Consumer medicine information

Lisinopril Generic Health

Lisinopril

BRAND INFORMATION

Brand name

Lisinopril Generichealth

Active ingredient

Lisinopril

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lisinopril Generic Health.

What is in this leaflet

This leaflet answers some common questions about Lisinopril generic health.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

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

What Lisinopril generic health is used for

Lisinopril generic health lowers high blood pressure, which doctors call hypertension. It is also used to treat heart failure and patients who have just had a heart attack.

Hypertension

Everyone has blood pressure. This pressure helps get your blood all around your body.

Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis.

If high blood pressure is not treated it can lead to serious health problems. You may feel fine and have no symptoms, but eventually hypertension can cause stroke, heart disease and kidney failure.

Lisinopril generic health helps to lower your blood pressure.

Heart Failure

Heart failure means that the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops working.

Heart failure may start off with no symptoms, but as the condition progresses, patients may feel short of breath or may get tired easily after light physical activity such as walking. Some patients may wake up short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet.

Lisinopril generic health helps to treat heart failure and may improve your symptoms. One of the ways Lisinopril generic health helps heart failure is that it widens the blood vessels, so that the heart does not have to pump as hard to move the blood around the body. This also means that when you place extra demands on your heart, such as during exercise, the heart may cope better so you may not get short of breath as easily.

When used to treat heart failure, Lisinopril generic health is almost always used with other medicines called diuretics or fluid tablets. These medicines help the kidney to get rid of excess fluid from the body.

Heart Attack

A heart attack occurs when one of the major blood vessels supplying blood to the heart muscle becomes blocked. As a result of the blockage, the heart does not receive the oxygen it needs and the heart muscle is damaged.

This damage may lead to further complications such as heart failure, irregular heart rhythms and blood clots. In some patients, lisinopril may help to prevent some complications of heart attack, such as heart failure.

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

Your doctor may prescribe Lisinopril generic health for another reason. Ask your doctor if you have any questions about why Lisinopril generic health has been prescribed for you.

Before you take Lisinopril generic health

When you must not take it

Do not take Lisinopril generic health if:

  • you have taken any medicines called 'ACE inhibitors' for high blood pressure or heart failure before, which caused your face, lips, tongue, throat, hands or feet to swell up, or made it hard for you to breathe. If you have had an allergic reaction to an ACE inhibitor before, you may be allergic to Lisinopril generic health.
  • you have an allergy to Lisinopril generic health, or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction to Lisinopril generic health may include skin rash, itchiness, difficulty breathing or swallowing, or swelling of the face, lips, tongue or throat.
  • you have a history of swelling of the face, lips, tongue, throat, hands or feet, for no apparent reason.
  • you are pregnant or breastfeeding. Your baby may absorb this medicine in the womb or from breast milk and therefore there is a possibility of harm to the baby.
  • the tablets show visible signs of deterioration.
  • you are undergoing haemodialysis.

Do not take Lisinopril generichealth 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 Lisinopril generichealth, talk to your doctor.

Before you start to take it

Your doctor must know about all of the following before you start to take Lisinopril generic health.

  • If you intend to become pregnant or intend to breastfeed. Lisinopril generic health should not be used during pregnancy or while breastfeeding.
  • If you suffer from:
    - kidney disease, or are undergoing dialysis;
    - low blood pressure (you may notice this as faintness or dizziness, especially when standing);
    - liver disease;
    - diabetes;
    - aortic stenosis, or hypertrophic cardiomyopathy;
    - any other medical conditions.
  • If you are taking any other medicines, including any that you have bought from your pharmacy, supermarket or health food shop.
    Some of the medicines in common use that may interfere with Lisinopril generic health include:
    - other medicines used to treat high blood pressure;
    - diuretic tablets - also called fluid or water tablets;
    - lithium, a medicine used to treat some types of depression;
    - potassium tablets;
    - potassium-containing salt substitutes;
    - any non-steroidal anti-inflammatory medicines (such as indomethacin);
    - other medicines used to treat diabetes.
These medicines may be affected by Lisinopril generic health, or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist has a more complete list of medicines to avoid while taking Lisinopril generic health.
  • If you are following a very low salt diet.
  • If you have had an allergy to any other medicines or any other substances, such as foods, preservatives or dyes.
  • If you are going to receive desensitisation treatment for an allergy, eg. to insect stings.

If you have not told your doctor about any of the above, tell him/her before you take Lisinopril generic health.

How to take Lisinopril generic health

How much to take

Your doctor will tell you how many tablets you need to take each day. This depends on your condition and whether you are taking other medicines.

Take Lisinopril generic health only when prescribed by your doctor.

For high blood pressure
For most patients, the usual starting dose is 5 mg to 10 mg 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 mg to 20 mg each day, taken once a day.

For heart failure
The usual starting dose is 2.5 mg taken once a day. Depending on your response, this dose may need to be increased. The usual dose is 5-20 mg each day, taken once a day.

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

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

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

How to take it

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

Swallow Lisinopril generichealth with a glass of water or other liquid. It does not matter if you take Lisinopril generic health before or after food.

How long to take it

Lisinopril generic health helps control your high blood pressure and helps improve your heart failure, but does not cure it. Lisinopril generic health must be taken every day.

Take Lisinopril generic health for as long as your doctor says to.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your tablet(s) as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not take a double dose to make up for the dose that you missed. If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone number 13 11 26 or New Zealand 0800 764 766) or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Lisinopril generic health. Do this even if there are no signs of discomfort or poisoning.

If you take too many tablets you will probably feel light-headed or dizzy, or you may faint.

While you are taking Lisinopril generic health

Things you must do

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

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

If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up. You may feel light-headed or dizzy, especially if you are also taking a diuretic (fluid tablet). This is because your blood pressure is falling suddenly.

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 gets worse or continues, talk to your doctor.

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

If you are about to be started on any new medicine tell your doctor and pharmacist that you are taking Lisinopril generic health.

If you plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking Lisinopril generic health. Your blood pressure may drop suddenly during surgery.

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

If you have excessive vomiting and/or diarrhoea while taking Lisinopril generic health, tell your doctor. This can result in you losing too much water and may drop your blood pressure too much.

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

Things you must not do

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

Things to be careful of

Be careful driving or operating machinery until you know how Lisinopril generic health affects you.

Lisinopril generic health may cause dizziness (light-headedness) or tiredness in some patients, especially after the first dose or if the dose is increased. Make sure you know how you react to Lisinopril generic health before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If you drink alcohol, dizziness or light-headedness may be worse.

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

Some self-help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information.

  • Alcohol: Your doctor may advise you to limit your alcohol intake.
  • Diet: Eat a healthy diet, which includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar.
  • Exercise: Regular exercise helps to reduce blood pressure and helps the heart get fitter, but it is important not to overdo it. Walking is good exercise, but try to find a route that is fairly flat. Before starting any exercise, ask your doctor about the best kind of program for you.
  • Salt: Your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake you should avoid using salt in cooking or at the table.
  • Smoking: Your doctor may advise you to stop smoking or at least cut down.
  • Weight: Your doctor may suggest losing some weight to help lower your blood pressure and help lessen the amount of work your heart has to do. Some people may need a dietitian's help to lose weight.

Side effects

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

Lisinopril generic health helps most people with high blood pressure and heart failure, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

  • light-headedness or dizziness;
  • headache;
  • fatigue;
  • dry cough;
  • mild stomach upsets such as feeling sick;
  • diarrhoea, or stomach pains.

These are usually mild side effects of Lisinopril generic health.

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

  • chest pain, angina;
  • changes in the way your heart beats, for example, if you notice it beating faster;
  • difficulty breathing;
  • wheeziness due to tightness in the chest;
  • itchy skin rash or other skin problems;
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers;
  • tingling or numbness of the hands and feet;
  • passing less urine than is normal for you;
  • bruising more easily than normal;
  • severe abdominal pain;
  • collapse, numbness or weakness of arms or legs.

These are all serious side effects. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop taking Lisinopril generic health and 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;
  • yellowing of the skin and/or eyes, also called jaundice.

These are all very serious side effects. If you have them, you may have had a serious allergic reaction to Lisinopril generic health. You may need urgent medical attention or hospitalisation. All of these side effects are rare. Also tell your doctor if you notice:

  • hair loss or thinning;
  • impotence;
  • psoriasis and other serious skin conditions;
  • changes in the way things taste;
  • feeling sleepy or difficulty in going to sleep, strange dreams;
  • running nose or sinus pain.

These are other side effects that have been reported with Lisinopril generic health.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

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

After taking Lisinopril generic health

Storage

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

Protect from light. Store below 25°C in a dry place.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on windowsills. Heat and dampness can destroy some medicines.

Keep your tablets in a safe place where children cannot see or reach them. 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 the tablets or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

Lisinopril generic health 5 mg are pink coloured, round, biconvex uncoated tablets, with “5” debossed on one side and breakline on the other side.

Lisinopril generic health 10 mg are pink coloured, round, biconvex uncoated tablets, with “10” debossed on one side and breakline on the other side.

Lisinopril generic health 20 mg are pink coloured, round, biconvex uncoated tablets, with “20” debossed on one side and breakline on the other side.

A box of Lisinopril generic health contains 30 tablets.

Ingredients

Active ingredient

Each Lisinopril generic health tablet contains 5 mg, 10 mg or 20 mg lisinopril (as dihydrate).

Other ingredients

  • mannitol;
  • calcium hydrogen phosphate dihydrate;
  • maize starch;
  • pregelatinised maize starch;
  • magnesium stearate;
  • iron oxide red;
  • colloidal anhydrous silica.

Australian Registration Numbers

Lisinopril generic health 5 mg: AUST R 128154.

Lisinopril generic health 10 mg: AUST R 128161.

Lisinopril generic health 20 mg: AUST R 128163.

Sponsor

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

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

Where to go for further information

This is not all the information that is available on Lisinopril generic health. If you have any more questions or are not sure about anything, ask your doctor or pharmacist.

This leaflet was prepared in June 2019

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Lisinopril Generichealth

Active ingredient

Lisinopril

Schedule

S4

 

1 Name of Medicine

Lisinopril dihydrate.

6.7 Physicochemical Properties

Lisinopril (lisinopril dihydrate), a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor. It is a lysine analogue of enalaprilat (active metabolite of enalapril).
Lisinopril dihydrate is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
Chemical Name: (S)-1-[N2-(1-Carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Molecular Formula: C21H31N3O5.2H2O. Molecular Weight: 441.53.

Chemical structure.


CAS number.

83915-83-7.

2 Qualitative and Quantitative Composition

Lisinopril Generichealth tablets are supplied as 5 mg, 10 mg and 20 mg tablets containing lisinopril as dihydrate.

List of excipients with known effects.

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

3 Pharmaceutical Form

The packaging for the tablets clearly states the strength enclosed and the different strengths can be identified by the following:
5 mg tablets are pink coloured, round, biconvex uncoated tablets, with "5" debossed on one side and breakline on the other side.
10 mg tablets are pink coloured, round, biconvex uncoated tablets, with "10" debossed on one side and breakline on the other side.
20 mg tablets are pink coloured, round, biconvex uncoated tablets, with "20" debossed on one side and breakline on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor substance, angiotensin ll. Angiotensin ll also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of plasma angiotensin ll 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). Removal of angiotensin ll 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 difference 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).

Pharmacodynamics.

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). When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs 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 3/4 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 blacks than in Caucasians.
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 in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

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 equal to or less than 35%) or heart failure and to improve survival, based on the outcome of the GISSI-3 trial. The Gruppo Italiano per lo Studio della Sporavvienza nell'Infarto Miocardico (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 ≤ 100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine > 2 mg/dL and/or proteinuria > 500 mg/24 h). 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 ≤ 35% or an akinetic-dyskinetic [A-D] score ≥ 45%. Patients receiving lisinopril (n = 9,646), alone or with nitrates, had an 11% lower risk of death (2p [two-tailed] = 0.04) compared to patients receiving no lisinopril (n = 9,672) (6.4% vs 7.2%, respectively) at six 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 end-point 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 1 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 g/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 3,164 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.

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.
Lisinopril absorption is not affected by the presence of food in the gastrointestinal tract.

Distribution.

Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. 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.

Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine.

Excretion.

Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12.6 hours.
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).
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, 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 (approximately doubled) higher 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). 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 drug 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.

Carcinogenicity.

There was no evidence of a tumourigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day or when lisinopril was administered for 92 weeks to male and female mice at doses up to 135 mg/kg/day. 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 Generichealth tablets are indicated in the treatment of hypertension. They 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 Generichealth tablets are also indicated in the treatment of heart failure. In such patients, it is recommended that Lisinopril Generichealth tablets be administered together with a diuretic.

Acute myocardial infarction.

Lisinopril Generichealth tablets are 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

This agent is contraindicated in:
Patients who are hypersensitive to lisinopril or any other component of this product.
Patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an angiotensin converting enzyme inhibitor.
Patients with hereditary or idiopathic angioedema.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Patients undergoing haemodialysis with polyacrylonitrile-metalylsulphonate 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-metalylsulphonate high flux dialysis membranes (e.g. AN69) 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.

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 angiotensin converting enzyme (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 dismissing the patient. 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. Where involvement of the tongue, glottis, or larynx is likely to cause airway obstruction appropriate emergency therapy, including adrenalin and oxygen administration and/or the 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.

Race.

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in Afro-Caribbean black patients than in non-Afro-Caribbean black patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema whilst receiving an ACE inhibitor.

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 that 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, 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 a supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased.
As with other vasodilators, lisinopril should be given with caution to patients with aortic stenosis or hypertrophic cardiomyopathy.

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 3 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 1 hour) then Lisinopril Generichealth tablets should be withdrawn.

Neutropenia/agranulocytosis.

Another angiotensin converting enzyme inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leukopenia/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 haematologic monitoring be considered in patients with diseases known to affect bone marrow function (e.g. renal dysfunction, collagen vascular disease, etc) 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.

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 the use of 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.

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 or potassium supplements, and in those consuming potassium-containing salt substitutes. Diabetics, and elderly diabetics particularly, may be at increased risk of hyperkalaemia. 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/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 upon the drug, 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 drugs may be required in severe cases.

Dermatological reactions.

Dermatological reactions characterised by maculo-papular 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 drug 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 1 to 3 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.

Information for patients.

Angioedema.

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

Symptomatic hypotension.

Patients should be cautioned to report light-headedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.
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 such as vomiting or diarrhoea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Hyperkalaemia.

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

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 drugs, 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 azotaemia, 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 (serum creatinine concentration exceeding 265 micromol/L or a doubling from the pre-treatment value) then the physician should consider withdrawal of lisinopril.
Evaluation of the hypertensive patient should always include assessment of renal function (see Section 4.2 Dose and Method of Administration). 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.

No data available.

Paediatric use.

Safety and effectiveness of Lisinopril Generichealth tablets in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 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.

Non-steroidal anti-inflammatory drugs.

Drugs with prostaglandin synthetase inhibitory properties (e.g. indomethacin) and selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors.
In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of angiotensin II receptor antagonists or lisinopril may result in a further deterioration in renal function including possible renal failure.

Gold.

Nitritoid reactions (symptoms of vasodilation including flushing, nausea, 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.

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 neurone blocking agents) may be used with caution. Beta-adrenergic blocking drugs are also antihypertensive in action, hence if they are combined with an ACE inhibitor, the patient should be closely monitored.

Serum potassium.

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, triamterene, or amiloride), potassium supplement, or potassium-containing salt substitute can increase the risk of hyperkalaemia, therefore if co-administration is indicated they should be used with caution and the patient's serum potassium should be monitored frequently.

Other antihypertensive agents.

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

Antidiabetics.

Epidemiological studies have suggested that the concomitant administration of ACE inhibitors and anti-diabetic medicines (such as insulins, oral hypoglycaemic agents) may cause increased blood glucose lowering effects with the risk of hypoglycaemia. This phenomenon appeared more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

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 Generichealth should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Lisinopril Generichealth 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 foetotoxicity is well documented in animal models. Data, however, 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.
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.
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 arterious 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.
Australian categorisation definition of Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known whether this drug is secreted in human milk. Because the possibility exists that lisinopril may be secreted in human milk, lisinopril should not be given to a nursing 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 3,702 patients (2,633 patients with hypertension, 636 patients with congestive heart failure and 433 diabetes patients) and may be grouped as follows:

Hypertension (2,633 patients).

See Table 2.

Congestive heart failure (636 patients).

The most common adverse reaction occurring in this patient population was dizziness (14.2%). The other adverse reactions were 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 in Table 4.
The adverse events from each trial that were reported by < 1% of the patients are not included.

Hypersensitivity/angioneurotic oedema.

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely (see Section 4.4 Special Warnings and Precautions for Use). In very rare cases, intestinal angioedema has been reported.

Additional adverse reactions.

Additional adverse reactions which occurred rarely, either during controlled clinical trials or after the drug was marketed, include:

Cardiovascular.

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.

Digestive system.

Abdominal pain; dry mouth; hepatitis (hepatocellular and cholestatic). Very rarely this can progress to renal failure; jaundice; pancreatitis; taste disturbance.

Endocrine.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolic.

Cases of hypoglycaemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Musculoskeletal system.

Joint pain.

Nervous system.

Mood alterations; mental confusion; stroke; sleep disturbances.

Respiratory system.

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

Skin.

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

Urogenital system.

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

Body as a whole.

Syncope. 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.

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% 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 leukopenia 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 co-existed, 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 leukopenia have been reported; a causal relationship to therapy with lisinopril cannot be excluded.

Reporting suspected adverse reactions.

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

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

Hypertension.

In patients with uncomplicated 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 dosage. Dosage should be adjusted at 2 to 4 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.

Diuretic-treated or severely salt/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). 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.

Dosage adjustment in renal impairment.

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

Dosage in the 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.

Congestive heart cardiac failure.

Note.

Treatment of heart failure with lisinopril should be initiated under close medical supervision. In patients not adequately controlled by diuretics (and digitalis, where indicated), lisinopril 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 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 3 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 1 hour) lisinopril should be withdrawn.
Dosing should continue for 6 weeks. Patients who develop symptoms of heart failure should continue with lisinopril (see Section 4.2 Dose and Method of Administration, Congestive heart cardiac failure).
Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and a beta-blocker.
Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate.

4.7 Effects on Ability to Drive and Use Machines

No specific precautions but see Section 4.8 Adverse Effects (Undesirable Effects).

4.9 Overdose

There are no data on overdosage in humans. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Lisinopril may be removed from the general circulation by haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lisinopril Generichealth tablets contain mannitol, calcium hydrogen phosphate dihydrate, maize starch, pregelatinised maize starch, magnesium stearate, colloidal anhydrous silica and iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Protect from light. Store below 25°C in a dry place.

6.5 Nature and Contents of Container

Lisinopril Generichealth tablets are available as 5 mg, 10 mg and 20 mg tablets in PVC/PVDC/Al blister packs of 30 tablets.
Care should be taken when dispensing.

Australian registration numbers.

5 mg tablets: AUST R 128154.
10 mg tablets: AUST R 128161.
20 mg tablets: AUST R 128163.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes