Consumer medicine information

Lisinopril Sandoz

Lisinopril

BRAND INFORMATION

Brand name

Lisinopril Sandoz

Active ingredient

Lisinopril

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Lisinopril 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 Lisinopril Sandoz is used for

This medicine is used to treat:

  • high blood pressure (hypertension)
  • heart failure
  • patients who have just had a heart attack.

It contains the active ingredient lisinopril dihydrate.

Lisinopril belongs to a group of medicines called angiotensin converting enzyme (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.

This also helps to increase the supply of oxygen to your heart, so that when you place extra demands on your heart, such as exercise, your heart may cope better and you may not get short of breath as easily.

By making it easier for your heart to pump blood around your body and by increasing the supply of oxygen to your heart, Lisinopril Sandoz may reduce the risk of further damage to your heart after you have had a heart attack.

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 Lisinopril Sandoz

When you must not take it

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

  • lisinopril dihydrate, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product description
  • any other similar medicines, called 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 undergoing haemodialysis. You may be at increased risk of a severe allergic reaction when Lisinopril Sandoz is combined with some dialysis treatments.

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 Lisinopril Sandoz may pass into breast milk and there is a possibility that your baby may be affected.

  • You are taking a blood pressure medicine containing aliskiren and you have diabetes mellitus.
  • You are taking a blood pressure medicine containing aliskiren and you have kidney problems.

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, or are undergoing dialysis
  • liver problems
  • heart problems
  • diabetes
  • low blood pressure, which you may notice as dizziness or light-headedness, especially when standing
  • any other medical conditions not listed in this leaflet.

Tell your doctor if you intend to become pregnant or intend to breastfeed Lisinopril Sandoz should not be used during pregnancy or while breastfeeding.

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 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 Lisinopril 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 Lisinopril Sandoz may interfere with each other. These include:

  • other medicines used to treat high blood pressure including any that contain aliskiren
  • diuretic tablets, also known as fluid or water tablets, such as Lasix®, Urex® or Natrilix®
  • lithium, a medicine used to treat mood swings and some types of depression
  • potassium tablets such as Slow-K®, Span-K®, K-Mag® or Chlorvescent®
  • potassium-containing salt substitutes such as Pressor K®
  • any non-steroidal anti-inflammatory medicines (such as indomethacin)
  • potassium-sparing agents such as spironolactone (Aldactone®), triamterene (Hydrene 25/50®) or amiloride (Moduretic®)
  • gold therapy, used in the treatment of rheumatoid arthritis
  • 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®).
  • insulin or oral antidiabetic medicines. You should be closely monitored for low blood glucose (sugar) levels, especially during the first month of treatment with Lisinopril Sandoz.

These medicines may be affected by Lisinopril 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 Lisinopril 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, Lisinopril Sandoz may not work as well and your condition may not improve.

For high blood pressure (hypertension):
The usual starting dose is 5 to 10mg taken once a day.

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

Most patients take between 10 and 20mg each day, taken once a day.

For heart failure:
The usual starting dose is 2.5mg taken once a day.

Depending on your response, this dose may need to be increased.

The usual dose is 5 to 20mg each day, taken once a day.

For heart attack:
Lisinopril Sandoz may be started within 24 hours of the onset of symptoms of heart attack. The usual starting dose is 5mg, which is followed 24 hours later by another 5mg dose. This is then followed 48 hours later by a 10mg dose, and then 10mg taken once a day thereafter.

Some patients may need a lower starting and maintenance dose.

How to take it

Swallow the tablets whole with a full glass of water.

When to take Lisinopril 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.

How long to take Lisinopril 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 Australia 13 11 26 or New Zealand 0800 POISON or 0800 764 766) 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 Lisinopril 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
  • fainting.

While you are taking Lisinopril 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 Lisinopril 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 the surgery.

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

Make sure you drink enough water during exercise and hot weather when you are taking Lisinopril Sandoz, especially if you sweat a lot. If you do not drink enough water while taking Lisinopril 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 excessive vomiting and/or diarrhoea while taking Lisinopril 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 Lisinopril 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 Lisinopril Sandoz to treat 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 Lisinopril 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 Lisinopril 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
  • hair loss or thinning
  • psoriasis or other serious skin conditions
  • inability to get or maintain an erection (impotence)
  • difficulty sleeping (insomnia) or strange dreams
  • changes in the way things taste or loss of taste.

These are usually mild side effects of the medicine, but some of them may be serious.

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

  • fast or irregular heart beats
  • blurred vision
  • 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
  • tingling or numbness of the hands, feet or ankles
  • passing less urine than is normal for you
  • severe stomach pain
  • 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
  • collapse, numbness or weakness in the arms or legs.

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

Storage

Keep your medicine in the original container.

If you take the tablets out of its original container they may not keep well.

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

Do not store Lisinopril 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

Lisinopril Sandoz comes in three types of tablets:

Lisinopril Sandoz 5mg - round, biconvex, uniformly red, mottled tablets with a score notch on one side.

Lisinopril Sandoz 10mg - round, biconvex, uniformly red, mottled tablets with a score notch on one side.

Lisinopril Sandoz 20mg - round, biconvex, uniformly red, mottled tablets with a score notch on one side.

Available in blisters of 30 tablets.

Ingredients

Active ingredients:

  • Lisinopril Sandoz 5mg - 5mg lisinopril (as lisinopril dihydrate)
  • Lisinopril Sandoz 10mg - 10mg lisinopril (as lisinopril dihydrate)
  • Lisinopril Sandoz 20mg - 20mg lisinopril (as lisinopril dihydrate)

Inactive ingredients:

  • calcium hydrogen phosphate dihydrate
  • mannitol
  • maize starch
  • croscarmellose sodium
  • magnesium stearate
  • iron oxide red.

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

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road,
Macquarie Park, NSW 2113,
Australia
Tel: 1800 726 369

Novartis New Zealand Ltd
PO Box 99102
Newmarket, Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was revised in June 2019.

Australian Register Numbers:

Lisinopril Sandoz 5mg tablets: AUST R 158100

Lisinopril Sandoz 10mg tablets: AUST R 158101

Lisinopril Sandoz 20mg tablets: AUST R 158108

Published by MIMS August 2019

BRAND INFORMATION

Brand name

Lisinopril Sandoz

Active ingredient

Lisinopril

Schedule

S4

 

1 Name of Medicine

Lisinopril dihydrate.

6.7 Physicochemical Properties

Lisinopril is a white to off-white, crystalline powder. It is soluble in water, sparingly soluble in methanol and practically insoluble in ethanol.
Chemical Name: (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate.
Chemical Formula: C21H31N3O5.2H2O.
Molecular Weight: 441.53.

Chemical structure.


CAS number.

83915-83-7.

2 Qualitative and Quantitative Composition

Each Lisinopril Sandoz 5 mg tablet contains 5.44 mg lisinopril dihydrate equivalent to 5 mg lisinopril.
Each Lisinopril Sandoz 10 mg tablet contains 10.89 mg lisinopril dihydrate equivalent to 10 mg lisinopril.
Each Lisinopril Sandoz 20 mg tablet contains 21.78 mg lisinopril dihydrate equivalent to 20 mg lisinopril.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Lisinopril Sandoz 5 mg tablets are round, biconvex and a score notch on one side. The tablets are uniformly red, mottled, the surface must be smooth.
Lisinopril Sandoz 10 mg tablets are round, biconvex and a score notch on one side. The tablets are uniformly red, mottled, the surface must be smooth.
Lisinopril Sandoz 20 mg tablets are round, biconvex and a score notch on one side. The tablets are uniformly red, mottled, the surface must be smooth.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Lisinopril Sandoz (lisinopril dihydrate), a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme (ACE) inhibitor. It is a lysine analogue of enalaprilat (active metabolite of enalapril).
Administration of lisinopril to patients with hypertension results in a reduction of supine and standing blood pressure to about the same extent, with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients (see Section 4.4 Special Warnings and Precautions for Use, Symptomatic hypotension). When given together with thiazide-type diuretics, the blood pressure lowering effects of the two medicines are approximately additive.
In most patients studied, onset of antihypertensive activity was seen one to two hours after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, in all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing.
In some patients, achievement of optimal blood pressure reduction may require two to four weeks of therapy.
The antihypertensive effects of lisinopril are maintained during long-term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure or a significant increase in blood pressure compared to pre-treatment levels.
Two dose-response studies utilising a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of lisinopril was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20, or 80 mg of lisinopril. In controlled clinical studies, lisinopril 20 to 80 mg has been compared in patients with mild to moderate hypertension with hydrochlorothiazide 12.5 to 50 mg and with atenolol 50 to 200 mg, and in patients with moderate to severe hypertension with metoprolol 100 to 200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic blood pressure in a population that was three-quarters Caucasian. Lisinopril was approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure and had somewhat greater effects on systolic blood pressure.
Lisinopril had similar effectiveness and adverse effects in younger and older (> 65 years) patients. It was less effective in the black population than in the Caucasian population.
In haemodynamic studies in patients with hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate (GFR) in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

Mechanism of action.

Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits ACE that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of plasma angiotensin II which results in decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.
In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mmol/L; however, approximately 15% of patients had increases greater than 0.5 mmol/L and approximately 6% had a decrease greater than 0.5 mmol/L. In the same study, patients treated with lisinopril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mmol/L; approximately 4% of patients had increases greater than 0.5 mmol/L and approximately 12% had a decrease greater than 0.5 mmol/L (see Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low renin hypertension. Although lisinopril was antihypertensive in all races studied, black hypertensive patients (usually a low renin hypertensive population) had a smaller average response to monotherapy than non-black patients.
Concomitant administration of lisinopril and hydrochlorothiazide further reduced blood pressure in black and non-black patients and any racial differences in blood pressure response was no longer evident.
ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.
When combined with other antihypertensive agents, additive falls in blood pressure may occur.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycaemia. ACE inhibitors, including lisinopril, inhibit the formation of angiotensin II and breakdown of bradykinin and hence ameliorate endothelial dysfunction.
The effects of lisinopril on urinary albumin excretion rate and on the progression of retinopathy in diabetic patients is mediated by a reduction in blood pressure as well as a direct mechanism on the renal and retinal tissues.
Lisinopril treatment is not associated with an increased incidence of hypoglycaemic events in diabetic patients and it does not affect glycaemic control as shown by a lack of significant effect on levels of glycosylated haemoglobin (HbA1c).

Clinical trials.

Acute myocardial infarction.

Lisinopril is indicated in the management of patients with acute myocardial infarction to prevent the subsequent development of left ventricular dysfunction (as defined by an ejection fraction less than or equal to 35%) or heart failure and to improve survival, based on the outcome of the Gruppo Italiano per lo Studio della Sporavvienza nell'Infarto Miocardico (GISSI-3) trial. The GISSI-3 study was a multicentre, controlled, randomised, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on longer-term death and markedly impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who were haemodynamically stable were randomised, in a 2 x 2 factorial design, to six weeks of either 1) lisinopril alone (n = 4,841), 2) nitrates alone (n = 4,869), 3) lisinopril plus nitrates (n = 4,841), or 4) open control (n = 4,843). All patients received routine therapies, including thrombolytics (72%), aspirin (84%) and a beta-blocker (31%), as appropriate, normally utilised in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure less than or equal to 100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine > 2 mg/dL and/or proteinuria > 500 mg/24 hours). Doses of lisinopril were adjusted as necessary according to protocol (see Section 4.2 Dose and Method of Administration).
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of treatment.
The primary outcomes of the trial were the overall mortality at 6 weeks and a combined endpoint at 6 months after the myocardial infarction, consisting of a number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction less than or equal to 35% or an akinetic-dyskinetic (A-D) score greater than or equal to 45%. Patients receiving lisinopril (n = 9,646), alone or with nitrates, had an 11% lower risk of death at six weeks (2p (two tailed) = 0.04) compared to patients receiving no lisinopril (n = 9,672) (6.4 versus 7.2%, respectively) at 6 weeks. The reduction in mortality at six months was not significant, but this was not a primary outcome measure. Although patients randomised to receive lisinopril for up to six weeks also fared numerically better on the combined endpoint at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group randomised to 6 weeks of lisinopril preclude any conclusion about this endpoint.
Patients with acute myocardial infarction treated with lisinopril had a higher (9.0% versus 3.7%) incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more than one hour) and renal dysfunction (2.4 versus 1.1%) in hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration).

Renal complication of diabetes.

EUCLID (EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes Mellitus) was an 18 centre, multinational, randomised, double-blind, placebo-controlled trial. It investigated the effects of lisinopril on the urinary albumin excretion rate (AER) in 530 normotensive men and women aged 20-59 years with insulin dependent diabetes mellitus (IDDM) and normoalbuminuria or microalbuminuria. The study recruited patients with a DBP in the range 75-90 mmHg inclusive provided that the SBP was ≤ 155 mmHg. Patients received either lisinopril 10 mg od or matching placebo for 2 years. Titration up to 20 mg od of lisinopril or 2 placebo tablets was permitted if sitting DBP had not reached the target value of less than 75 mmHg after 3 months of treatment. Nifedipine treatment (20 mg bd) was initiated if the BP remained inadequately controlled (SBP > 160 mmHg, DBP > 95 mmHg).
The primary efficacy variable was the rate of change in the urinary albumin excretion rate (AER) measured from two consecutive overnight urine collections at six monthly intervals from baseline to 24 months in the whole patient group (i.e. normoalbuminuric and microalbuminuric at baseline). After 24 months treatment the AER was 18.8% [95% CI: 2.0, 32.7] lower in the lisinopril group (n = 230) compared to the placebo group (n = 226) with a between group difference of 2.2 microgram/min (p = 0.03) when adjusted for baseline AER and centre. After adjustment for DBP reduction produced by lisinopril the between group relative difference in AER was reduced to 17.3% (95% CI: 0.2, 31.5, p = 0.05). There were no statistically significant differences in AER between lisinopril and placebo in patients with good baseline glycaemic control (HbA1C < 7%) or with a baseline DBP > 80 mmHg.
In patients with baseline microalbuminuria the AER was 49.7% [95% CI: -14.5, 77.9] lower in the lisinopril group (n = 39) compared to placebo (n = 34), p = 0.1. Only 15% (n = 79) of the randomised patients had baseline microalbuminuria compared to 40% anticipated by the protocol. This may have left the study underpowered to detect a statistically significant difference in the AER between treatments in patients with baseline microalbuminuria. In a non-protocol specified subgroup analysis in patients with baseline microalbuminuria (AER 20-200 microgram/min) and endpoint AER the absolute difference in mean AER between the lisinopril group (n = 39) and the placebo group (n = 34) was 38.5 microgram/min (p = 0.001).
The results also show that lisinopril does not increase the risk of hypoglycaemic events in IDDM as there was no treatment difference in hypoglycaemic events or glycaemic control throughout the study.

Congestive heart failure.

The effect of lisinopril on mortality and morbidity in congestive heart failure has been studied by comparing a high dose (32.5 mg or 35 mg once daily) with a low dose (2.5 mg or 5 mg once daily). Patients receiving high dose lisinopril were titrated gradually up to the highest dose tolerated up to a maximum of 32.5 mg or 35 mg once daily. Patients who were intolerant to lisinopril were excluded from the study. In a study of 3164 patients, with a median follow-up period of 46 months for surviving patients, statistically non-significant reductions were observed in the primary endpoint all-cause mortality or the secondary endpoint of cardiovascular mortality. However, compared with low dose, high-dose lisinopril produced a 12% risk reduction in the combined endpoint of all-cause mortality and all-cause hospitalisation (p = 0.002), an endpoint added during the trial. In a post-hoc analysis, the number of hospitalisations for heart failure was reduced by 24% (p = 0.002) in patients treated with high-dose lisinopril compared with low dose. Symptomatic benefits were similar in patients treated with high and low doses of lisinopril. This trial did not study whether 35 mg is more effective than the currently recommended upper limit of the usual dose of 20 mg.
The results of the study showed that the overall adverse event profiles for patients treated with high or low dose lisinopril were similar in both nature and number. The overall adverse event rate included deaths and hospitalisations that contributed to the estimation of efficacy. The percentage of drug-related adverse events was 8% higher in the high dose group (a relative difference of 25%). The excess in the high dose group was due to events of the type, which would be expected from the pharmacological actions of lisinopril. Predictable events resulting from ACE inhibition, such as hypotension or altered renal function, were manageable and rarely led to treatment withdrawal. Cough was less frequent in patients treated with high-dose lisinopril compared with low dose. NYHA classification (a measure of quality of life) did not differ between treatment groups.

5.2 Pharmacokinetic Properties

Absorption and distribution.

Following oral administration of lisinopril, peak serum concentrations of lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to medicine accumulation.
Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with large inter-patient variability (6 to 60%) at all doses tested (5 to 80 mg). Lisinopril absorption is not significantly influenced by the presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Following oral administration of 20 mg (1 x 20 mg tablet) lisinopril to healthy subjects under fasting conditions, a mean peak plasma concentration (Cmax) of lisinopril of approximately 73.08 nanogram/mL was achieved within approximately 6.79 hours (Tmax).
This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum proteins.

Metabolism and excretion.

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the GFR is below 30 mL/minute. Above this GFR, the elimination half-life is little changed.
With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have higher (approximately doubled) blood levels and higher values for the area under the plasma concentration time curve (AUC) than younger patients (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Elderly). Lisinopril can be removed by haemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contained radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labelled medicine to pregnant rats, but none was found in the foetuses.

5.3 Preclinical Safety Data

Genotoxicity.

Lisinopril was not genotoxic in assays for gene mutations, chromosomal damage and DNA damage. There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril.

Carcinogenicity.

There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day. Lisinopril has also been administered for 92 weeks to male and female mice at doses up to 135 mg/kg/day and show no evidence of carcinogenicity.
At least one other ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential for lisinopril to cause a similar effect is unknown.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Lisinopril Sandoz is indicated for the treatment of hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents. Sufficient data have not been provided to support the use of lisinopril in severe hypertension or renovascular hypertension.

Congestive heart failure.

Lisinopril Sandoz is also indicated for the treatment of heart failure. In such patients, it is recommended that lisinopril be administered together with a diuretic.

Acute myocardial infarction.

Lisinopril Sandoz is indicated for the treatment of acute myocardial infarction in haemodynamically stable patients, defined as patients who are not in cardiogenic shock and who have a systolic blood pressure greater than 100 mmHg. Lisinopril may be initiated within 24 hours of an acute myocardial infarction.

4.3 Contraindications

Lisinopril is contraindicated in:
patients who are hypersensitive to lisinopril or any other component of Lisinopril Sandoz;
patients with a history of hereditary and/or idiopathic angioedema, anaphylactic/anaphylactoid reactions or angioedema associated with previous treatment with an ACE inhibitor;
patients with hereditary or idiopathic angioedema;
pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy);
patients undergoing haemodialysis with polyacrylonitrile-metalylsulfonate high flux membranes. There is a risk of anaphylactoid reaction (hypersensitivity reactions which may be severe, e.g. shock) with the simultaneous use of an ACE inhibitor and polyacrylonitrile-metalylsulfonate high flux dialysis membranes (e.g. AN69) or during low-density lipoproteins (LDL) apheresis with dextran sulphate within the framework of dialysis treatment. This combination thus needs to be avoided, either by using other medical products to control high blood pressure or cardiac insufficiency or by using other membranes during dialysis;
in combination with aliskiren-containing medicines in patients with diabetes mellitus (type I or II) or with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2).

4.4 Special Warnings and Precautions for Use

Anaphylactoid reactions during hymenoptera desensitisation.

Patients receiving ACE inhibitors during desensitisation (e.g. to Hymenoptera venom) have sustained anaphylactoid reactions. These reactions have been avoided when ACE inhibitors were temporarily withheld.

Angioedema.

Severe life-threatening angioedema has been reported rarely with most of the ACE inhibitors. 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. Most commonly, angioedema occurs during the first week of therapy but it has also been reported after long-term therapy. Patients may have multiple episodes of angioedema with long symptom-free intervals.
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors. This may occur at any time during treatment. In such cases, the product should be discontinued promptly and appropriate monitoring instituted to ensure complete resolution of symptoms prior to the patient being dismissed. Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.
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. Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where involvement of the tongue, glottis or larynx is likely to cause airway obstruction, appropriate emergency therapy, including adrenaline and oxygen administration, and/or measures to ensure maintenance of a patent airway, should be carried out promptly and the patient may need to be hospitalised. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Angioedema may occur with or without urticaria.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema whilst receiving an ACE inhibitor.
Some drugs if given concomitantly with ACE inhibitors may increase the risk of angioedema (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Race.

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in Afro-Caribbean black patients than in non-Afro-Caribbean black patients.
ACE inhibitors may have a lesser effect on blood pressure in black hypertensive patients than in non-black hypertensive patients.

Symptomatic hypotension.

Hypotension may occur 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 or 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, Use in renal impairment; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed. This may be associated with syncope, neurological deficits, oliguria and/or progressive azotaemia, 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 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 the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can usually be given without difficulty once the blood pressure has increased.

Hypotension in acute myocardial infarction.

Treatment with lisinopril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mmHg or lower or cardiogenic shock. During the first three days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mmHg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than one hour), then lisinopril should be withdrawn.

Aortic stenosis/ hypertrophic cardiomyopathy.

As with other vasodilators, Lisinopril Sandoz should be given with caution to patients with aortic stenosis or hypertrophic cardiomyopathy.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin II receptor blockers or aliskiren-containing medicines.

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the renin-angiotensin-aldosterone system by combining lisinopril with angiotensin II receptor blockers or aliskiren is not recommended since there is an increased risk of hypotension, hyperkalaemia and changes in renal function (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If dual blockade therapy is considered necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Neutropenia/ agranulocytosis.

Another ACE inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia and neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to lisinopril cannot be excluded.
It is recommended that periodic haematological monitoring be considered in patients with diseases known to affect bone marrow function (e.g. renal dysfunction, collagen vascular disease) and/or who are taking concomitant therapy known to be associated with bone marrow depression.

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

(Also see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), 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. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Hyperkalaemia.

(Also see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
Because the ACE inhibitors decrease the formation of angiotensin II and the subsequent production of aldosterone, serum potassium concentrations exceeding 5.5 mEq/L may occur. Hyperkalaemia is more likely in patients with some degree of renal impairment, those treated with potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride) or potassium supplements, and in those consuming potassium-containing salt substitutes. Diabetics, and elderly diabetic patients particularly, may be at increased risk of hyperkalaemia. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. In some patients, hyponatraemia may coexist with 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.

Surgery and anaesthesia.

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

Cough.

A persistent dry (non-productive) irritating cough has been reported with ACE inhibitors. In various studies, the incidence of cough varies depending on the medicine, dosage, duration of use and method of analysis.
The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins which accumulate because of ACE inhibition. A change to another class of medicines may be required in severe cases.

Dermatological reactions.

Dermatological reactions characterised by maculopapular pruritic rashes and sometimes photosensitivity have been reported rarely with ACE inhibitors. Rare and occasionally severe skin reactions (e.g. lichenoid eruptions, psoriasis, pemphigus-like rash, Stevens-Johnson syndrome) have also been reported with some ACE inhibitors. A causal relationship is sometimes difficult to assess.
Patients who develop a cutaneous reaction with one ACE inhibitor might not when switched to another medicine of the same class, but there are reports of cross reactivity.

Taste disturbances (dysgeusia).

The incidence of taste disturbance was reported to be high (up to 12.5%) with high doses of another ACE inhibitor but the overall incidence for the class is probably low. However, the relevant data are scarce and difficult to interpret.
The 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 one to three months despite continued treatment.

Diabetic patients.

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with lisinopril (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Information for patients.

Angioedema.

Angioedema, including laryngeal oedema, may occur at any time during treatment with lisinopril. While this condition is uncommon, patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips or tongue, difficulty in swallowing or breathing) and to take no more medicine until they have consulted with the prescribing doctor.

Symptomatic hypotension.

Patients should be cautioned to report lightheadedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the medicine until they have consulted with the prescribing doctor.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion, e.g. vomiting or diarrhoea, may also lead to a fall in blood pressure; patients should be advised to consult with their doctor.

Hyperkalaemia.

Patients should be told not to use salt substitutes containing potassium without consulting their doctor.

Neutropenia.

Patients should be told to report promptly any indication of infection (e.g. sore throat, fever) which may be a sign of neutropenia.

Note.

As with many other medicines, certain advice to patients being treated with lisinopril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Use in hepatic impairment.

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases, the changes were reversed on discontinuation of the drug.
There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Lisinopril should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Use in renal impairment.

Changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.
In patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed. These increases are usually reversible upon discontinuation of ACE treatment. ACE inhibitors should be avoided in patients with known or suspected bilateral renal artery stenosis. When an ACE inhibitor is given to a patient with stenosis of the renal artery supplying a solitary kidney or with bilateral renal artery stenosis, acute renal insufficiency may occur. ACE inhibition may also cause a decrease in renal function in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces glomerular filtration pressure. Under these circumstances, renal function is dependent on angiotensin II-induced vasoconstriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration decreases, and renal failure may result. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors.
Some patients with no apparent pre-existing renovascular disease have developed increases in blood urea nitrogen and serum creatinine, which is usually minor and transient. This is more likely to occur in patients with pre-existing renal impairment or in those on diuretics.
Dosage reduction of the ACE inhibitor and/or discontinuation of the diuretic may be required.
In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/L and/or proteinuria exceeding 500 mg/24 h. If renal dysfunction develops during treatment with Lisinopril Sandoz (serum creatinine concentration exceeding 265 micromol/L or a doubling from the pre-treatment value) then the physician should consider withdrawal of Lisinopril Sandoz.
Evaluation of the hypertensive patient should always include assessment of renal function (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment). In patients with renal artery stenosis, 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 stenosis present a special problem, as deterioration of function may not be apparent from measurement of blood urea and serum creatinine.
It is possible that in patients with compromised renal function who are being treated with NSAIDs, the co-administration of lisinopril may result in a further deterioration of renal function. This may result in an increase in serum potassium, but it appears that these effects are usually reversible.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

Safety and effectiveness of lisinopril in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Antihypertensive agents.

When combined with other antihypertensive agents, additive falls in blood pressure may occur. Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
The combination of lisinopril with aliskiren-containing medicines should be avoided (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Drugs that may increase the risk of angioedema.

Concomitant treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) or tissue plasminogen activator may increase the risk of angioedema.

Diuretics.

When a diuretic is added to the therapy of a patient receiving an ACE inhibitor, 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 after initiation of therapy with an ACE inhibitor. 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 the ACE inhibitor should be reduced and the patient closely observed for several hours following the initial dose of the ACE inhibitor and until the blood pressure has stabilised.

Lithium.

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving lithium concomitantly with medicines, which cause elimination of sodium, including ACE inhibitors. These medicines should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Gold.

Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, vomiting, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

Non-steroidal anti-inflammatory drugs (NSAIDs).

Non-Steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive medicines. Therefore, the antihypertensive effect of ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g. elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with NSAIDs including COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration in renal function, including possible renal failure.
These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly.
Drugs with prostaglandin synthetase inhibitory properties (e.g. indomethacin) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors.

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

The use of an ACE inhibiting medicine (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory medicine (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 medicine. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of medicines from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Agents causing renin release.

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

Agents affecting sympathetic activity.

Agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking medicines are also antihypertensive in action, hence if they are combined with an ACE inhibitor the patient should be closely monitored.

Serum potassium.

(Also see Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia.)
ACE inhibitors can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. The concomitant therapy of an ACE inhibitor with a potassium-sparing diuretic (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements, potassium-containing salt substitutes or other drugs that may increase serum potassium levels (e.g. heparin, cotrimoxazole) can increase the risk of hyperkalaemia. Therefore, if coadministration is indicated these agents should be used with caution and the patient's serum potassium should be monitored frequently.

Antidiabetics.

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (such as insulins, oral hypoglycaemic agents) may cause increased blood glucose lowering effect with the risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored for hypoglycaemia, especially during the first month of treatment with an ACE inhibitor.

Other antihypertensive agents.

When combined with other antihypertensive agents, additive falls in blood pressure may occur.

Tissue plasminogen activators.

Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril.
(Category D)
As with all ACE inhibitors, lisinopril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with lisinopril 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.
There are no adequate and well-controlled studies of ACE inhibitors in pregnant women, but fetotoxicity is well documented in animal models.
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 first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02), respectively, compared to no exposure.
Data show that ACE inhibitors cross the human placenta. Post-marketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero. Adverse effects appear to be most likely in the second and third trimesters.
When ACE inhibitors have been used during the second and third trimesters of pregnancy, there have been reports of foetal hypotension, renal failure, hyperkalaemia, skull hypoplasia and death. It is not known whether exposure limited to the first trimester can adversely affect foetal outcome.
Oligohydramnios has been reported, presumably resulting from decreased foetal renal function; oligohydramnios has been associated with foetal limb contractures, craniofacial deformities, hypoplastic lung development and intra-uterine growth retardation. Prematurity and patent ductus arteriosus have been reported, however it is not clear whether these events were due to ACE inhibitor exposure.
Infants exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia. If such complications arise, appropriate medical treatment should be initiated to support blood pressure and renal perfusion. Lisinopril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and theoretically may be removed by exchange transfusion.
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known whether this medicine is secreted in human milk. Because the possibility exists that lisinopril may be secreted in human milk, lisinopril should not be given to a breastfeeding mother.

4.8 Adverse Effects (Undesirable Effects)

Lisinopril has been found to be generally well tolerated in controlled clinical trials. For the most part, adverse experiences were mild and transient in nature. In patients with congestive heart failure high doses of lisinopril may predispose to symptoms related to hypotension (dizziness, syncope) and to biochemical changes related to impaired renal function (hyperkalaemia and increased serum creatinine) as would be expected with ACE inhibitor therapy.
The adverse events which occurred in controlled clinical trials with lisinopril are taken from the case reports of 3702 patients (2633 patients with hypertension, 636 patients with congestive heart failure and 433 diabetes patients) and may be grouped as follows.

Hypertension (2,633).

(See Table 2.)

Congestive heart failure (636).

The most common adverse reaction occurring in this patient population was dizziness (14.2%). The other adverse reactions are found in Table 3.

Renal and retinal complications of diabetes mellitus (433 patients).

Adverse events from 2 clinical trials in diabetic patients (433 patients receiving lisinopril) are as follows. (See Table 4.)
The adverse events from each trial that were reported by < 1% of the patients are not included.

Hypersensitivity/angioneurotic oedema.

Hypersensitivity/ angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported uncommonly (see Section 4.4 Special Warnings and Precautions for Use, Angioedema). In very rare cases, intestinal angioedema has been reported.
The following adverse reactions have been reported during post-marketing experience with a frequency of common (≥ 1% to < 10%).

Renal and urinary disorders.

Renal dysfunction.
The following adverse reactions have been reported during post-marketing experience with a frequency of uncommon (≥ 0.1% to < 1%).

Metabolism and nutrition disorders.

Hyperkalaemia.

Cardiac and vascular disorders.

Syncope in the hypertensive population, while in the congestive heart failure population the frequency of syncope is common.
Myocardial infarction or cerebrovascular accident; possibly secondary to excessive hypotension in high risk patients (see Section 4.4 Special Warnings and Precautions for Use); tachycardia.

Nervous system and psychiatric disorders.

Mood alterations (including depressive symptoms); taste disturbance; sleep disturbances, hallucinations.
Additional adverse reactions which occurred rarely, either during controlled clinical trials or after the drug was marketed, include:

Digestive system.

Abdominal pain; dry mouth; hepatitis (hepatocellular and cholestatic) very rarely this may progress to hepatic failure; jaundice; pancreatitis.
Patients receiving lisinopril who develop jaundice or marked elevation of hepatic enzymes should discontinue and receive appropriate medical follow up.

Endocrine disorders.

Inappropriate antidiuretic hormone secretion.

Musculoskeletal system.

Joint pain.

Nervous system and psychiatric disorders.

Mental confusion; stroke; olfactory disturbance.

Respiratory system.

Bronchitis; bronchospasm; nasal congestion; pharyngeal pain; sinusitis; rhinitis.

Skin.

Alopecia; urticaria; diaphoresis; cutaneous pseudolymphoma; psoriasis and severe skin disorders have been reported, including pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme.

Urogenital system.

Uraemia; oliguria/anuria; proteinuria; acute renal failure; impotence; urinary tract infection.

Body as a whole.

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, an elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity, or other dermatologic manifestations may occur.

Immune system disorders.

Frequency not known: anaphylactic/anaphylactoid reaction.

Clinical laboratory test findings.

Serum electrolytes.

Hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use) and hyponatraemia have occurred.

Creatinine, blood urea nitrogen.

Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in 1.1 and 1.6 percent of patients respectively with hypertension treated with lisinopril alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (see Section 4.4 Special Warnings and Precautions for Use).
Reversible minor increases in blood urea nitrogen and serum creatinine were observed in approximately 12.0% of patients with congestive heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.

Bone marrow depression.

Bone marrow depression, manifest as anaemia, and/or thrombocytopenia and/or leucopenia has been reported. Agranulocytosis has been rarely reported, although a causal relationship has not been established. Rarely, haemolytic anaemia has been reported.

Haemoglobin and haematocrit.

Small decreases in haemoglobin and haematocrit, rarely of clinical importance unless another cause of anaemia coexisted, have occurred.

Other (causal relationship unknown).

Rarely, elevations of liver enzymes and/or serum bilirubin have occurred. Rare cases of bone marrow depression have been reported. Thrombocytopenia and leucopenia have been reported; a causal relationship to therapy with lisinopril cannot be excluded.

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.

4.2 Dose and Method of Administration

Dosage.

Lisinopril Sandoz should be administered in a single daily dose. Since there is no clinically significant effect of food on the absorption of lisinopril, the tablets may be administered before, during or after meals.

Hypertension.

In patients with uncomplicated essential hypertension not on diuretic therapy, the usual recommended starting dose is 5 to 10 mg. The usual maintenance dosage is 10 to 20 mg/day administered in a single daily dose. Dosage should be adjusted at two to four week intervals according to blood pressure response. In some patients, doses up to 40 mg/day may be required. If blood pressure is not controlled with lisinopril, a low dose of a diuretic may be added. Hydrochlorothiazide (12.5 mg) has been shown to provide an additive effect. After addition of a diuretic, the dose of lisinopril may be reduced.

Use in diuretic treated or severely salt or volume depleted patients.

Symptomatic hypotension following the initial dose of lisinopril may occur occasionally in patients receiving concomitant diuretics. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with lisinopril (see Section 4.4 Special Warnings and Precautions for Use, Symptomatic hypotension). In hypertensive patients in whom the diuretic cannot be discontinued, the initial dose of lisinopril should be 2.5 mg, followed then by 5 mg. The subsequent dosage of lisinopril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed gradually.

Congestive heart failure.

Note.

Treatment of heart failure with Lisinopril Sandoz should be initiated under close medical supervision. In patients not adequately controlled by diuretics (and digitalis, where indicated), Lisinopril Sandoz may be added with a starting dose of 2.5 mg once a day. Dose adjustment should be increased:
by increments of no greater than 10 mg;
at intervals of no less than 2 weeks.
The usual dosage is 5-20 mg/day administered as a single dose. The dose of Lisinopril Sandoz should not be titrated according to symptoms, as higher doses may not give additional symptomatic relief. The optimal upper dose has not been determined; 35 mg/day has been shown to be more effective than 5 mg/day but there is no evidence regarding the effectiveness of intermediate doses.
Patients at a high risk of symptomatic hypotension, e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy, should have these conditions corrected, if possible, prior to therapy with lisinopril. The effect of the starting dosage of lisinopril on blood pressure should be monitored carefully.

Acute myocardial infarction.

Treatment with lisinopril may be started within 24 hours of the onset of symptoms. The first dose of lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter. Patients with a low systolic blood pressure (120 mmHg or less) when treatment is started or during the first three days after the infarct should be given a lower dose (2.5 mg) orally (see Section 4.4 Special Warnings and Precautions for Use). If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg), a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than one hour), lisinopril should be withdrawn.
Dosing for patients with acute myocardial infarction should continue for six weeks. Patients who develop symptoms of heart failure should continue with lisinopril (see Section 4.2 Dose and Method of Administration, Congestive heart failure).
Patients should receive, as appropriate, the standard recommended treatments, e.g. thrombolytics, aspirin and a beta-blocker.
Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate.

Dosage adjustment.

Renal impairment.

The usual dose of lisinopril is recommended for patients with a creatinine clearance > 30 mL/minute. Dosage in patients with renal impairment should be based on creatinine clearance as outlined in Table 1.
The dosage may be titrated upward until blood pressure is controlled or to a maximum of 20 mg daily.

Elderly.

In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution.

4.7 Effects on Ability to Drive and Use Machines

When driving vehicles or operating machines, patients may experience dizziness or tiredness.

4.9 Overdose

Symptoms.

There are no data on overdosage in humans. The most likely manifestation of overdosage would be hypotension.

Treatment.

In the case of an overdose, treatment should be administration of normal saline solution by intravenous infusion.
Lisinopril may be removed from the general circulation by haemodialysis.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lisinopril Sandoz tablets also contain calcium hydrogen phosphate dihydrate, mannitol, maize starch, croscarmellose sodium, magnesium stearate and iron oxide red.

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.

6.5 Nature and Contents of Container

Lisinopril Sandoz tablets are available in PVC/Al blister packs of 30 tablets.

6.6 Special Precautions for Disposal

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

Summary Table of Changes