Zestril - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Lisinopril

Zestril 5 mg tablets
Zestril 10 mg tablets
Zestril 20 mg tablets

Why is Zestril used? What is it for?

Zestril contains an active ingredient called lisinopril. This belongs to a group of medicines called ACE inhibitors.

Zestril can be used for the following conditions:

  • to treat high blood pressure (hypertension).
  • to treat heart failure.
  • if you have recently had a heart attack (myocardial infarction).
  • to treat kidney problems caused by type II diabetes in people with high blood pressure.

Zestril works by causing blood vessels to widen. This helps reduce blood pressure. It also makes it easier for your heart to pump blood to all parts of your body.

Contraindications When Zestril should not be used

Do not take Zestril:

  • if you are allergic to lisinopril or any of the other ingredients of this medicine (listed in section 6).
  • if you have ever had an allergic reaction to another ACE inhibitor. The allergic reaction may have caused swelling of the hands, feet, ankles, face, lips, tongue or throat. It may also have made it difficult to swallow or breathe (angioedema).
  • if a member of your family has had a severe allergic reaction (angioedema) with an ACE inhibitor or you have had a severe allergic reaction (angioedema) with no known reason.
  • if you are past the first trimester of pregnancy (Zestril should also be avoided in the first months of pregnancy). See "Pregnancy".
  • if you are taking a blood pressure medicine containing aliskiren and have diabetes.
  • if you are taking a blood pressure medicine containing aliskiren and have kidney problems.

If you are not sure if any of these apply to you, talk to your doctor or pharmacist before taking Zestril.

Contact your doctor if you develop a persistent dry cough for a long time after starting treatment with Zestril.

Precautions for use What you need to know before taking Zestril

Talk to your doctor or pharmacist before taking Zestril:

  • if you have a narrowing (stenosis) of the aorta (an artery in your heart) or a narrowing of the heart valves (mitral valve).
  • if you have a narrowing (stenosis) of the renal artery.
  • if you have an increase in the thickness of the heart muscle (known as hypertrophic cardiomyopathy).
  • if you have problems with your blood vessels (vascular collagen disease).
  • if you have low blood pressure. You may notice a feeling of lightheadedness or lightheadedness, especially when standing up.
  • if you have kidney problems or are on dialysis.
  • if you have liver problems.
  • if you have diabetes.
  • if you have recently had diarrhea or have been vomiting (being sick).
  • if your doctor told you to check the amount of salt in your diet.
  • if you have high cholesterol levels and are undergoing a treatment called 'LDL apheresis'.
  • you should tell your doctor if you think you are (or may become) pregnant. Zestril is not recommended in the first months of pregnancy, and must not be taken if you are past the first trimester of pregnancy, as it can cause serious harm to your baby if used at that stage (see "pregnancy").
  • if it is of black origin as Zestril may be less effective. You may also experience the "angioedema side effect" (a severe allergic reaction) more easily.

If you are not sure if any of these apply to you, consult your doctor or pharmacist before taking Zestril.

Treatment for allergies such as insect bites

Tell your doctor if you are taking or are about to take treatments to mitigate the effects of an "allergy such as insect bites" (desensitizing treatment). If you take Zestril while taking this treatment, this can cause a severe allergic reaction.

Interventions

If you need to have surgery (including dental surgery) tell your doctor or dentist that you are taking Zestril. This is because you may have low blood pressure (hypotension) if you are given certain local or general anesthetics while you are taking Zestril.

Children and adolescents

Zestril has been studied in children. For more information, ask your doctor. Zestril is not recommended in children under 6 years of age or in children with severe kidney problems.

Interactions Which drugs or foods can change the effect of Zestril

Other medicines and Zestril

Tell your doctor if you are taking, have recently taken or might take any other medicines. This is because Zestril can affect the way some other medicines work, and some medicines can have an effect on Zestril. In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

  • Other medicines that help lower blood pressure.
  • Medicines containing aliskiren (to treat high blood pressure).
  • Medicines that help you pass urine (diuretics).
  • Medicines to dissolve blood clots (usually given in a hospital).
  • Beta blocking medicines, such as atenolol and propranolol.
  • Nitrate medicines (for heart problems).
  • Non-steroidal anti-inflammatory drugs (NSAIDs) used to treat pain and arthritis.
  • Aspirin (acetylsalicylic acid), if you are taking more than 3g per day.
  • Medicines for depression and mental problems, including lithium.
  • Potassium supplements or potassium-containing salt substitutes.
  • Insulin or medicines taken by mouth for diabetes.
  • Medicines used to treat asthma.
  • Medicines used to treat nasal or sinus congestion or other cold remedies (including those you can buy at a pharmacy).
  • Medicines to suppress the body's immune response (immunosuppressants).
  • Allopurinol (for gout).
  • Procainamide (for problems related to heart beat).
  • Medicines containing gold, such as sodium aurothiomalate, which can be given as an injection.

Warnings It is important to know that:

Pregnancy and breastfeeding

Pregnancy

Tell your doctor if you think you are (or may become) pregnant. Your doctor will usually advise you to stop taking Zestril before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Zestril. Zestril is not recommended in the first months of pregnancy and is not recommended. should be taken after the first trimester of pregnancy as it can cause serious problems for the baby if used after the third month of pregnancy.

Feeding time

Tell your doctor if you are breastfeeding or if you intend to start breastfeeding. Zestril is not recommended for nursing mothers and your doctor may choose another treatment if you wish to breastfeed, especially if the baby is newborn or premature.

Driving and using machines

  • Some people may feel tired or lightheaded when taking this medicine. If this happens to you, do not drive or use any tools or machines.
  • You should wait to see how the drug works on you before undertaking these activities.

Dose, Method and Time of Administration How to use Zestril: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

Once you have started treatment with Zestril, your doctor may ask you to have blood tests. Your doctor may later change your dose so that you take the correct dose of the medicine for you.

Taking your medication

  • Swallow the tablet with some water.
  • Try to take the tablets at the same time each day. It doesn't matter if Zestril is taken before or after meals.
  • Continue to take Zestril for as long as your doctor recommends it is a long-lasting treatment. It is important to keep taking Zestril every day.

Taking the first dose

  • Pay special attention when taking the first dose of Zestril or if the dose is increased. This can cause a greater decrease in blood pressure than previous doses.
  • This can cause you to feel dizzy or lightheaded. If this happens, it may be helpful to lie down. If you are worried, contact your doctor as soon as possible.

Adults

Your dose depends on your medical condition and whether you are taking other medicines. Your doctor will tell you how many tablets to take each day. Consult your doctor or pharmacist if in doubt.

For high blood pressure

  • The recommended starting dose is 10 mg once a day.
  • The maintenance dose is usually 20 mg once a day.

For heart failure

  • The recommended starting dose is 2.5 mg once a day.
  • The maintenance dose is 5 to 35 mg once daily.

After a heart attack

  • The recommended starting dose is 5 mg within 24 hours of the attack and 5 mg the next day.
  • The maintenance dose is usually 10 mg once a day.

For kidney problems caused by diabetes

  • The recommended dose is 10 mg or 20 mg once a day.

If you are elderly, have kidney problems or are taking diuretic medicines, your doctor may give you a lower dose than usual.

Use in children and adolescents (6 to 16 years of age) with high blood pressure

  • Zestril is not recommended for children under the age of 6 or in children with severe kidney problems.
  • Your doctor will prescribe the correct dose for your child. The dose depends on the weight of the child.
  • For children weighing between 20 kg and 50 kg, the recommended starting dose is 2.5 mg once daily.
  • For children weighing more than 50 kg, the recommended starting dose is 5 mg once a day.

Overdose What to do if you have taken too much Zestril

If you take more Zestril than you should

If you take more Zestril than prescribed by your doctor, you should immediately contact your doctor or go to a hospital. The following symptoms are likely to occur: dizziness, palpitations.

If you forget to take Zestril

  • If you forget to take a dose, take it as soon as you remember it. However, if your next dose is near, skip the missed dose.
  • Do not take a double dose to make up for a forgotten dose.

If you stop taking Zestril

Do not stop taking your tablets, even if you feel well, unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Zestril

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Zestril and see your doctor immediately if you experience any of the following allergic reactions:

  • Severe allergic reactions (rare, affects 1 to 10 people in 10,000). Symptoms may include a sudden onset of: - swelling of the face, lips, tongue or throat. This can cause difficulty in swallowing. - Severe or sudden swelling of the hands, feet and ankles. - Difficulty in breathing. - Severe itching of the skin (with raised blisters).
  • Serious skin disorders, such as a sudden and unexpected rash or burning, redness or peeling skin (very rare, affects less than 1 in 10,000 people)
  • An infection with symptoms such as fever and severe deterioration of general condition, or fever with local symptoms of infection such as pain in the throat / pharynx / mouth or urinary problems (very rare, affecting less than 1 in 10,000 people).

Other possible side effects:

Common (affects 1 to 10 users in 100)

  • Headache.
  • Feeling spinning or lightheaded, especially when standing up quickly.
  • Diarrhea.
  • Dry cough that does not go away.
  • Being sick (vomiting).
  • Kidney problems (found in blood tests).

Uncommon (affects 1 to 10 users in 1,000)

  • Changes in mood.
  • Change in color of the fingers or toes (bluish followed by redness) or numbness or tingling in the fingers or toes.
  • Changes in taste.
  • Drowsiness.
  • Sensation of spinning (vertigo).
  • Difficulty falling asleep.
  • Stroke.
  • Rapid heartbeats.
  • Runny nose.
  • Feeling sick (nausea).
  • Stomach pains or indigestion.
  • Skin rash or itching.
  • Inability to get an erection (impotence).
  • Feeling tired or weak (loss of strength).
  • An excessive drop in blood pressure can occur in people with the following conditions: with coronary artery disease; with narrowing of the aorta (heart artery), renal artery or heart valves; with increased thickness of the heart muscle. If this happens to you, you may feel dizzy or lightheaded, especially when standing up quickly.
  • Changes in blood tests related to liver and kidney function.
  • Heart attack.
  • Visual and auditory hallucinations.

Rare (affects 1 to 10 users in 10,000)

  • Feeling confused.
  • Lumpy skin rash (hives).
  • Dry mouth.
  • Hair loss
  • Psoriasis (a skin problem).
  • Change in the perception of odors.
  • Breast development in humans.
  • Changes in some cells or other components of the blood. Your doctor may occasionally request blood tests to check if Zestril has an effect on your blood. The signs may include feeling tired, pale, sore throat, high temperature (fever), pain in the joints or muscles, swollen joints or glands, or sensitivity to sunlight.
  • Low levels of sodium in your blood (symptoms can be tiredness, headache, nausea, vomiting).
  • Sudden kidney failure.

Very rare (affects less than 1 user in 10,000)

  • Sinusitis (feeling of pain or fullness behind the cheeks and eyes).
  • Wheezing.
  • Low blood sugar levels (hypoglycemia). The signs can include a feeling of hunger or weakness, sweating, and a rapid heart rate.
  • Inflammation of the lungs. The signs may include coughing, feeling short of breath, and a high temperature (fever).
  • Yellowing of the skin or whites of the eyes (jaundice).
  • Inflammation of the liver. This can cause loss of appetite, yellowing of the skin and eyes, and dark urine.
  • Inflammation of the pancreas.This can cause moderate to severe stomach pain.
  • Severe skin disorders. Symptoms include redness, blistering, exfoliation.
  • Sweating.
  • Poor than normal or no urination.
  • Hepatic insufficiency.
  • Swelling.
  • Inflamed intestine.

Not known (frequency cannot be estimated from the available data).

  • Symptoms of depression.
  • Fainting.

Side effects in children are comparable to those seen in adults.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at "www.agenziafarmaco.gov.it/it/responsabili".

Expiry and Retention

  • Keep this medicine out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the blister and carton. The expiry date refers to the last day of that month.
  • Do not store above 30 ° C.
  • Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Zestril contains

  • The active ingredient is lisinopril (as dihydrate).
  • The other ingredients are mannitol, calcium hydrogen phosphate dihydrate, maize starch, pregelatinised starch and magnesium stearate. In addition, the pink and brown-red tablets contain red iron oxide (E172).

Zestril is available in packs of 5 mg, 10 mg and 20 mg of lisinopril (as dihydrate).

What Zestril looks like and contents of the pack

5 mg tablets: Round, pink, uncoated, biconvex tablets with "♥ 5" on one side and a score line on the other side. Diameter 6 mm.

The tablet can be divided into equal halves.

10 mg tablets: Round, pink, uncoated, biconvex tablets with "♥ 10" on one side and plain on the other side. Diameter 8 mm.

20 mg tablets: Round, brownish-red, uncoated, biconvex tablets with "♥ 20" on one side and plain on the other side. Diameter 8 mm.

Zestril tablets are available in aluminum blisters containing 14, 20, 28, 30, 42, 50, 56, 60, 84, 98, 100, 400 and 500 tablets.

Blisters containing 7 tablets and multiples are also available with marked days.

Zestril tablets are also available in bottles containing 20, 30, 50, 100 and 400 tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Zestril can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

ZESTRIL TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains lisinopril dihydrate equivalent to 5 mg of anhydrous lisinopril.

Each tablet contains lisinopril dihydrate equivalent to 10 mg of anhydrous lisinopril.

Each tablet contains lisinopril dihydrate equivalent to 20 mg of anhydrous lisinopril.

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

5 mg tablets: Round, pink, uncoated, biconvex tablets with "? 5" on one side and score line on the other side. Diameter 6 mm.

The tablet can be divided into equal halves.

10 mg tablets: Round, pink, uncoated, biconvex tablets with "? 10" on one side and plain on the other side. Diameter 8 mm.

20 mg tablets: Round, brownish-red, uncoated, biconvex tablets with "? 20" on one side and plain on the other side. Diameter 8 mm.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Hypertension

Treatment of hypertension.

Heart failure

Treatment of symptomatic heart failure.

Acute myocardial infarction

Short-term (6 weeks) treatment of haemodynamically stable patients within 24 hours of an acute myocardial infarction.

Renal complications of diabetes mellitus

Treatment of renal complications in hypertensive patients with Type 2 diabetes mellitus and incipient nephropathy (see section 5.1).


04.2 Posology and method of administration

Zestril should be administered orally in a single daily dose. As with all once-a-day medications, Zestril should be taken at approximately the same time each day. The absorption of Zestril tablets is not affected by food.

The dose should be individualized according to the patient profile and blood pressure response (see section 4.4).

Hypertension

Zestril can be used alone or in combination with other classes of antihypertensive medicinal products (see sections 4.3, 4.4, 4.5 and 5.1).

Initial dose

In patients with hypertension the usual recommended starting dose is 10 mg. In patients with a strongly activated renin-angiotensin-aldosterone system (particularly renovascular hypertension, sodium and / or volume depletion, cardiac decompensation, or severe hypertension) an excessive fall in blood pressure may occur following the initial dose. An initial dose of 2.5-5 mg is recommended in these patients and the initiation of treatment should take place under medical supervision. In the presence of renal insufficiency a lower starting dose is required (see table 1 below).

Maintenance dose

The usual effective maintenance dosage is 20 mg administered in a single daily dose. Generally, if the desired therapeutic effect cannot be achieved within 2-4 weeks at a given dose level, the dose can be further increased. The maximum dose used in long-term controlled clinical trials was 80 mg / day.

Patients being treated with diuretics

Initiation of Zestril therapy may cause symptomatic hypotension. This is more likely in patients currently being treated with diuretics. Caution is therefore recommended, as these patients may be volume and / or sodium depleted. If possible, the diuretic should be discontinued 2-3 days prior to initiation of Zestril therapy In hypertensive patients in whom the diuretic cannot be withdrawn, Zestril therapy should be initiated with a dose of 5 mg Renal function and serum potassium should be monitored. Subsequent Zestril dosage should be adjusted based on blood pressure response, and diuretic therapy may be resumed if necessary (see sections 4.4 and 4.5).

Dosage adjustments in renal impairment

Dosing in patients with renal impairment should be based on creatinine clearance as outlined in Table 1 below.

Table 1 Dosage adjustments in case of renal impairment

Creatinine clearance (ml / min) Starting dose (mg / day) 2.5 mg * 10 - 30 ml / min 2.5 - 5 mg 31 - 80 ml / min 5 - 10 mg

* Dosage and / or frequency of administration should be adjusted according to blood pressure response.

Dosage can be gradually increased until blood pressure is controlled or up to a maximum of 40 mg / day.

Use in pediatric hypertensive patients aged 6 to 16 years

The recommended starting dose is 2.5 mg once daily in patients weighing 20 to

In children with decreased renal function, a lower starting dose or intervals for increasing the dose should be considered.

Heart failure

In patients with symptomatic heart failure, Zestril should be used as an add-on to diuretics and, where appropriate, digitalis or beta-blockers. Zestril can be started with a starting dose of 2.5 mg once daily, which should be administered under medical observation to determine the initial effect on blood pressure. The dose of Zestril should be increased:

≥ in increments of no more than 10 mg;

≥ at intervals of not less than two weeks;

≥ the maximum tolerated dose by the patient, up to a maximum of 35 mg once daily.

Dose adjustment should be based on the clinical response of the individual patients.

In patients at high risk of symptomatic hypotension, eg. salt-depleted patients with or without hyponatremia, patients with hypovolaemia or patients treated with high dose diuretics, these conditions should be corrected if possible prior to Zestril therapy. Renal function and serum potassium should be monitored (see section 4.4).

Dosage in acute myocardial infarction

Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers. Intravenous or transdermal glyceryl trinitrate can be used together with Zestril.

Initial dose (first 3 days after heart attack)

Treatment with Zestril can be started within 24 hours of the onset of symptoms. Treatment should not be started if the systolic blood pressure is less than 100 mmHg. The first dose of Zestril is 5 mg orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily. Patients with low systolic blood pressure (120 mmHg or less) at the start of treatment or during the first 3 days after heart attack should be given a reduced oral dose of 2.5 mg (see section 4.4).

In case of renal insufficiency (creatinine clearance

Maintenance dose

The maintenance dose is 10 mg once a day. If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg) a daily maintenance dose of 5 mg can be administered with temporary reduction to 2.5 mg if necessary. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than one "hour) Zestril should be discontinued.

Treatment should continue for 6 weeks and then the patient should be re-examined. Patients who develop symptoms of heart failure should continue Zestril therapy (see section 4.2).

Renal complications of diabetes mellitus

In hypertensive patients with Type 2 diabetes mellitus and incipient nephropathy, the dose of Zestril is 10 mg once daily which can be increased, if necessary, up to 20 mg once daily to achieve diastolic blood pressure in a sitting position. less than 90 mmHg.

In cases of renal insufficiency (creatinine clearance

Pediatric population

The experience of safety and efficacy in hypertensive children> 6 years of age is limited, but there is no experience with the other indications (see Section 5.1).

Zestril is not recommended in children in any indication other than hypertension.

Zestril is not recommended in children under 6 years of age, or in children with severe renal impairment (GFR

Elderly patients

In clinical trials, there were no age-related changes in the efficacy or safety profile of the drug. However, when older age is associated with decreased renal function, the indications given in Table 1 should be used to determine the starting dose of Zestril. Thereafter, the dosage should be adjusted according to blood pressure response.

Use in kidney transplant patients

There is no experience with the administration of Zestril in patients who have recently undergone kidney transplantation. Treatment with Zestril is therefore not recommended.


04.3 Contraindications

≥ Hypersensitivity to Zestril, to any of the excipients listed in section 6.1 or to any other angiotensin converting enzyme (ACE) inhibitor.

≥ History of angioedema associated with previous treatment with an ACE inhibitor.

≥ Hereditary or idiopathic angioedema.

≥ Second and third trimester of pregnancy (see sections 4.4 and 4.6).

≥ Concomitant use of Zestril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).


04.4 Special warnings and appropriate precautions for use

Symptomatic hypotension

Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. In hypertensive patients treated with Zestril, hypotension is more likely to occur in the patient with reduced blood volume e.g. from diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting or with severe renin-dependent hypertension (see section 4.5 and section 4.8). Symptomatic hypotension has been observed in patients with heart failure, with or without associated renal failure. This is more likely to occur in those patients with more severe forms of heart failure, as demonstrated by the use of high doses of loop diuretics, due to hyponatremia or impaired renal function. In patients with increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischemic heart disease or cerebrovasculopathy in whom an excessive drop in blood pressure can result in a myocardial infarction or cerebrovascular event. If hypotension occurs, the patient should be placed in the supine position and, if necessary, received an intravenous infusion of saline.

A transient hypotensive response is not a contraindication to further doses, which can usually be given without difficulty, once blood pressure has increased after volume expansion.

In some patients with heart failure and normal or low blood pressure, further lowering of blood pressure may occur with Zestril. This effect is expected and does not usually constitute a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction in dosage or discontinuation of Zestril may be necessary.

Hypotension in acute myocardial infarction

Treatment with Zestril should not be initiated in patients with acute myocardial infarction who are at risk of further severe deterioration of their haemodynamic conditions after treatment with a vasodilator. These are patients with systolic blood pressure values ​​≤ 100 mmHg or those with cardiogenic shock. During the first 3 days following the heart attack, the dose should be reduced if systolic blood pressure is found to be ≤ 120 mmHg. Maintenance doses should be reduced to 5 mg or, temporarily, to 2.5 mg if systolic blood pressure has values ​​≤ 100 mmHg. If hypotension persists (systolic blood pressure

Aortic or mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, Zestril should be administered with caution to patients with mitral valve stenosis and left ventricular outflow obstruction such as aortic stenosis or hypertrophic cardiomyopathy.

Impaired renal function

In case of renal insufficiency (creatinine clearance

In patients with insufficiency cardiac, hypotension following initiation of ACE inhibitor therapy may lead to further impairment of renal function. Acute renal failure, usually reversible, has been reported in this situation.

In some patients with bilateral stenosis of the renal artery or stenosis of the renal artery in monorene, When treated with angiotensin converting enzyme inhibitors, increases in blood urea nitrogen and serum creatinine have been observed which are usually reversible after discontinuation of therapy. This is particularly likely in patients with renal insufficiency. The concomitant presence of renovascular hypertension leads to greater risk of severe hypotension and renal insufficiency In these patients, treatment should be initiated under close medical supervision, with low doses and careful dose titration.Since treatment with diuretics may contribute to the above, these should be discontinued and renal function monitored during the first few weeks of Zestril therapy.

Some hypertensive patients without apparent pre-existing renal vascular disease, they developed increases, usually mild and transient, in BUN and serum creatinine, especially when Zestril was administered concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal insufficiency. It may be necessary to reduce the dosage and / or discontinue the diuretic and / or Zestril.

In the"acute myocardial infarction, Zestril treatment should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration> 177 mmol / l, and / or proteinuria> 500 mg / 24h. If renal dysfunction develops during treatment with Zestril (serum creatinine concentration> 265 mmol / L, or doubling the pre-treatment value), the physician should consider discontinuing treatment.

Hypersensitivity / angioedema

Angioedema of the face, extremities, lips, tongue, glottis and / or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including Zestril. This can occur at any time. during treatment. In such cases, Zestril should be promptly discontinued and appropriate treatment and monitoring instituted to ensure complete resolution of symptoms before patients are discharged. Even in cases where swelling is confined to the tongue, without respiratory distress , the patient may require prolonged observation as treatment with antihistamines and corticosteroids may not be sufficient.

Fatal events due to angioedema associated with edema of the larynx or tongue have been reported very rarely.

In patients with affected tongue, glottis, or larynx, airway obstruction is likely, especially in those with a history of airway surgery. In these cases, emergency therapy should be given promptly. This may include administering adrenaline and / or maintaining an open airway. The patient should be placed under close medical surveillance until complete and prolonged resolution of symptoms.

Angiotensin converting enzyme inhibitors cause angioedema more frequently in black patients than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while taking an ACE inhibitor (see section 4.3).

Anaphylactoid reactions in hemodialysis patients

Anaphylactoid reactions have been reported in patients undergoing dialysis with high flux membranes (eg AN 69) and concomitant treatment with an ACE inhibitor. The use of different types of dialysis membranes or different classes of antihypertensive agents should be considered for these patients.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during low-density lipoprotein apheresis with dextran sulfate. These reactions were avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis.

Desensitization

Patients who received ACE inhibitors during desensitizing treatment (eg hymenoptera venom) have suffered from anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withdrawn but reappeared soon after the drug was inadvertently re-administered.

Hepatic insufficiency

Very rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not known. Patients on Zestril who develop jaundice or marked elevation of liver enzymes should discontinue treatment with Zestril and receive appropriate medical follow-up.

Neutropenia / agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complications, neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible after discontinuation of ACE inhibitor treatment. Zestril should be used with extreme caution in patients with collagen disease involving vasculitis, immunosuppressive therapy, treatment with allopurinol or procainamide, or with a combination of such conditions, especially if there is pre-existing impairment of renal function. Some of these patients developed severe infections, which in some cases did not respond to intensive antibiotic therapy. If Zestril is used in these patients, periodic monitoring of the white blood cell count is recommended and the patient should be asked to report any manifestations of infection.

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

There is evidence that 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 RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Ethnicity

Angiotensin converting enzyme inhibitors cause angioedema more frequently in black patients than in non-black patients.

As with other ACE inhibitors, Zestril may be less effective in lowering blood pressure in black hypertensive patients than in non-black hypertensive patients, possibly due to a higher prevalence of low-renin conditions in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. This is characteristically nonproductive, persistent and resolves upon discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery / anesthesia

In patients undergoing major surgery or during anesthesia with agents that cause hypotension, Zestril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is believed to be an effect of this mechanism, it can be corrected by volume expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Zestril. Patients at risk of developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those on concomitant treatment with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients on other drugs with which an increase in serum potassium (eg heparin). If concomitant use of the above agents is considered necessary, regular monitoring of serum potassium is recommended (see section 4.5).

Diabetic patients

In diabetic patients being treated with oral antidiabetic drugs or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5 Interactions with other medicinal products and other forms of interaction).

Lithium

The combination of lithium with Zestril is generally not recommended (see section 4.5).

Pregnancy

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be switched to alternative antihypertensive treatments that have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).


04.5 Interactions with other medicinal products and other forms of interaction

Antihypertensives

When Zestril is given in combination with other antihypertensive agents (e.g. nitroglycerin and other nitrates, or other vasodilators), an additive hypotensive effect may occur.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (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 agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).

Diuretics

The antihypertensive effect is usually additive when a diuretic is added to the therapy of a patient being treated with Zestril.

In patients already being treated with diuretics, especially those in whom diuretic therapy has recently been instituted, an "excessive reduction in blood pressure may occasionally occur when Zestril is added. The possibility of symptomatic hypotension with Zestril can be minimized by stopping the diuretic before starting treatment with Zestril (see section 4.4 and section 4.2).

Potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes

Although in clinical studies, serum potassium usually remained within normal limits, hyperkalaemia occurred in some patients. Risk factors for developing hyperkalaemia include renal failure, diabetes mellitus, and concomitant use of potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes. The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium.

If Zestril is given with a potassium-dispersing diuretic, the diuretic-induced hypokalaemia may be improved.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and increase the already increased lithium toxicity with ACE inhibitors. The use of Zestril with lithium is not recommended, but if combination treatment is necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid ≥3g / day

When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (eg acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), "attenuation of the antihypertensive effect" may occur. The concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of deterioration of renal function, including acute renal failure and an increase in serum potassium, especially in patients with pre-existing poor renal function. These effects are generally reversible. combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and renal function monitoring should be considered after initiation of concomitant therapy, and periodically thereafter.

Gold

Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension, which can be very severe) have been reported more frequently in patients treated with ACE inhibitors following administration of injectable gold (e.g. sodium aurothiomalate).

Tricyclic Antidepressants / Antipsychotics / Anesthetics

The concomitant use of certain anesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in a further reduction in blood pressure (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Antidiabetic

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic drugs (insulins and oral hypoglycemic agents) may cause an increase in the blood glucose lowering effect with the risk of hypoglycaemia. This phenomenon appears to occur more likely during the first weeks of combined treatment and in patients with impaired renal function.

Tissue Plasminogen Activators

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

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

Zestril can be used concomitantly with acetylsalicylic acid, (at cardiological doses), thrombolytics, beta blockers and / or nitrates.


04.6 Pregnancy and breastfeeding

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy has not been comprehensive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential. , patients planning pregnancy should be switched to alternative antihypertensive treatments that have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimester of pregnancy is known to cause human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (See paragraph 5.3).

Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound evaluation of renal function and skull is recommended.

Children whose mothers have taken ACE inhibitors should be carefully observed due to hypotension (see sections 4.3 and 4.4).

Feeding time

Since no information is available on the use of Zestril during breastfeeding, Zestril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially when breastfeeding an infant or premature baby.


04.7 Effects on ability to drive and use machines

When driving vehicles or using machines it should be taken into account that occasionally dizziness or tiredness may occur.


04.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with Zestril and other ACE inhibitors with the following frequencies: very common, (≥1 / 10), common, (≥1 / 100 and

Disorders of the blood and lymphatic system

Rare: decrease in hemoglobin, decrease in hematocrit.

Very rare: bone marrow depression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anemia, lymphadenopathy, autoimmune diseases.

Metabolism and nutrition disorders

Very rare: hypoglycaemia.

Nervous system disorders and psychiatric disorders

Common: dizziness, headache.

Uncommon: mood changes, paraesthesia, dizziness, taste disturbances, sleep disturbances, hallucinations.

Rare: mental confusion, olfactory disturbances.

Frequency not known: depressive symptoms, syncope.

Cardiac and vascular disorders

Common: orthostatic effects (including hypotension).

Uncommon: myocardial infarction or cerebrovascular event, possibly secondary to excessive hypotension in high-risk patients (see section 4.4), palpitations, tachycardia. Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders

Common: cough.

Uncommon: rhinitis.

Very rare: bronchospasm, sinusitis. Allergic alveolitis / eosinophilic pneumonia.

Gastrointestinal disorders

Common: diarrhea, vomiting.

Uncommon: nausea, abdominal pain and indigestion.

Rare: dry mouth.

Very rare: pancreatitis, intestinal angioedema, hepatocellular or cholestatic hepatitis, jaundice and hepatic failure (see section 4.4).

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

Rare: urticaria, alopecia, psoriasis, hypersensitivity / angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis, and / or larynx (see section 4.4).

Very rare: sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma.

A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody (ANA) positivity, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis may occur, rash, photosensitivity and other dermatological manifestations.

Renal and urinary disorders

Common: renal dysfunction.

Rare: uremia, acute renal failure.

Very rare: oliguria / anuria.

Endocrine pathologies

Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Diseases of the reproductive system and breast

Uncommon: impotence.

Rare: gynecomastia.

General disorders and administration site conditions

Uncommon: fatigue, asthenia.

Diagnostic tests

Uncommon: blood urea increased, serum creatinine increased, liver enzymes increased, hyperkalaemia.

Rare: increased serum bilirubin, hyponatremia.

Safety data from clinical studies suggest that lisinopril is generally well tolerated in pediatric hypertensive patients and that the safety profile in this age group is comparable to that seen in adults.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address" www.agenziafarmaco.gov.it/it/responsabili ".


04.9 Overdose

There are limited data on overdose in humans. Symptoms associated with overdose with ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

The recommended treatment for overdose is intravenous infusion of saline. In case of hypotension the patient should be placed in a shock position. If available, treatment with angiotensin II infusion and / or catecholamines may also be considered. intravenously.

If ingestion is recent, measures aimed at eliminating Zestril should be implemented (eg vomiting, gastric lavage, administration of adsorbents and sodium sulphate). Zestril can be removed from the circulation by hemodialysis (see section 4.4 Special warnings and precautions for use).

Pacemaker therapy is indicated for therapy resistant bradycardia. Vital signs, serum electrolytes and creatinine concentration should be monitored frequently.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors. ATC code: C09AA03

Mechanism of action

Zestril is a peptidyl dipeptidase inhibitor. The drug inhibits the angiotensin converting enzyme (ACE) which catalyzes the conversion of angiotensin I into angiotensin II, a peptide with vasoconstrictive action. Angiotensin II also stimulates the secretion of aldosterone by the adrenal cortex. Inhibition of ACE results in a reduction in angiotensin II concentrations with consequent decrease in vasopressor activity and aldosterone secretion. This latter reduction may cause an increase in serum potassium concentration.

Pharmacodynamic effects

Although the mechanism by which lisinopril lowers blood pressure is thought to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is also antihypertensive in patients with low-renin hypertension. ACE is identical to kinase II, an enzyme that degrades bradykinin. It is not yet clear whether increased levels of bradykinin, a potent vasodilator peptide, play a role in the therapeutic effects of lisinopril.

Clinical efficacy and safety

The effect of Zestril on mortality and morbidity in heart failure was 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). ). In a study in 3,164 patients, with a median follow-up for surviving patients of 46 months, high-dose versus low-dose Zestril resulted in a 12% risk reduction in the combined endpoint of all mortality. cause and all-cause hospitalization (p = 0.002) and an 8% risk reduction in all-cause mortality and cardiovascular hospitalization (p = 0.036). Reductions in mortality risk were observed for all causes (8%; p = 0.128) and cardiovascular mortality (10%; p = 0.073). In a post-hoc analysis, the number of hospitalizations for heart failure was reduced by 24% (p = 0.002) in patients treated with high-dose versus low-dose Zestril Symptomatic benefits were similar in patients treated with high and low-dose Zestril.

The results of the study showed that the overall adverse event profile in patients treated with high or low doses of Zestril was similar in both nature and number. Predictable events resulting from ACE inhibition, such as hypotension or renal impairment, were manageable and rarely led to treatment discontinuation.

Cough was less frequent in patients treated with high-dose Zestril compared to low-dose.

In the GISSI-3 study, in which a 2x2 factorial design was used to compare the effects of Zestril and glyceryl trinitrate given alone or in combination for 6 weeks versus a control group in 19,394 patients who received treatment within 24 hours after an acute myocardial infarction, Zestril produced a statistically significant 11% reduction in mortality versus control (2p = 0.03). The risk reduction with glyceryl trinitrate was not significant but the combination of Zestril with glyceryl trinitrate produced a significant reduction in mortality risk of 17% versus control (2p = 0.02). In the subgroup of elderly (over 70 years of age) and women, predefined as high-risk mortality patients , a significant benefit was observed for a combined endpoint of mortality and cardiac function. The combined endpoint for all patients, as well as for the subgroup of p high-risk patients at 6 months also showed significant benefit for those treated with Zestril or Zestril plus glyceryl trinitrate for 6 weeks, indicating a preventative effect of Zestril. As would be expected from any vasodilator treatment, increased incidences of hypotension and renal dysfunction have been associated with Zestril but these have not been associated with a proportional increase in mortality.

In a double-blind, randomized, multicenter study comparing Zestril with a calcium channel blocker in 335 hypertensive subjects with Type 2 diabetes mellitus and incipient nephropathy characterized by microalbuminuria, Zestril administered at doses ranging from 10 mg to 20 mg once daily for 12 months, reduced systolic / diastolic blood pressure by 13/10 mmHg and urinary albumin excretion rate by 40%. When compared with the calcium channel blocker, which produced a similar lowering of blood pressure, patients treated with Zestril showed a significantly greater reduction in the urinary albumin excretion rate, providing evidence that the ACE inhibitory action of Zestril reduced microalbuminuria. with a direct mechanism on the kidney tissues in addition to its effect on blood pressure reduction.

Lisinopril treatment does not affect glycemic control, as shown by a lack of significant effect on glycated hemoglobin (HbA1C) levels.

Agents acting on the renin-angiotensin system (RAS)

Two large randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) examined the use of the combination of an ACE inhibitor with an antagonist of the angiotensin II receptor.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus associated with evidence of organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy.

These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.

ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Pediatric population

In a clinical study including 115 hypertensive pediatric patients, aged 6 to 16 years, patients weighing less than 50 kg received 0.625 mg, 2.5 mg, or 20 mg of Zestril per day and patients weighing 50 kg or more received 1.25 mg, 5 mg or 40 mg of Zestril per day. After two weeks, Zestril administered once daily lowered blood pressure in a dose-dependent manner with consistent efficacy demonstrated at doses greater than 1.25 mg.

This effect was confirmed at discharge, where blood pressure increased by approximately 9 mmHg in patients randomized to placebo compared with randomized patients staying on the medium and higher dose of Zestril. The dose-dependent antihypertensive effect of Zestril was evaluated across different demographic subgroups: age, Tanner stage, gender and ethnicity.


05.2 "Pharmacokinetic properties

Lisinopril is an orally active ACE inhibitor that does not contain a hydrogen sulfide group.

Absorption

After oral administration of lisinopril peak plasma concentrations are observed within approximately 7 hours, although there has been a tendency for a slight delay in the time to reach peak plasma concentrations in patients with acute myocardial infarction. Based on urinary recovery, the mean degree of absorption of lisinopril is approximately 25%, with interpatient variability of 6-60% at the dose range tested (5-80 mg). Absolute bioavailability is reduced by approximately 16% in patients with heart failure. Absorption of lisinopril is not affected by food.

Distribution

Lisinopril does not appear to be bound to other plasma proteins other than the enzyme responsible for converting angiotensin (ACE). Studies in rats indicate that lisinopril crosses the blood brain barrier poorly.

Elimination

Lisinopril is not metabolised and is excreted completely unchanged in the urine. At multiple doses, lisinopril has an effective accumulation half-life of 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 ml / min. The decrease in serum concentrations shows a prolonged terminal phase that does not contribute to drug accumulation. This terminal phase probably represents the saturable binding at the ACE level and is not proportional to dose.

Hepatic impairment

Impaired liver function in cirrhotic patients leads to a decrease in the absorption of lisinopril (approximately 30% based on urinary recovery), but an increase in exposure (approximately 50%) compared to healthy subjects, due to the decrease in clearance.

Renal impairment

Impaired renal function reduces the elimination of lisinopril, which is excreted via the kidney, but this reduction becomes clinically important only when the glomerular filtration rate is less than 30 ml / min. In cases of mild to renal impairment. moderate (creatinine clearance 30-80 ml / min) the mean AUC was increased by only 13%, while in severe renal impairment (creatinine clearance 5-30 ml / min) a 4-5 fold increase was observed .

Lisinopril can be removed by dialysis. During a 4-hour hemodialysis, plasma concentrations of lisinopril decreased on average by 60% with a dialysis clearance between 40 and 55 mL / min.

Heart failure

Compared to healthy subjects, patients with heart failure have a higher exposure to lisinopril (an average increase in AUC of 125%), but based on urinary recovery of lisinopril, there is a reduction in absorption of approximately 16 %.

Pediatric population

The pharmacokinetic profile of lisinopril was studied in 29 pediatric hypertensive patients, aged 6 to 16 years, with GFR below 30 ml / min / 1.73 m2. Following doses of 0.1 to 0.2 mg / kg, the steady state peak plasma concentration of lisinopril appeared within 6 hours and the extent of absorption based on urinary recovery was approximately 28%. These values ​​are similar to those obtained in previous studies in adults.

The AUC and Cmax values ​​in children were consistent with those observed in adults.

Elderly patients

Compared to younger subjects, older patients have higher blood levels and higher AUC values ​​(approximate 60% increase).


05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of general pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. ACE inhibitors, as a class, have been shown to induce adverse effects on late fetal development. which result in fetal death and congenital effects, which particularly affect the skull. In addition, fetotoxicity, intrauterine growth retardation and patent ductus arteriosus have been reported. These developmental abnormalities are thought to be in part due to the direct action of ACEs. -inhibitors on the fetal renin-angiotensin system and in part due to ischemia resulting from maternal hypotension and decreased fetal-placental blood flow and oxygen / nutrient supply to the fetus.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Mannitol,

calcium hydrogen phosphate dihydrate,

red iron oxide (E172),

cornstarch,

pregelatinised starch,

magnesium stearate.


06.2 Incompatibility

Not relevant.


06.3 Period of validity

4 years.


06.4 Special precautions for storage

Do not store above 30 ° C.


06.5 Nature of the immediate packaging and contents of the package

5 mg tablets:

Aluminum / PVC-PVDC or Aluminum / PVC blisters of 14, 20, 28, 28x1, 30, 42, 50, 56, 60, 84, 98, 100, 400 and 500 tablets.

Aluminum / PVC-PVDC or Aluminum / PVC blister with calendar of 14, 28, 42, 56, 84 and 98 tablets.

HDPE bottle containing 20, 30, 50, 100 and 400 tablets.

10 mg tablets:

Aluminum / PVC-PVDC or Aluminum / PVC blisters of 14, 20, 28, 30, 50, 56, 84, 98, 100 and 400 tablets.

Aluminum / PVC-PVDC or Aluminum / PVC blister with calendar of 14, 28, 56, 84 and 98 tablets.

HDPE bottle containing 20, 30, 50, 100 and 400 tablets.

20 mg tablets:

Aluminum / PVC-PVDC or Aluminum / PVC blisters of 14, 20, 28, 30, 42, 50, 56, 56x1, 60, 84, 98, 100, 400 and 500 tablets.

Aluminum / PVC-PVDC or Aluminum / PVC blister with calendar of 14, 28, 42, 56, 84 and 98 tablets.

HDPE bottle containing 20, 30, 50, 100 and 400 tablets.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

AstraZeneca S.p.A.

Ferraris Palace,

Via Ludovico il Moro 6 / C

20080 Basiglio (MI)

08.0 MARKETING AUTHORIZATION NUMBER

Zestril 5 mg 14 tablets - A.I.C. 026834010

Zestril 5 mg, 28 tablets - A.I.C. 026834059

Zestril 5 mg, 42 tablets - A.I.C. 026834061

Zestril 10 mg, 14 tablets - A.I.C. 026834034

Zestril 20 mg, 14 tablets - A.I.C. 026834022

Zestril 20 mg, 28 tablets - A.I.C. 026834073

Zestril 20 mg, 42 tablets - A.I.C. 026834085

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 16.08.1989.

Date of latest renewal: 27.04.2012

10.0 DATE OF REVISION OF THE TEXT

January 2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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