Consumer medicine information

Captopril Sandoz

Captopril

BRAND INFORMATION

Brand name

Captopril Sandoz

Active ingredient

Captopril

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Captopril Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Captopril Sandoz.

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 this medicine 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 the medicine. You may need to read it again.

WHAT CAPTOPRIL SANDOZ IS USED FOR

This medicine is used to treat:

  • high blood pressure (hypertension)
  • certain heart conditions
  • certain kidney conditions associated with diabetes.

It contains the active ingredient captopril.

Captopril belongs to a group of medicines called angiotensin converting enzymes (ACE) inhibitors.

It works by widening your blood vessels, which reduces pressure in the vessels. This makes it easier for your heart to pump blood around your body, and helps your kidneys work better.

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

This medicine is not addictive.

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

BEFORE YOU TAKE CAPTOPRIL SANDOZ

When you must not take it

Do not take this medicine if you have an allergy to:

  • captopril, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.
  • any other similar medicines such as ACE inhibitors. Examples include perindopril (Coversyl®), ramipril (Tritace®) and enalapril (Renitec®).

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you have or have had a history of swelling of the face, lips, tongue, throat, hands or feet, for no apparent reason.

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. The active ingredient in Captopril Sandoz may pass into breast milk and there is a possibility that your baby may be affected.

Do not use this medicine in combination with aliskiren in patients with type 2 diabetes. Concomitant use of angiotensin-converting enzyme inhibitors (ACEIs)- including captopril with aliskiren is associated with an increased incidence of hypotension, hyperkalemia and changes in renal function.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • kidney problems, you have one kidney, or are undergoing dialysis. You may be at increased risk of a severe allergic reaction when Captopril Sandoz is combined with some dialysis treatments.
  • liver problems
  • heart problems
  • cerebrovascular disease (disease of the blood vessels supplying blood to the brain)
  • diabetes
  • low blood pressure, which you may notice as dizziness or light-headedness, especially when standing
  • neutropenia (low white blood cell count)
  • collagen vascular diseases such as systemic lupus erythematosus or scleroderma
  • any other medical conditions not listed in this leaflet.

Tell your doctor if you:

  • have a family history of swelling of the face, lips, tongue, throat, hands or feet
  • are following a very low salt diet. Low blood pressure may develop in people who are following a very low salt diet.
  • have recently suffered from excessive vomiting or diarrhoea
  • are about to receive desensitisation treatment for an allergy, e.g. to insect stings
  • are taking immunosuppressant medicines (medicines that lower your immune system)
  • are scheduled to have surgery (including at the dentist) under general anaesthetic. Your blood pressure may drop suddenly.

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

Taking other medicines

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

Some medicines and Captopril Sandoz may interfere with each other. These include:

  • other medicines used to treat high blood pressure
  • diuretic tablets, also known as fluid or water tablets, such as frusemide (Lasix®, Urex®) or indapamide (Natrilix®)
  • any medicines used for angina, such as glyceryl trinitrate
  • lithium, a medicine used to treat mood swings and some types of depression
  • potassium tablets such as Duro-K®, Slow-K®, Span-K®, K-Mag®, K-Sol® or Chlorvescent®
  • potassium-containing salt substitutes such as Pressor K®potassium-sparing agents such as spironolactone (Aldactone®), triamterene (Hydrene 25/50®) or amiloride (Moduretic®)
  • medicines which may increase potassium levels (e.g. heparin, trimethoprim/sulfamethoxazole)
  • non-steroidal anti-inflammatory drugs (NSAIDs or COX-2 inhibitors), medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis. Examples include aspirin, ibuprofen (Nurofen®) and celecoxib (Celebrex®
  • mammalian target of rapamycin inhibitors (e.g. temsirolimus, sirolimus, everolimus).

These medicines may be affected by Captopril Sandoz 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 and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE CAPTOPRIL SANDOZ

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, ask your doctor or pharmacist for help.

How much to take

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Captopril Sandoz may not work as well and your condition may not improve.

The usual dose ranges from 12.5mg to 50mg taken two or three times per day.

Some patients may need a lower starting dose. The dose may need to be increased, depending on your response.

How to take it

Swallow the tablets whole with a full glass of water.

When to take Captopril Sandoz

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

Take your medicine on an empty stomach, for example, 1 hour before food. Food can interfere with the absorption of this medicine.

How long to take Captopril Sandoz

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

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

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

Do not take a double dose to make up for the dose 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 Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Captopril Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include light-headedness, dizziness or fainting.

WHILE YOU ARETAKING CAPTOPRIL SANDOZ

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Captopril Sandoz.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery (even at the dentist) that needs a general anaesthetic, tell the surgeon, dentist or anaesthetist that you are taking this medicine. Your blood pressure may drop suddenly during surgery.

Tell your doctor immediately if you feel any light-headedness or dizziness after you take your first dose of Captopril Sandoz or if your dose is increased. This is especially important if you are taking Captopril Sandoz for heart failure.

Make sure you drink enough water during exercise and hot weather while you are taking Captopril Sandoz, especially if you sweat a lot. If you do not drink enough water while you are taking Captopril Sandoz, 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.

If you experience excess vomiting or diarrhoea while taking Captopril Sandoz, tell your doctor. You may lose too much water and salt and your blood pressure may drop too much.

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

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

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will need to check your blood pressure to make sure Captopril Sandoz is working.

Your doctor may do some blood tests from time to time to check your potassium levels and to see how your kidneys are working.

Things you must not do

Do not take Captopril Sandoz totreat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Captopril Sandoz affects you. This medicine may cause dizziness, light-headedness and tiredness in some people, especially after the first dose or if the dose is increased. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness or light-headedness may be worse.

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.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Captopril Sandoz.

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

Do not be alarmed by the following lists 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 or pharmacist if you notice any of the following and they worry you:

  • light-headedness or dizziness
  • headache
  • tiredness
  • dry cough
  • muscle cramps
  • mild stomach upsets such as feeling sick, diarrhoea or stomach pains
  • inability to get or maintain an erection (impotence)
  • difficulty sleeping (insomnia) or strange dreams
  • changes in the way things taste or loss of taste
  • symptoms of hyperkalaemia (high levels of potassium in your body) such as confusion, irregular heartbeat, nervousness, numbness or tingling of the hands, feet or lips, shortness of breath or difficulty breathing, weakness or heaviness of the legs.

These are the more common side effects of the medicine.

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

  • fast or irregular heart beats
  • yellowing of the skin and/or eyes, also called jaundice
  • itchy skin rash or other skin problems
  • signs of frequent or worrying infections such as fever, mouth or tongue ulcers
  • bruising more easily than normal
  • signs of anaemia such as tiredness, being short of breath and looking pale
  • passing less urine than is normal for you
  • changes in mood, confusion or depression.

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

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • pinkish, itchy swellings on the skin, also called hives or nettle rash
  • fainting
  • chest pain or feeling of tightness, pressure or heaviness in the chest
  • wheeziness due to tightness in the chest.

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

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

Some side effects (for example changes in kidney and liver function or low blood cell counts) can only be found when your doctor does tests from time to time to check your progress.

AFTER TAKING CAPTOPRIL SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Do not store Captopril Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

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 tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Captopril Sandoz comes in three types of tablets:

Captopril Sandoz 12.5mg - round, white tablets with a score mark on one side.

Captopril Sandoz 25mg - round, cloverleaf shaped, white tablets with a crossed break mark on both sides.

Captopril Sandoz 50mg - round, cloverleaf shaped, white tablets with a crossed break mark on both sides.

Available in blisters of 90 tablets.

Ingredients

Active ingredient:

  • Captopril Sandoz 12.5mg - 12.5mg captopril
  • Captopril Sandoz 25mg - 25mg captopril
  • Captopril Sandoz 50mg - 50mg captopril.

Inactive ingredients:

  • lactose
  • microcrystalline cellulose
  • maize starch
  • stearic acid.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier/Distributor

Sandoz Pty Ltd
ABN 60 075 449 55354 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in August 2017.

Australian Register Numbers

12.5mg tablets: AUST R 61419 (blisters)

25mg tablets: AUST R 61416 (blisters)

50mg tablets: AUST R 61420 (blisters)

Published by MIMS October 2017

BRAND INFORMATION

Brand name

Captopril Sandoz

Active ingredient

Captopril

Schedule

S4

 

1 Name of Medicine

Captopril.

2 Qualitative and Quantitative Composition

Each Captopril Sandoz 12.5 mg film coated tablet contains 12.5 mg captopril.
Each Captopril Sandoz 25 mg film coated tablet contains 25 mg captopril.
Each Captopril Sandoz 50 mg film coated tablet contains 50 mg captopril.
Not all strengths may be marketed in Australia.

Excipient with known effect.

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

3 Pharmaceutical Form

Captopril Sandoz 12.5 mg film coated tablets are round tablets with a "snap tab" break mark on one side, convex on the other side, uniform white surface - diameter 6.0 - 6.2 mm.
Captopril Sandoz 25 mg film coated tablets are round tablets of a "cloverleaf" shape with facet and a crossed break mark on both sides, uniform white surface - diameter 8.0 - 8.2 mm.
Captopril Sandoz 50 mg film coated tablets are round tablets of a "cloverleaf" shape with facet and a crossed break mark on both sides, uniform white surface - diameter 10.0 - 10.2 mm.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Captopril Sandoz is indicated for the treatment of hypertension.
In using Captopril Sandoz, consideration should be given to the risk of neutropenia/agranulocytosis (see Section 4.4 Special Warnings and Precautions for Use).
Captopril Sandoz is effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive.

Myocardial infarction.

Captopril Sandoz is indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction, manifested as an ejection fraction ≤ 40%, and to reduce the incidence of overt heart failure and subsequent hospitalisations for congestive heart failure in these patients. The efficacy data for the use of Captopril Sandoz following myocardial infarction are strongest for initiation of therapy beyond 3 days post-infarction.

Heart failure.

Captopril Sandoz is indicated for the treatment of heart failure. In symptomatic patients, it is recommended that Captopril Sandoz be administered together with a diuretic.

Diabetic nephropathy.

Captopril Sandoz is indicated for the treatment of diabetic nephropathy (proteinuria > 500 mg/day) in patients with type I insulin dependent diabetes mellitus. In these patients, Captopril Sandoz reduces the progression of renal disease and reduces associated clinical sequelae (dialysis, renal transplantation and death).

4.2 Dose and Method of Administration

Dosage.

A first dose of hypotensive effect, severe in some patients, may occur. To minimise this effect, the dosage should be individualised and titrated from a low starting dose to the maintenance dose.
Captopril Sandoz should be taken one hour before meals.

Hypertension.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient's previous antihypertensive drug regime for one week before starting Captopril Sandoz.
In most patients, a starting dose of 12.5 mg may be used. The dose may then be increased to 25 mg twice daily. If a satisfactory reduction of blood pressure has not been achieved after 2 - 4 weeks, the dose of Captopril Sandoz may be increased to 50 mg twice daily. Concomitant sodium restriction may be beneficial when Captopril Sandoz is used alone.
In patients in whom a satisfactory reduction in blood pressure is not achieved after a further two weeks at this dosage, it is likely that the hypertension may have a substantial volume dependent component. In these patients, it may be appropriate to add a thiazide diuretic. The diuretic dose may be increased at one to two week intervals until its highest usual antihypertensive dose is reached. The usual effective dose of Captopril Sandoz in mild to moderate hypertension does not exceed 50 mg twice daily.
In patients with severe refractory hypertension, or on high doses of diuretics, low salt diet or dialysis, a lower starting dose (6.25 - 12.5 mg) may be used, with titration to daily doses of 25 or 50 mg twice daily.
If Captopril Sandoz is being started in a patient already receiving a diuretic, Captopril Sandoz therapy should be initiated under close medical supervision (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In severe hypertension where further blood pressure reduction is required, larger or more frequent dosing may be necessary. A daily dose of Captopril Sandoz 75 mg twice daily should not normally be exceeded.
For patients with accelerated or malignant hypertension, particularly those unresponsive to conventional therapy, it may be necessary to implement the schedule given above at intervals of 24 hours, under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of Captopril Sandoz is reached.

Myocardial infarction.

Therapy may be initiated as early as 3 days following a myocardial infarction. After an initial dose of 6.25 mg, Captopril Sandoz therapy should be increased as tolerated to 25 mg three times daily during the next several days and to a final target dose of 50 mg three times daily over the next several weeks.
If symptomatic hypotension occurs, a dosage reduction may be required. Subsequent attempts at achieving the target dose of 150 mg should be based on the patient's tolerance to Captopril Sandoz.
Captopril Sandoz may be used in patients treated with other post-myocardial infarction therapies, e.g. thrombolytics, aspirin and β-blockers.

Heart failure.

Captopril Sandoz therapy must be started under close medical supervision. It should be added to conventional treatment with a diuretic (and digitalis where indicated).
Patients with cardiac failure may demonstrate sensitivity to the effects of Captopril Sandoz in the early stages of therapy.
In patients in whom greater sensitivity may be suspected (e.g. sodium depletion and/or high doses of diuretics), the hypotensive effects of the first dose may be minimised by the use of a 2.5 mg starting dose. This product should not be used to initiate therapy in such patients, as the smallest achievable dose with Captopril Sandoz Tablets is 6.25 mg. In other patients, a starting dose of 6.25 mg three times daily may be used, although a transient hypotensive effect may occur at this dosage.
The maintenance dose of Captopril Sandoz is usually in the range 25 - 75 mg twice daily. Where possible, a period of at least two weeks should be allowed before dose increase within this range. A maximum daily dose of 150 mg should normally not be exceeded.
Patients treated for severe congestive heart failure should be cautioned to increase their physical activity slowly.

Diabetic nephropathy.

In patients with diabetic nephropathy, the recommended dose of captopril is 75 - 100 mg daily, in divided doses.
Clinical trials in normotensive type 1 diabetic patients with microalbuminuria (albumin excretion rate between 30 - 300 mg/day) showed that captopril at a dose of 50 mg twice daily attenuated the progression of the disease.
Clinical trials in normotensive and controlled hypertensive type 1 diabetic patients with overt proteinuria (total protein excretion > 500 mg/day) demonstrated that captopril at a dose of 25 mg three times daily had significant beneficial effects by reducing the need for dialysis and transplantation or the occurrence of death.
The effects of captopril were independent of, and additional to, its antihypertensive activity. If further blood pressure reduction is required, other antihypertensive agents such as diuretics, β-adrenoreceptor blockers, centrally acting agents or vasodilators may be used in conjunction with captopril.

Dosage adjustment in renal impairment.

Captopril excretion is reduced in the presence of impaired renal function. Accordingly, for patients with significant renal impairment, initial daily dosage of Captopril Sandoz should be reduced, and smaller increments utilised for titration, which should be quite slow (1 - 2 week intervals). After the desired therapeutic effect has been achieved, the total daily dose should be reduced or the dose intervals increased.
Captopril is removed by haemodialysis.
When concomitant diuretic therapy is required, a loop diuretic (e.g. frusemide) rather than a thiazide diuretic is preferred in patients with impaired renal function.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients or to any other angiotensin-converting enzyme (ACE) inhibitor.
History of previous hypersensitivity to captopril.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor.
Concomitant use of ACE inhibitors - including captopril - or of angiotensin receptor antagonists (ARBs) with aliskiren in patients with type 2 diabetes.

4.4 Special Warnings and Precautions for Use

Anaphylactoid and possibly related reactions.

Presumably because ACE is essential for degradation of endogenous bradykinin, patients receiving ACE inhibitors are subject to a variety of adverse reactions producing effects ranging from relatively mild, such as cough (see Section 4.4 Special Warnings and Precautions for Use), to serious such as the following.

Head and neck angioedema.

Severe life-threatening angioedema has been reported rarely with most of the ACE inhibitors. The overall incidence is approximately 0.1 - 0.2%. There seems to be no sex difference in the incidence of angioedema or in the predisposition to angioedema in patients with heart failure or hypertension. In the majority of reported cases, the symptoms occurred during the first week of therapy, although the onset of angioedema may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom-free intervals. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually the angioedema involves non-pitting oedema of the skin and oedema of the subcutaneous tissues and mucous membranes. 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 discontinued promptly and appropriate monitoring instituted to ensure complete resolution of symptoms.
In instances when swelling has been confined to the face and lips, the angioedema has generally resolved either without treatment or with antihistamines. Angioedema associated with laryngeal oedema is potentially life threatening. Where involvement of the 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. Patients who respond to medical treatment should be observed carefully for a possible re-emergence of symptoms of angioedema.
There are reports where changing the patient over to another ACE inhibitor was followed by recurrence of oedema and others when 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).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

Intestinal angioedema.

Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including CT scans 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 receiving co-administration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Anaphylactoid reactions during desensitisation.

Two patients undergoing desensitising treatment with hymenoptera venom while receiving another ACE inhibitor, enalapril, sustained life threatening anaphylactoid reactions. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.

Anaphylactoid reactions during high flux dialysis/lipoprotein apheresis membrane exposure.

Patients haemodialysed using high flux polyacrylonitrile ("AN69") membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein aphaeresis with dextran sulfate absorption. These combinations should therefore be avoided, either by use of a different class of medication or alternative membranes (e.g. cuprophane or polysulfone (PSF) for haemodialysis).

Proteinuria.

Total urinary proteins greater than 1 g/day were seen in about 0.7% of patients receiving captopril, the majority of whom had prior renal disease or were receiving relatively high doses (in excess of 150 mg/day), or both. In mild to moderate hypersensitive patients, the incidence dropped to 0.06%. Alterations in renal function (as assessed by blood urea nitrogen and serum creatinine) were infrequent and did not occur in those who had no prior renal disease.
Nephrotic syndrome (hypoalbuminaemia, oedema and proteinuria > 3 g/day) occurred in about one-fifth of the proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function such as BUN and creatinine were seldom altered in the patients proteinuria.
Although membranous glomerulopathy was found in biopsies taken from proteinuric patients, a causal relationship to captopril has not been established since pre-treatment biopsies were not taken and membranous glomerulopathy has been shown to occur in hypertensive patients not receiving captopril.
In a multicentre, double blind, placebo controlled trial in 207 patients with diabetic nephropathy and proteinuria (≥ 500 mg/day) receiving captopril at 75 mg/day for a median of 3 years, there was a consistent reduction in proteinuria. It is unknown whether long-term therapy in patients with other types of renal disease would have similar effects.
Patients with prior renal disease or those receiving captopril at doses > 150 mg/day should have urinary protein estimations (dipstick on first morning urine) prior to treatment and periodically thereafter.

Neutropenia/agranulocytosis.

Neutropenia has occurred in some patients receiving captopril, but this has been limited chiefly to those who had pre-existing impaired renal function, collagen vascular disease, immunosuppressant therapy, or a combination of these complicating factors.
In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen vascular disease), neutropenia has been seen in one patient out of over 8,600 exposed.
In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function. In foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia.
In patients with collagen vascular disease (e.g. systemic lupus erythematosus, scleroderma), particularly those with co-existing renal impairment, captopril should be prescribed only after an assessment of benefit and risk since neutropenia has occurred in 8 out of the 124 such patients in clinical trials.
Neutropenia was noted 2 to 13 weeks after captopril therapy started and it developed relatively slowly, the white cell count falling to its nadir over 10 to 30 days.
Neutropenia was usually not associated with significant alterations in red cell or platelet counts.
Evaluation of white cell counts in the total patient population suggests a possible general, but milder, effect on neutrophils. In most studies, there was a 5 to 10 percent decrease in leucocyte count over the first eight weeks of treatment. This was not seen in patients on placebo, propranolol or hydrochlorothiazide, although it was seen on standard triple therapy. The change in white cell count was not progressive and the effect was no longer apparent after 12 weeks in most patients. The significance of these changes is uncertain.
For patients with significantly impaired renal function, collagen vascular disease, or who are receiving immunosuppressant drugs and for patients with pre-existing neutropenia, white blood cell and differential counts should be performed prior to therapy and at regular intervals thereafter.
All patients receiving captopril should be instructed to report any signs of infection (e.g. sore throat, fever). A complete white blood cell count should be performed immediately when such report is made.
In general, neutrophils returned to normal in about two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13% of neutropenia cases have ended fatally, but almost all fatalities were in patients with serious illness, i.e. collagen vascular disease, renal failure, heart failure or on immunosuppressant therapy, or a combination of these complicating factors.
Evaluation of the hypertensive or heart failure patient should include assessment of renal function.
If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two week intervals for three months, then periodically.
Since discontinuation of captopril and other drugs has generally led to prompt return of the white cell count to normal, upon confirmation of neutropenia (neutrophil count < 1,000/mm3), the physician should withdraw captopril and closely follow the patient's course.

Hypotension.

Hypotension may occur occasionally in patients commencing treatment with ACE inhibitors. Excessive hypotension is rarely seen in patients with uncomplicated hypertension but can develop in patients with impaired renal function, in those who are salt/volume depleted because of renovascular disease, diuretic therapy, vomiting or diarrhoea, and in 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 heart failure, where the blood pressure was either normal or low, transient decreases in mean blood pressure greater than 20% are recorded in about half of the patients. This transient hypotension may occur after any of the first several doses and is usually well tolerated producing either no symptoms or mild light headedness, although in rare instances it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6% of patients with heart failure.
Only a few patients with refractory heart failure secondary to a mechanical lesion of the heart have been studied with captopril. Of possible concern in patients with aortic stenosis are the potentially harmful consequences of reduced coronary perfusion secondary to hypotension. Patients treated for severe congestive heart failure should be cautioned to increase their physical activity slowly.
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 and, 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 (6.25 or 12.5 mg twice or three times daily) under very close supervision. Such patients should be followed closely for the first two 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, respectively. 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 difficultly once the blood pressure has increased. The magnitude of the decrease is greatest early in the course of treatment: this effect stabilises within a week or two, and generally returns to pre-treatment levels, without a decrease in therapeutic efficacy, within two months.

Hyperkalaemia.

Because the ACE inhibitors decrease the formation of angiotensin II and the subsequent production of aldosterone, serum potassium exceeding 5.5 mEq/L may occur, although frank hyperkalaemia is uncommon. Hyperkalaemia is more likely in patients with some degree of renal impairment, hypoaldosteronism or those treated with potassium sparing diuretics or potassium supplements, and in those consuming potassium containing salt substitutes or other drugs associated with increases in serum potassium (e.g. heparin, trimethoprim containing medicines including, cotrimoxazole also known as trimethoprim/sulfamethoxazole). Diabetic patients and elderly diabetics particularly, may be at increased risk of hyperkalaemia. It is recommended that patients taking an ACE inhibitor should have serum electrolytes (including potassium, sodium and urea) measured from time to time. This is more important in patients taking diuretics.

Cough.

A persistent, dry (non-productive) cough has been reported with all of the ACE inhibitors and appears to be a class effect. In studies with various ACE inhibitors, the incidence of cough varies between 2% and 15% depending upon the drug, dosage and duration of use. The cough, which may be due to increased bronchial reactivity, appears to be more common in women (approximately 2:1) and often worse when lying down. It may resolve or diminish with continued use or with dose reduction, but usually returns on rechallenge. The cough is most likely caused by increased bronchial reactivity attributed 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 drugs may be required in severe cases. No residual effects have been reported. ACE inhibitor induced cough should be considered part of the differential diagnosis of cough.

Use in diabetic nephropathy.

In managing a patient with microalbuminuria the physician should be mindful of the importance of reducing other risk factors for progression to proteinuria, for example, the need to maintain adequate control of blood glucose and blood pressure.
The physician should also alert normotensive patients with diabetic nephropathy to the possibility of the rare occurrence of hypotension during treatment with captopril.

Surgery/anaesthesia.

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, captopril will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension, which can be corrected by volume expansion.

Risk of hypokalaemia.

The combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular monitoring of potassium should be performed.

Use in hepatic impairment.

Rarely, ACE inhibitors have been associated with a syndrome, which starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical attention.

Use in renal impairment.

Hypertension.

Some patients with renal disease, particularly those with renal artery stenosis, have developed increases in serum concentrations of BUN and serum creatinine after reduction of blood pressure with captopril, usually in conjunction with a diuretic. Captopril dosage reduction and/or discontinuation of diuretic may be required. For some of these patients, it may not be possible to normalise blood pressure and maintain adequate renal perfusion; therefore, titration to acceptable blood pressure may be necessary.
In patients with low renal perfusion (bilateral renal artery stenosis, renal artery stenosis to a solitary kidney), the renin-angiotensin may be an important regulator of glomerular filtration rate. Captopril should be administered cautiously in such patients.
Evaluation of the hypertensive patient 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 function may not be apparent from measurement of blood urea nitrogen and serum creatinine.

Heart failure.

About 20% of patients develop stable elevations of BUN and serum creatinine greater than 20% above normal or baseline upon long-term treatment with captopril. Less than 5% of patients, generally those with severe pre-existing renal disease, required discontinuation of treatment due to progressively increasing creatinine. Subsequent improvement probably depends upon the severity of the underlying renal disease.

Use in the elderly.

No data available.

Paediatric use.

Safety and effectiveness in children have not been established, although there is limited experience in children with secondary hypertension and varying degrees of renal failure. Dosage, on a weight basis, was comparable to that used in adults. Captopril should be used only if the potential benefit justifies the risk.

Effects on laboratory tests.

Captopril may cause a false positive urine test for acetone.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Hypotension in patients on diuretic therapy.

When a diuretic is added to the therapy of a patient receiving captopril, the antihypertensive effect is usually additive. Patients receiving diuretics, especially those in whom diuretic therapy was recently instituted or in those with intravascular volume depletion, may sometimes experience an excessive reduction of blood pressure usually within the first hour of therapy with captopril. The possibility of hypotensive effects may be minimised by discontinuing the diuretic and ensuring adequate hydration and salt intake prior to commencing ACE inhibitor therapy. If it is not possible to discontinue the diuretic, the starting dose of captopril should be reduced and the patient closely observed for several hours following the initial dose of the ACE inhibitor and until blood pressure has stabilised.

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

Concomitant use of a renin-angiotensin system inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID, including 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. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination, and periodically thereafter.
Dual blockade of the renin-angiotensin-system (RAS) with ACE inhibitors, angiotensin receptor antagonists or aliskiren is associated with an increased incidence of hypotension, hyperkalemia, and changes in renal function compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on captopril and other agents that affect the RAS. The concomitant use of ACE inhibitors, including captopril, or of angiotensin receptor antagonists with aliskiren should be avoided in patients with severe renal impairment (GFR < 30 mL/min). The concomitant use of ACE inhibitors, including captopril, or of angiotensin receptor antagonists with aliskiren is contraindicated in patients with type 2 diabetes.

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 co-administered 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.

Agents affecting sympathetic activity.

The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. β-adrenergic blocking drugs add some further antihypertensive effect to captopril, but the overall response is less than additive, patients will need to be closely supervised.

Agents increasing serum potassium.

Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics (e.g. spironolactone, triamterene or amiloride) or potassium supplements should be given only for documented hypokalaemia, and then with caution, since they lead to a significant increase in serum potassium. Salt substitutes containing potassium or other medicines with increases in serum potassium (e.g. trimethoprim containing medicines) should also be used with caution.

Nonsteroidal anti-inflammatory drugs.

There is some evidence to suggest that concomitant administration of NSAIDs such as indomethacin may reduce the response to ACE inhibitors, but further data are needed to clarify whether such an effect is of clinical significance. Further, concomitant administration of the two classes of agents may increase the risk of hyperkalaemia.

Agents having vasodilator activity.

Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available. Therefore, glyceryl trinitrate or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting captopril. If resumed during captopril therapy, such agents should be administered cautiously and perhaps at lower dosage.

Haemodialysis membranes.

Hypersensitivity-like (anaphylactoid) reactions have been reported with high flux dialysis membranes (see Section 4.4 Special Warnings and Precautions for Use).

Alpha blocking agents.

Concomitant use of alpha blocking agents may increase the antihypertensive effects of captopril and increase the risk of orthostatic hypotension.

Mammalian target of rapamycin (mTOR) inhibitors.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Co-trimoxazole (trimethoprim/sulfamethoxazole).

Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use).

Combination of ACE inhibitors and vildagliptin.

Patients taking concomitant vildagliptin therapy may be increased risk of angioedema.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
As with all ACE inhibitors, Captopril Sandoz should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Captopril Sandoz and avoided during treatment.
If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment.
If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management. Monitoring of the foetal development should be performed on a regular basis.
When used in pregnancy, ACE inhibitors can cause injury and even death to the developing foetus.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with foetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure and death.
Oligohydramnios has also been reported, presumably resulting from decreased foetal renal function. Oligohydramnios has been associated with foetal limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation. Prematurity and patent ductus arteriosus have been reported.
A historical cohort study in over 29,000 infants born to non-diabetic mothers has shown 2.7 times higher risk for congenital malformations in infants exposed to any ACE inhibitor during 1st trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02) respectively, compared to no exposure.
 Following oral administration, concentrations of captopril in human breast milk are 1% or less of those in maternal blood. The effect of this low level of captopril on the breastfed infant has not been determined. Caution should be exercised when captopril is administered to a woman who is breastfeeding and, in general, breastfeeding should be interrupted.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, adverse effects of captopril include dizziness and disturbed vision, which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Reported incidences are based on clinical trials involving approximately 7,000 patients treated with captopril.

More common reactions.

Cardiovascular.

Hypotension occurs in about 2% of patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Dermatological.

Rash occurred in 3.8% of patients with normal renal function and 13.1% of patients with evidence of prior renal function impairment. The rash is usually pruritic and maculopapular, but rarely urticarial, and generally occurs during the first 4 weeks of treatment. It is usually self-limited and reversible and may respond to antihistamine therapy.
In the majority of patients, the condition resolves with the continuation of therapy.
The rash was sometimes accompanied by fever and arthralgia, and in 7 to 10% of patients, by eosinophilia and/or positive antinuclear antibody (ANA) titres.

Cough.

Cough has been reported in 0.5 to 2% of patients in clinical trials of captopril (see Section 4.4 Special Warnings and Precautions for Use).

Taste disturbances (dysgeusia).

1.6% of patients receiving 150 mg or less of captopril per day developed a diminution or loss of taste perception. At doses in excess of 150 mg/day, 7.3% of patients experienced this effect. Taste impairment is reversible and usually self-limited to 2 - 3 months, even with continued drug administration. Weight loss may be associated with the loss of taste.

Less common reactions.

Cardiovascular.

Tachycardia, chest pain and palpitations have been observed in about 1% of patients.
Angina pectoris, myocardial infarction, Raynaud's phenomenon and congestive heart failure have occurred in 0.2 - 0.3% of patients. Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances/orthostatic hypotension, syncope.

Gastrointestinal.

Gastric irritation, abdominal pain and pancreatitis have been reported. Nausea, vomiting, diarrhoea, anorexia and constipation may occur. Stomatitis resembling aphthous ulcers, tongue ulceration and a scalded sensation of the oral mucosa have been reported.
Cases of hepatitis have been reported in association with captopril administration. The predominant form of captopril associated hepatic injury is cholestasis, although mixed or pure hepatocellular injury has also been reported.

Genitourinary.

Proteinuria (see Section 4.4 Special Warnings and Precautions for Use). Renal insufficiency, acute renal failure, polyuria, oliguria and urinary frequency have been reported in 0.1 - 0.2% of patients. Cases of nephrotic syndrome and glomerulopathy have also been reported.

Haematological and reticuloendothelial.

Neutropenia/agranulocytosis (see Section 4.4 Special Warnings and Precautions for Use). Reversible lymphadenopathy, eosinophilia, anaemia, pancytopenia and thrombocytopenia have been reported.

Dermatological.

Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been observed in approximately 1 in 1000 patients (see Section 4.4 Special Warnings and Precautions for Use). Flushing or pallor has been reported in 0.2 - 0.5% of patients. Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis, photosensitivity.

Other.

Paraesthesia of the hands, serum sickness-like syndrome, myalgia, fatigue, malaise and dizziness have been reported. Dry mouth, dyspnoea, bronchospasm, disturbed vision, itching and/or dry eyes, impotence, loss of libido and insomnia have occurred rarely, often in patients on multiple drug therapy. Asthenia and gynaecomastia.

Severe or life-threatening reactions.

Angioedema/hypotension (see Section 4.4 Special Warnings and Precautions for Use).
Neutropenia/agranulocytosis (see Section 4.4 Special Warnings and Precautions for Use).

Altered laboratory findings.

Elevations of hepatic transaminases, alkaline phosphatase and serum bilirubin have occurred but no causal relationship to captopril use has been established.
A transient elevation BUN and serum creatinine may occur, especially in patients who are volume depleted or who have renovascular hypertension. In instances of rapid reduction of long standing or severely elevated blood pressure, the glomerular filtration rate may decrease transiently also resulting in transient rises in serum creatinine and BUN.
Small increases in the serum potassium concentration frequently occur, especially in patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use). Hyponatraemia may occur, particularly in patients receiving a low sodium diet or concomitant diuretics.
Changes in blood cell counts and anaemia have occurred during treatment with captopril (see Section 4.8 Adverse Effects (Undesirable Effects), Less common reactions, Haematological and reticuloendothelial).

Post-introduction safety experience.

Other clinical adverse effects reported since the medicine was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined.

Foetal/neonatal morbidity and mortality.

The use of ACE inhibitors during pregnancy has been associated with foetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased foetal renal function; oligohydramnios in this setting has been associated with foetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported. More recently, prematurity, patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have been reported following exposure limited to the first trimester of pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Musculoskeletal.

Myasthenia.

Nervous/psychiatric.

Ataxia, confusion, depression, nervousness, somnolence, insomnia, dream abnormality, hallucinations.

Respiratory.

Eosinophilic pneumonitis, rhinitis.
As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

While Captopril Sandoz may be removed from the adult circulation by haemodialysis, there is inadequate data concerning the effectiveness of haemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing Captopril Sandoz; there is no information concerning exchange transfusion for removing Captopril Sandoz from the general circulation.

Treatment.

Treatment should be symptomatic if overdosage occurs.
Correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure.
While captopril may be removed from the adult circulation by haemodialysis, there are inadequate data concerning the effectiveness of haemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing captopril. There is no information concerning exchange transfusion for removing captopril from the general circulation.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

Captopril is the first of a new chemical class of antihypertensive agents. It also has been shown to be of benefit in the management of heart failure. It is a highly specific competitive inhibitor of angiotensin I converting enzyme, the enzyme responsible for the conversion of angiotensin I to angiotensin II.

5.1 Pharmacodynamic Properties

Administration of captopril results in a reduction in peripheral arterial resistance in hypertensive patients with either no change or an increase in cardiac output.
Clinically significant reductions of blood pressure are often observed 60 to 90 minutes after oral administration of captopril. However, the reduction in blood pressure is usually progressive and to achieve maximal therapeutic effects of a given dosage regimen, several weeks of administration may be required. The duration of effect appears to be dose related.
Blood pressure is lowered in both standing and supine positions. Orthostatic effects and tachycardia are infrequent, occurring most commonly in volume depleted patients. No sudden increase in blood pressure after withdrawal of the drug has been observed.
Studies have demonstrated an increase in renal blood flow after administration of captopril. Glomerular filtration rate is usually unchanged. In instances of rapid reduction of long standing or severely elevated blood pressure, the glomerular filtration rate may decrease transiently, resulting in transient rises in serum creatinine and urea nitrogen. In humans, the renin-angiotensin system plays a role in regulating the glomerular filtration rate when renal perfusion is low. Administration of captopril may result in acute deterioration of glomerular filtration in such patients.

Mechanism of action.

The mechanism of action of captopril has not yet been fully elucidated, however its beneficial effects in hypertension and heart failure appear to result primarily through suppression of the renin-angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesised by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted enzymatically by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II, one of the most potent endogenous vasoconstrictor substances. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex thereby contributing to sodium and fluid retention and potassium loss.
Captopril prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxyhydrolase. This is reflected by a decrease in the pressor substance angiotensin II, and an increase in plasma renin activity (PRA). The latter is due to the relative lack of negative feedback on renin release caused by reduction in angiotensin II. Decreased concentrations of aldosterone are found in blood and urine and, as a result, small increases in serum potassium may occur along with sodium and fluid loss.
ACE is identical to bradykininase, and captopril may also interfere with the degradation of the vasopressor peptide bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril.

Clinical trials.

Captopril improved long-term survival and clinical outcome compared to placebo among 2,231 patients with myocardial infarction who participated in the Survival and Ventricular Enlargement (SAVE) trial. For inclusion in the study (a randomised, double-blind, placebo controlled, multicentre trial), patients (aged 21 - 79 years) had to demonstrate left ventricular dysfunction (ejection fraction < 40%) without overt heart failure. Specifically, captopril, when given 3-16 days (mean 11 days) after myocardial infarction, reduced the following: all cause mortality (risk reduction 19%, p = 0.022); cardiovascular death (risk reduction 21%, p = 0.017); manifestations of heart failure requiring initiation or augmentation of digitalis and diuretics (risk reduction 19%, p = 0.008) or requiring the use of ACE inhibitor therapy (risk reduction 35%, p < 0.001); hospitalisation for heart failure (risk reduction 20%, p = 0.034); clinical recurrent myocardial infarction (risk reduction 25%, p = 0.011); and coronary revascularisation procedures (coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty) (risk reduction 24%, p = 0.014).
Potential mechanism by which captopril improves survival and clinical outcome in patients following myocardial infarction include attenuation of the progressive left ventricular dilatation and deterioration in left ventricular function, and inhibition of neurohumoral activation.
Heart failure patients treated with captopril demonstrate increases in exercise time, ability to perform at higher workloads, and improvement in functional capabilities by New York Heart Association criteria. Administration of captopril to heart failure patients has resulted in consistent increases in cardiac output, cardiac index and stroke volume index. The effects were accompanied by reductions in systemic vascular resistance, pulmonary vascular resistance, total vascular resistance, pulmonary arterial pressure, pulmonary capillary wedge pressure and right atrial pressure. A consistent fall in mean arterial pressure was generally seen but it rarely became symptomatic. After short-term administration, a slight reduction in heart rate occurred which generally returned to pre-captopril levels with long-term therapy. Occasionally, a more marked reduction in heart rate may occur.
In studies involving a small number of patients with heart failure, a reduction in coronary blood flow which correlated with a fall in myocardial oxygen demand has been observed, with simultaneous increases in cardiac index and reduction in systemic vascular resistance.
In a multicentre, double-blind, placebo controlled trial among 409 patients with insulin dependent diabetes mellitus and proteinuria with or without hypertension (conventional antihypertensive agents were allowed to achieve blood pressure control), captopril treatment provided a 51% risk reduction in doubling of serum creatinine (p ≤ 0.01). The effects of treatment with captopril on the preservation of renal function are in addition to any benefit that may have been derived from the reduction in blood pressure.
In two multicentre, double blind, placebo controlled studies, a total of 235 normotensive patients with insulin dependent diabetes mellitus of 4 - 30 years duration with onset before the age of 39 years, retinopathy, serum creatinine within the normal range and microalbuminuria (albumin excretion rate 20 - 200 microgram/min) were randomised to placebo or captopril 50 mg twice daily and followed for up to two years. Captopril delayed the progression to overt nephropathy (albumin excretion rate > 200 microgram/min, i.e. proteinuria greater than or equal to 500 mg/day) in both studies (risk reduction 67 to 76%: p < 0.05). However, the long-term clinical benefit of reducing the progression from microalbuminuria to proteinuria has not been established.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of captopril, rapid absorption occurs with peak blood levels of approximately 1 microgram/L being found ½ to 1 hour after a 100 mg dose. The average minimal absorption is approximately 75%. The presence of food in the gastrointestinal tract reduces absorption by 25% - 40%. Approximately 30% of the drug is bound to plasma proteins. The apparent oral bioavailability is increased in patients receiving captopril chronically compared with acute use. It may be possible to reduce the dosage during chronic therapy and still maintain adequate blood pressure control.

Distribution.

Captopril appears to be distributed between three compartments in humans. The terminal phase volume of distribution (2 L/kg) suggests that captopril is distributed into deep tissues.

Metabolism.

Captopril is extensively metabolised. The major metabolite is captopril dimer (SQ 14,551).
In vitro studies have demonstrated that captopril dimer (SQ 14,551) is significantly less active than captopril as an inhibitor of angiotensin converting enzyme.

Excretion.

Captopril and its metabolites (captopril dimer and conjugates with endogenous thiol compounds, e.g. captopril-cysteine) are excreted principally in the urine. In vitro studies suggest that the metabolites are labile and that interconversions may occur in vivo. Approximately 40% of an administered dose is excreted unchanged in the urine in 24 hours and 35% as metabolites. Total body clearance is approximately 0.8 L/kg/h.
The elimination half-life of captopril is 1 to 2 hours and of total radioactivity is approximately 4 hours. The elimination half-life of captopril increases with decreasing renal function; the elimination rate correlates with creatinine clearance. The half-life for non-renal elimination is 156 hours. Dosage adjustment is required in patients with renal impairment (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Two year studies with doses of 50 to 1,350 mg/kg/day in mice and rats failed to show any evidence of carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Captopril Sandoz tablets contain microcrystalline cellulose, maize starch, lactose monohydrate, stearic acid.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Protect from moisture.

6.5 Nature and Contents of Container

Captopril Sandoz film-coated tablets are available in PP/Al blister packs or bottles of 90 tablets.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Captopril is a white or almost white crystalline powder; and is soluble in water, chloroform, dichloromethane, and ethanol (96%).

Chemical Structure.


Chemical name: 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline.
Molecular formula: C9H15NO3S.
Molecular weight: 217.3.

CAS number.

62571-86-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes