reactions, 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 Accuretic 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 Accuretic 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 nonimmunogenic and may be related to accentuated bradykinin activity. Usually the angioedema is nonpitting 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 nonblack 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 nonblack 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 in a patient already taking an ACE inhibitor (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other drugs known to cause angioedema).

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.

Accuretic can cause symptomatic hypotension, usually not more frequently than either drug as monotherapy. Symptomatic hypotension was rarely seen in uncomplicated hypertensive patients treated with quinapril but is a possible consequence of ACE inhibition therapy in salt/ volume depleted patients such as those previously treated with diuretics, who have a dietary salt restriction, or who are on dialysis (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).
Accuretic should be used cautiously in patients receiving concomitant therapy with other antihypertensive agents. The thiazide component of Accuretic may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patients.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy for hypertension may cause an excessive drop in blood pressure, which may be associated with oliguria, azotaemia, and in rare instances, with acute renal failure and death in such patients. Accuretic therapy should be started under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased.
If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses; however, lower doses of the drug should be considered if this event occurs.

Anaphylactoid reactions.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

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.

LDL apheresis.

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

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 alternative antihypertensive drugs, or alternative membranes for haemodialysis is recommended (e.g. cuprophane or polysulphone PSF).

Systemic lupus erythematosus.

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Fetal/ 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, nonproductive 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 nonsmokers 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 that 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.

Diabetes.

Thiazide induced hyperglycaemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycaemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
ACE inhibitors have been associated with hypoglycaemia in diabetic patients on insulin or oral hypoglycaemic agents; closer monitoring of diabetic patients may be required.

Serum electrolytes.

Serum electrolyte evaluation should be performed at appropriate intervals to detect possible electrolyte imbalance. As with other ACE inhibitors, patients on quinapril alone may have increased serum potassium levels. In clinical trials, hyperkalaemia (serum potassium ≥ 5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril. In most cases, elevated serum potassium levels were isolated values that resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalaemia. Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus and the concomitant use of potassium sparing diuretics, potassium supplements, potassium containing salt substitutes, or other drugs known to raise serum potassium levels. The addition of a potassium sparing diuretic to Accuretic, which contains a diuretic, is not recommended.
Conversely, treatment with thiazide diuretics has been associated with hypokalaemia, hyponatraemia and hypochloraemic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures and vomiting. Hypokalaemia can also sensitise or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids, adrenocorticotrophic hormone (ACTH) or other drugs known to increase the risk of hypokalaemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Chloride deficits secondary to thiazide therapy are generally mild and require specific treatment only under extraordinary circumstances (e.g. in liver disease or renal disease). Dilutional hyponatraemia may occur in oedematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatraemia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcaemia and hypophosphataemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption and peptic ulceration) have not been seen.
Thiazides should be discontinued before performing tests for parathyroid function.
Thiazides increase the urinary excretion of magnesium, and hypomagnesaemia may result (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Other metabolic disturbances.

Thiazide diuretics tend to raise serum levels of cholesterol, triglycerides and uric acid. These effects are usually minor, but frank gout may be precipitated in susceptible patients (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Neutropenia/ agranulocytosis.

ACE inhibitors have been rarely associated with agranulocytosis and bone marrow depression in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease. Agranulocytosis has been rarely reported during treatment with quinapril. As with other ACE inhibitors, periodic monitoring of white blood cell counts in quinapril treated patients with collagen vascular disease and/or renal disease should be considered.

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, and 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.

Caution should be exercised when patients undergo major surgery or anaesthesia since angiotensin converting enzyme inhibitors have been shown to block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension that can be corrected by volume expansion.

Choroidal effusion, acute myopia and secondary angle closure glaucoma.

Hydrochlorothiazide, a sulphonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, acute transient myopia and acute angle closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle close glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulphonamide or penicillin allergy.

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see Section 4.8 Adverse Effects (Undesirable Effects)).

Acute respiratory distress syndrome (ARDS).

Severe cases of acute respiratory toxicity, including ARDS have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Accuretic should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Psoriasis and aggravation of psoriasis.

Psoriasis or aggravation of psoriasis have been reported in patients receiving ACE inhibitors. Accuretic should be used with caution in patients, especially those with a medical history or family history of psoriasis. Consider discontinuation of Accuretic if clinically significant psoriasis or psoriasis aggravation occurs.

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.

Accuretic 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. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase, patients with impaired liver function could develop markedly elevated plasma levels of quinapril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.

Use in renal impairment.

Accuretic is not recommended in patients with severe renal disease. Thiazides may precipitate azotaemia in such patients, and the effects of repeated dosing may be cumulative.
Some quinapril treated hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or quinapril may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see Section 4.2 Dose and Method of Administration).
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, 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)).
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 the drug (see Section 4.2 Dose and Method of Administration). These patients' dosage should be titrated upwards based upon therapeutic response; renal function should be closely monitored, although initial studies do not indicate that the drug produces further deterioration in renal function.
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 some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

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 be related to decreased renal function rather than to age itself. Of the total number of patients who received Accuretic in clinical trials, 15% were 65 or older, while 1.5% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tetracycline and other drugs that interact with magnesium.

Administration of tetracycline with quinapril reduced the absorption of tetracycline by approximately 28% to 37%. Decreased absorption is due to the presence of magnesium carbonate as an excipient in the quinapril formulation. This interaction should be considered when contemplating concurrent therapy with Accuretic and tetracycline or other drugs that interact with magnesium.

Lithium.

Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy due to the sodium losing effect of these agents. With Accuretic, the risk of lithium toxicity may be increased. Accuretic should be administered with caution and frequent monitoring of serum lithium levels is recommended.

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.

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

In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium sparing and thiazide diuretics. Therefore, when Accuretic and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of Accuretic is obtained.
In patients who are elderly, volume depleted (including those on diuretic therapy), or with compromised renal function, coadministration 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 in a patient already taking an ACE inhibitor (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Angioedema).

Agents increasing serum potassium.

If concomitant therapy of quinapril with potassium supplements, potassium containing salt substitutes, or other drugs known to raise serum potassium levels is indicated, they should be used with caution along with appropriate monitoring of serum potassium (see Section 4.4 Special Warnings and Precautions for Use). Since Accuretic contains a diuretic, the addition of a potassium sparing diuretic is not recommended. In patients who are elderly or have compromised renal function, coadministration of an ACE inhibitor with sulfamethoxazole/ trimethoprim has been associated with severe hyperkalaemia, which is thought to be due to trimethoprim. Quinapril/ HCTZ and trimethoprim containing products should therefore be coadministered 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 Accuretic and other agents that affect the RAAS (see Section 4.4 Special Warnings and Precautions for Use).
Do not administer quinapril/ HCTZ 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/ HCTZ 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).

Anion exchange resins.

Absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins, such as cholestyramine and colestipol. Single doses of the resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Other agents.

No clinically important pharmacokinetic interactions occurred when quinapril was used concomitantly with propranolol, hydrochlorothiazide or cimetidine. The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily.
When administered concurrently, the following drugs may interact with thiazide diuretics.

Alcohol, barbiturates, or narcotics.

Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral hypoglycaemic agents and insulin).

Thiazide induced hyperglycaemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycaemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (see Section 4.4 Special Warnings and Precautions for Use).

Other antihypertensive drugs.

Additive effect or potentiation.

Corticosteroids, ACTH.

Intensified electrolyte depletion, particularly hypokalaemia.

Digoxin.

Thiazide induced electrolyte disturbances (i.e. hypokalaemia, hypomagnesaemia) increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (see Section 4.4 Special Warnings and Precautions for Use).

Gout medications (allopurinol, uricosurics, xanthine oxidase inhibitors).

Thiazide induced hyperuricaemia may compromise control of gout by allopurinol and probenecid. The coadministration of hydrochlorothiazide and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol.

Pressor amines (e.g. noradrenaline).

Possible decreased response to pressor amines, but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarising (e.g. tubocurarine).

Possible increased responsiveness to the muscle relaxant.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of hydrochlorothiazide and the quinapril/ hydrochlorothiazide combination on fertility have not been evaluated in animal studies. However, with quinapril alone, there were no adverse effects on fertility or reproduction in rats at oral doses up to 100 mg/kg/day.
(Category D)
As with all ACE inhibitors, Accuretic is contraindicated in pregnancy (see Section 4.3 Contraindications). Pregnancy should be excluded before starting treatment with Accuretic 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.
Infants exposed to ACE inhibitors during pregnancy may be at an increased risk for malformations of the cardiovascular system and central nervous system. 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 with 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.
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, fetal death and/or death in the newborn in association with the maternal use of ACE inhibitors.
Infants exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Thiazides cross the placental barrier and appear in cord blood. Nonteratogenic effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in the adult.
ACE inhibitors, including quinapril, are secreted in human milk to a limited extent. Thiazides appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue Accuretic or discontinue nursing, taking into account the importance of the drug to the 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 Accuretic therapy.

4.8 Adverse Effects (Undesirable Effects)

Accuretic has been evaluated for safety in 1571 patients in controlled and uncontrolled studies. In clinical trials with Accuretic, no adverse experience specific to the combination has been observed. Adverse experiences that have occurred have been limited to those previously reported with quinapril or hydrochlorothiazide. In controlled trials, the most frequent adverse experiences reported in at least 1% of patients with any combination of quinapril and hydrochlorothiazide were headache (6.7%), dizziness (4.8%), cough (3.2%) and fatigue (2.9%). It should be noted that, characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy.
Generally, adverse experiences were mild and transient in nature, and there was no relationship between side effects and age, sex, race, or duration of therapy (see Section 4.4 Special Warnings and Precautions for Use regarding angioedema and excessive hypotension or syncope).
Discontinuation of therapy due to adverse effects was required in approximately 2% of patients. Headache (0.5%) was the most common reason for withdrawal followed by cough and nausea and/or vomiting (0.2%). Adverse experiences occurring in ≥ 1% of patients treated with Accuretic in controlled trials are shown in Table 1 (n = 943).
Clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy, occurring in 0.5% to ≤ 1.0% of patients treated with quinapril plus hydrochlorothiazide in controlled and uncontrolled trials and less frequent clinically significant events seen in clinical trials, postmarketing experience, or with hydrochlorothiazide included (see Table 2):

Postmarketing experience.

Adverse reactions that have been reported postmarketing with Accuretic which are not listed above, regardless of causality, include the following.

Body as a whole.

Face oedema, tongue oedema, angioedema and oedema.

Neoplasms benign, malignant and unspecified (including cysts and polyps) - frequency 'not known'.

Non-melanoma skin cancer (Basal cell carcinoma, and Squamous cell carcinoma) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Haematological.

Leucopenia.

Renal.

Acute kidney failure.

Laboratory findings.

Serum electrolytes.

See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.

Creatinine, blood urea nitrogen.

Increases (> 1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with Accuretic (see Section 4.4 Special Warnings and Precautions for Use).

Serum uric acid, glucose, magnesium, cholesterol, triglyceride, PBI, parathyroid function tests and calcium.

See Section 4.4 Special Warnings and Precautions for Use.

Haematology.

See Section 4.4 Special Warnings and Precautions for Use.
Quinapril has been evaluated for safety in 4960 subjects and patients and was well tolerated. Of these, 3203 patients including 655 elderly patients, participated in controlled clinical trials. Quinapril has been evaluated for long-term safety in over 1400 patients treated for one year or more.

Other adverse events reported when quinapril is taken separately.

The following adverse events, other than those listed above for Accuretic, have been reported with quinapril therapy as probably, possibly, or definitely related, or of uncertain relationship to therapy in 0.5 to ≤ 1.0% of patients in both hypertension and/or heart failure studies. See Table 3.

Other adverse events reported when hydrochlorothiazide is taken separately.

The following adverse events, other than those listed above for Accuretic, have been reported with hydrochlorothiazide.

Body as a whole.

Fever.

Cardiovascular.

Hypotension including orthostatic hypotension, necrotising angiitis.

Gastrointestinal.

Anorexia, constipation, gastric irritation, jaundice (intrahepatic cholestatic jaundice) and sialoadenitis.

Haematological.

Agranulocytosis, aplastic anaemia and purpura.

Integumentary.

Urticaria, toxic epidermal necrolysis.

Metabolic.

Glycosuria, hyperglycaemia, hyperuricaemia, hyponatraemia and hypokalaemia.

Nervous/ psychiatric.

Xanthopsia.

Renal.

Interstitial nephritis, renal dysfunction.

Respiratory.

Respiratory distress (including pneumonitis and pulmonary oedema).

Other.

Muscle spasm, restlessness and transient blurred vision.

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 overdosage with Accuretic.

Signs and symptoms.

Available data suggest that Accuretic overdosage, due to its ACE inhibitor component might be expected to produce severe hypotension.
The most common signs and symptoms observed for hydrochlorothiazide monotherapy overdosage are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.

Recommended treatment.

Treatment is symptomatic and supportive. Dehydration and electrolyte imbalance should be treated by established procedures. Hypotension would normally be treated by intravenous volume expansion, such as an infusion of normal saline, with established procedures being implemented to treat persistent hypotension. 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 physiological manoeuvres (e.g. manoeuvres to change 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 and quinaprilat. In a case report of a patient with endstage renal failure, toxicity due to inadvertently high dose hydrochlorothiazide treatment was successfully managed by haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In clinical studies, concomitant administration of quinapril and hydrochlorothiazide produced greater reductions in blood pressure than the single agents given alone.
As a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity (PRA), increases aldosterone secretion, decreases serum potassium and increases urinary potassium loss. Administration of quinapril inhibits the renin angiotensin aldosterone axis and tends to attenuate the potassium decrease associated with hydrochlorothiazide.
Quinapril is de-esterified to the principal metabolite, quinaprilat, which is an inhibitor of angiotensin converting enzyme (ACE) activity in human and animal studies. 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 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 PRA.
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 monotherapy was an effective antihypertensive in all races studied, although it was somewhat less effective in black patients (usually a predominantly low renin group) than in nonblack patients. 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.
In a study in spontaneously hypertensive rats, the magnitude of the antihypertensive effect of quinapril correlated more closely with inhibition of tissue ACE than inhibition of plasma ACE.

Clinical trials.

Administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within one hour with peak effects usually achieved by two to four hours after dosing. Achievement of maximum blood pressure lowering effects may require two weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24 hour dosing interval and continue during long-term therapy. Therapeutic effects of quinapril 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.
Haemodynamic assessments in patients with hypertension have indicated 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.
The mechanism underlying the antihypertensive activity of diuretics is unknown. During chronic administration peripheral vascular resistance is reduced; however, this may be secondary to changes in sodium balance.
Hydrochlorothiazide is a diuretic that acts directly on the kidney to increase excretion of sodium and chloride and an accompanying volume of water. Hydrochlorothiazide also increases the excretion of potassium and bicarbonate and decreases calcium excretion. Chronic treatment with hydrochlorothiazide elevates PRA two to sixfold. After oral administration of hydrochlorothiazide, diuresis begins within two hours, peaks in about four hours and lasts about six to twelve hours.
Combination therapy with quinapril and hydrochlorothiazide gives a blood pressure lowering effect greater than that seen with either agent alone.

Non-melanoma skin cancer.

Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,553 cases of BCC and of 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High HCTZ use (≥ 50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

5.2 Pharmacokinetic Properties

Concomitant administration of quinapril and hydrochlorothiazide has no effect on the pharmacokinetics of either drug.

Absorption.

Following oral administration, peak plasma quinapril concentrations are observed within one hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is approximately 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50-80%).
The rate of quinapril absorption was reduced by 14% when Accuretic tablets were administered with a high fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when Accuretic tablets were administered with a high fat meal, while the extent of absorption was not significantly affected. Therefore, Accuretic may be administered without regard to food.

Distribution.

Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is 68% bound to plasma proteins and has an apparent volume of distribution of 0.83 to 1.141 L/kg.

Metabolism.

Following absorption, 38% of orally administered quinapril is systemically available as quinaprilat. Peak plasma quinaprilat concentrations are observed approximately two hours following an oral dose of quinapril. Hydrochlorothiazide is not metabolised.
Studies in rats indicate that quinapril and its metabolites do not cross the blood brain barrier. Hydrochlorothiazide crosses the placental but not the blood brain barrier.

Excretion.

Quinaprilat 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. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of three hours following multiple oral dosing of quinapril.
Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.

Special populations.

Renal impairment.

In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. Pharmacokinetic studies in patients with endstage renal disease on chronic haemodialysis or continuous ambulatory peritoneal dialysis indicate that dialysis has little effect on the elimination of quinapril and quinaprilat (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 4.2 Dose and Method of Administration, Use in renal impairment).

Hepatic impairment.

Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Elderly (≥ 65 years).

Elimination of quinaprilat is reduced in elderly patients (≥ 65 years) and correlates well with their level of renal function (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly; Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow.
Hydrochlorothiazide was not genotoxic in a gene mutation assay in bacterial cells, or in tests for clastogenic activity in vitro and in vivo. However, positive results were obtained in a mammalian cell assay for gene mutation (mouse lymphoma cell assay) and in two other tests (sister chromatid exchange assay in Chinese hamster ovary cells and nondisjunction assay in Aspergillus nidulans).

Carcinogenicity.

Carcinogenicity and mutagenicity studies of quinapril in combination with hydrochlorothiazide have not been conducted in animals.
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 humans 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 hydrochloride 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.
With hydrochlorothiazide, two year feeding studies in mice and rats uncovered no evidence of carcinogenic potential in female mice at doses up to approximately 600 mg/kg/day, or in male and female rats at doses up to approximately 100 mg/kg/day. The studies, however, uncovered equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide at approximately 600 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Crospovidone, lactose monohydrate, magnesium carbonate hydrate, magnesium stearate, povidone, candelilla wax, Opadry Pink OY-S-6937.

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

Tablets should be stored below 25°C.

6.5 Nature and Contents of Container

Accuretic 10/12.5 tablets.

Blister pack of 7s, 10s and 30s.

Accuretic 20/12.5 tablets.

Blister pack of 7s, 10s and 30s.
Not all pack sizes are marketed in Australia.

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 hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents.
Hydrochlorothiazide is a white to off-white, crystalline powder that is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Chemical structure.

Quinapril hydrochloride.


Chemical name: 2-(S)-[N-[[1-ethoxycarbonyl]- 3-phenylpropyl]-(S)-alanyl]- 1,2,3,4-tetrahydro-3-(S)-isoquinoline carboxylic acid, monohydrochloride.
Molecular formula: C25H30N2O5.HCl.
Molecular weight: 474.98.

Hydrochlorothiazide.


Chemical name: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.
Molecular formula: C7H8ClN3O4S2.
Molecular weight: 297.72.

CAS number.

Quinapril hydrochloride: 82586-55-8.
Hydrochlorothiazide: 58-93-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes