This data is intended for employ by health professionals

Lisinopril 20 mg Tablets

Each tablet contains lisinopril dihydrate equivalent to twenty mg anhydrous lisinopril.

For the full list of excipients, see department half-dozen.one

Tablets.

20 mg tablets are white, round arched tablets with embossing "20" on one side and breakline on the other side.

The tablets tin can be divided into equal halves.

Hypertension

Treatment of hypertension.

Heart Failure

Handling of symptomatic center failure.

Acute Myocardial Infarction

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

Renal Complications of Diabetes Mellitus

Treatment of renal illness in hypertensive patients with Type two diabetes mellitus and incipient nephropathy (see department 5.1).

Lisinopril tin can be used alone or in combination with other antihypertensive agents (run into sections 4.3, 4.4, 4.5 and 5.1).

Lisinopril tablets should be administered orally in a unmarried daily dose. As with all other medication taken once daily, Lisinopril tablets should be taken at approximately the same time each day. The absorption of Lisinopril tablets is not affected by food.

The dose should be individualised according to patient profile and claret pressure response (run across section four.iv)

Hypertension

Lisinopril tablets may exist used as monotherapy or in combination with other classes of antihypertensive therapy (encounter sections four.three, iv.4, iv.5 and 5.one).

Starting dose

In patients with hypertension the usual recommended starting dose is x mg. Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and /or volume depletion, cardiac decompensation, or astringent hypertension) may experience an excessive claret force per unit area fall following the initial dose. A starting dose of 2.5-5 mg is recommended in such patients and the initiation of treatment should take place under medical supervision. A lower starting dose is required in the presence of renal damage (see Table i below).

Maintenance dose

The usual effective maintenance dosage is 20 mg administered in a single daily dose. In full general if the desired therapeutic effect cannot exist achieved in a catamenia of 2 to 4 weeks on a certain dose level, the dose can be further increased. The maximum dose used in long-term, controlled clinical trials was 80 mg/24-hour interval.

Diuretic-Treated Patients

Symptomatic hypotension may occur post-obit initiation of therapy with Lisinopril tablets. This is more likely in patients who are being treated currently with diuretics. Circumspection is recommended therefore, since these patients may exist book and/or salt depleted. If possible, the diuretic should be discontinued ii to 3 days before offset therapy with Lisinopril tablets. In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Lisinopril tablets should be initiated with a 5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Lisinopril tablets should be adapted according to blood force per unit area response. If required, diuretic therapy may be resumed (see department 4.4 and section 4.5).

Dosage Adjustment In Renal Harm

Dosage in patients with renal impairment should exist based on creatinine clearance every bit outlined in Table 1 below.

Table 1 Dosage adjustment in renal harm.

Creatinine Clearance (ml/min)

Starting Dose (mg/solar day)

Less than x ml/min (including patients on dialysis)

2.v mg*

ten-xxx ml/min

two.5-5 mg

31-80 ml/min

v-10 mg

* Dosage and/or frequency of administration should be adapted depending on the blood pressure response.

The dosage may exist titrated upwardly until claret pressure level is controlled or to a maximum of 40 mg daily.

Use in Hypertensive Paediatric Patients aged 6-16 years

The recommended initial dose is 2.5 mg once daily in patients twenty to <50 kg, and v mg once daily in patients ≥50 kg. The dosage should be individually adjusted to a maximum of twenty mg daily in patients weighing 20 to <50 kg, and 40 mg in patients ≥50 kg. Doses to a higher place 0.61 mg/kg (or in excess of 40 mg) accept not been studied in paediatric patients (see section 5.1).

In children with decreased renal function, a lower starting dose or increased dosing interval should be considered.

Centre Failure

In patients with symptomatic center failure, Lisinopril tablets should be used every bit adjunctive therapy to diuretics and, where advisable, digitalis or beta-blockers. Lisinopril tablets may be initiated at a starting dose of 2.five mg in one case a 24-hour interval, which should be administered under medical supervision to determine the initial outcome on the blood pressure level. The dose of Lisinopril tablets should be increased:

• By increments of no greater than 10 mg

• At intervals of no less than 2 weeks

• To the highest dose tolerated by the patient up to a maximum of 35 mg in one case daily.

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

Patients at loftier run a risk of symptomatic hypotension e.g. patients with common salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these weather corrected, if possible, prior to therapy with Lisinopril tablets. Renal office and serum potassium should exist monitored (see section 4.4).

Posology in Astute Myocardial Infarction

Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers. Intravenous or transdermal glyceryl trinitrate may exist used together with Lisinopril tablets.

Starting dose (kickoff 3 days after infarction)

Treatment with Lisinopril tablets may exist started inside 24 hours of the onset of symptoms. Treatment should not exist started if systolic claret pressure level is lower than 100 mm Hg. The first dose of Lisinopril tablets is 5 mg given orally, followed by 5 mg subsequently 24 hours, 10 mg after 48 hours and then 10 mg once daily. Patients with a depression systolic blood pressure level (120 mm Hg or less) when treatment is started or during the first 3 days afterward the infarction should be given a lower dose - 2.5 mg orally (come across section 4.4).

In cases of renal impairment (creatinine clearance <80 ml/min), the initial Lisinopril tablets dosage should be adjusted according to the patient's creatinine clearance (run across Tabular array 1).

Maintenance dose

The maintenance dose is 10 mg one time daily. If hypotension occurs (systolic claret pressure less than or equal to 100 mm Hg) a daily maintenance dose of five mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure level less than 90 mm Hg for more than than 1 hour) Lisinopril tablets should be withdrawn.

Treatment should continue for half dozen weeks so the patient should exist re-evaluated. Patients who develop symptoms of centre failure should continue with Lisinopril tablets (see section 4.two).

Renal Complications of Diabetes Mellitus

In hypertensive patients with type 2 diabetes mellitus and incipient nephropathy, the dose is 10 mg Lisinopril tablets once daily which tin be increased to 20 mg one time daily, if necessary, to achieve a sitting diastolic blood pressure beneath 90 mm Hg.

In cases of renal damage (creatinine clearance <80 ml/min), the initial Lisinopril tablets dosage should be adjusted according to the patient'due south creatinine clearance (encounter Table ane).

Paediatric population

There is limited efficacy and safety experience in hypertensive children >6 years old, but no experience in other indications (see section 5.one). Lisinopril is not recommended in children in other indications than hypertension.

Lisinopril is not recommended in children below the age of 6, or in children with severe renal damage (GFR <30ml/min/one.73m2) (encounter section five.2).

Elderly

In clinical studies, there was no age-related modify in the efficacy or safety profile of the drug. When avant-garde age is associated with decrease in renal part, however, the guidelines set up out in Table ane should be used to decide the starting dose of Lisinopril tablets. Thereafter, the dosage should exist adjusted according to the blood pressure response.

Utilise in kidney transplant patients

There is no experience regarding the administration of Lisinopril tablets in patients with recent kidney transplantation. Treatment with Lisinopril tablets is therefore non recommended.

• Hypersensitivity to Lisinopril tablets, to any of the excipients listed in section 6.1 or whatsoever other angiotensin converting enzyme (ACE) inhibitor

• History of angioedema associated with previous ACE inhibitor therapy

• Concomitant employ of Lisinopril tablets with sacubitril/valsartan therapy. Lisinopril tablets must not exist initiated earlier than 36 hours after the concluding dose of sacubitril/valsartan (see sections four.iv and iv.5).

• Hereditary or idiopathic angioedema

• Second and tertiary trimesters of pregnancy (see sections 4.4 and 4.6).

• In combination with aliskiren-containing medicines in patients with diabetes mellitus (type I or II) or with moderate to astringent renal harm (GFR < 60 ml/min/1.73mtwo (see sections four.v and 5.ane).

Symptomatic Hypotension

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Lisinopril tablets, hypotension is more than likely to occur if the patient has been volume-depleted eastward.g. by diuretic therapy, dietary table salt restriction, dialysis, diarrhoea or airsickness, or has severe renin-dependent hypertension (encounter section 4.5 and department 4.8). In patients with middle failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is about likely to occur in those patients with more than astringent degrees of heart failure, every bit reflected by the utilize of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischaemic middle or cerebrovascular disease in whom an excessive fall in blood pressure level could issue in a myocardial infarction or cerebrovascular accident.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is non a contraindication to further doses, which tin can be given commonly without difficulty one time the blood pressure has increased subsequently volume expansion.

In some patients with heart failure who accept normal or low claret pressure, additional lowering of systemic claret pressure may occur with Lisinopril tablets. This upshot is predictable and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Lisinopril tablets may be necessary.

Hypotension In Astute Myocardial Infarction

Treatment with Lisinopril tablets must non be initiated in acute myocardial infarction patients who are at risk of farther serious haemodynamic deterioration after handling with a vasodilator. These are patients with systolic claret pressure of 100 mm Hg or lower or those in cardiogenic daze. During the get-go 3 days following the infarction, the dose should be reduced if the systolic claret pressure is 120 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily to two.5 mg if systolic claret pressure level is 100 mm Hg or lower. If hypotension persists (systolic blood pressure less than ninety mm Hg for more than 1 hour) then Lisinopril tablets should be withdrawn.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, Lisinopril tablets should exist given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.

Renal Function Impairment

In cases of renal impairment (creatinine clearance <80 ml/min), the initial Lisinopril tablets dosage should be adjusted co-ordinate to the patient's creatinine clearance (meet Table 1 in department four.2) and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine is office of normal medical practise for these patients.

In patients with heart failure, hypotension post-obit the initiation of therapy with ACE inhibitors may pb to some further harm in renal function. Acute renal failure, usually reversible, has been reported in this situation.

In some patients with bilateral renal avenue stenosis or with a stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present in that location is an increased gamble of severe hypotension and renal insufficiency. In these patients, treatment should be started nether close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal role should be monitored during the first weeks of Lisinopril tablets therapy.

Some hypertensive patients with no credible pre-existing renal vascular disease have developed increases in claret urea and serum creatinine, usually small-scale and transient, especially when Lisinopril tablets has been given concomitantly with a diuretic. This is more probable to occur in patients with pre-existing renal harm. Dosage reduction and/or discontinuation of the diuretic and/or Lisinopril tablets may be required.

In acute myocardial infarction, treatment with Lisinopril tablets 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 tablets (serum creatinine concentration exceeding 265 micromol/fifty or a doubling from the pre-treatment value) then the physician should consider withdrawal of Lisinopril tablets.

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 Lisinopril tablets. This may occur at any fourth dimension during therapy. In such cases, Lisinopril tablets should be discontinued promptly and advisable treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. Fifty-fifty in those instances where swelling of merely the tongue is involved, without respiratory distress, patients may crave prolonged ascertainment since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities take been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patient'south airway. The patient should exist under close medical supervision until consummate and sustained resolution of symptoms has occurred.

Angiotensin converting enzyme inhibitors cause a college rate of angioedema 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 receiving an ACE inhibitor (see 4.three ).

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased chance of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of Lisinopril. Treatment with Lisinopril must not be initiated earlier than 36 hours after the final dose of sacubitril/valsartan (see sections 4.3 and 4.5).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may pb to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory damage) (see section 4.five). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

Anaphylactoid reactions in Haemodialysis Patients

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.1000. AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate take experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Desensitisation

Patients receiving ACE inhibitors during desensitisation handling (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld only they have reappeared upon inadvertent re-assistants of the medicinal product.

Hepatic failure

Very rarely, ACE inhibitors take been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) decease. The mechanism of this syndrome is not understood. Patients receiving Lisinopril tablets who develop jaundice or marked elevations of hepatic enzymes should discontinue Lisinopril tablets and receive appropriate medical follow-up.

Neutropenia/ Agranulocytosis

Neutropenia/ Agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible subsequently discontinuation of the ACE inhibitor. Lisinopril tablets should be used with extreme circumspection in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, peculiarly if there is pre-existing dumb renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibody therapy. If Lisinopril tablets are used in such patients, periodic monitoring of white blood cell counts is brash and patients should be instructed to report any sign of infection.

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

There is bear witness that the concomitant utilise of ACE-inhibitors, angiotensin Two receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal role (including acute renal failure). Dual occludent of 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 blockade therapy is considered absolutely necessary, this should merely occur under specialist supervision and subject area to frequent shut monitoring of renal function, electrolytes and blood pressure.

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

Race

ACE inhibitors crusade a higher charge per unit of angioedema in black patients than in non-black patients.

As with other ACE inhibitors, Lisinopril tablets may be less constructive in lowering claret pressure in black patients than in non-blacks, perchance because of a college prevalence of depression-renin states in the black hypertensive population.

Cough

Coughing has been reported with the utilise of ACE inhibitors. Characteristically, the coughing is not-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced coughing should be considered equally role of the differential diagnosis of coughing.

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Lisinopril tablets may cake angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to exist due to this mechanism, it can be corrected by book expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Lisinopril tablets. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics (eastward.1000. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes, or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, the combination trimethoprim/sulfamethoxazole also known as cotrimoxazole). If concomitant use of the above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the starting time month of treatment with an ACE inhibitor (see section 4.five Interaction with other medicinal products and other forms of interaction).

Lithium

The combination of lithium and Lisinopril tablets 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 exist inverse to alternative antihypertensive treatments which take an established safety profile for utilise in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (encounter sections 4.iii and four.vi).

Antihypertensive agents

When Lisinopril tablets is combined with other antihypertensive agents (e.g. glyceryl trinitrate and other nitrates, or other vasodilators), additive falls in blood pressure may occur.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin 2 receptor blockers or aliskiren is associated with a higher frequency of adverse events such equally hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (run across sections 4.3, 4.four and five.1).

Drugs that may increment the take chances of angioedema

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

Diuretics

When a diuretic is added to the therapy of a patient receiving Lisinopril tablets the antihypertensive upshot is usually additive.

Patients already on diuretics and specially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when Lisinopril tablets is added. The possibility of symptomatic hypotension with Lisinopril tablets can exist minimised by discontinuing the diuretic prior to initiation of treatment with Lisinopril tablets (see section 4.2 and section 4.4).

Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutesand other drugs that may increase serum potassium levels

Although in clinical trials, serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients. The use of potassium supplements, potassium-sparing diuretics or potassium-containing common salt substitutes and other drugs that may increase serum potassium levels, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium.

Monitoring of potassium should exist undertaken equally appropriate. See department four.4. If Lisinopril is given with a potassiumlosing diuretic, diuretic induced hypokalaemia may be ameliorated.

Ciclosporin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with cislosporin.

Monitoring of serum potassium ids recommended.

Heparin

Hyperkalaemia may occur during concomitant employ of ACE inhibitors with heparin.

Monitoring of serum potassium is recommended.

Lithium

Reversible increases in serum lithium concentrations and toxicity take been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increment the hazard of lithium toxicity and raise the already increased lithium toxicity with ACE inhibitors. Use of Lisinopril tablets with lithium is non recommended, but if the combination proves necessary, conscientious monitoring of serum lithium levels should be performed (see section iv.4).

Non steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acrid ≥3g/twenty-four hours

When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-ii inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, peculiarly in patients with poor pre-existing renal function. These effects are ordinarily reversible. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should exist given to monitoring renal role later initiation of concomitant therapy, and periodically thereafter.

Gold

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

Tricyclic antidepressants / Antipsychotics /Anaesthetics

Concomitant apply of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in farther reduction of blood pressure (meet section iv.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Antidiabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering result with risk of hypoglycaemia. This phenomenon appeared to exist more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk of hyperkalaemia (see department 4.4).

Acetylsalicylic acrid, thrombolytics, beta-blockers, nitrates

Lisinopril tablets may exist used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates.

Pregnancy

The use of ACE inhibitors is non recommended during the first trimester of pregnancy (meet section iv.4). The use of ACE inhibitors is contra indicated during the second and third trimester of pregnancy (see department 4.3 and 4.iv).

Epidemiological testify regarding the risk of teratogenicity following exposure to ACE inhibitors during the starting time trimester of pregnancy has not been conclusive; however a pocket-size increment in take chances cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be inverse to culling antihypertensive treatments which take an established condom profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should exist stopped immediately, and, if advisable, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (Run into section 5.3.). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.three and 4.4).

Chest-feedingConsidering no data is bachelor regarding the utilise of Lisinopril tablet during breastfeeding, Lisinopril tablet is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, peculiarly while nursing a newborn or preterm babe.

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

The following undesirable effects have been observed and reported during handling with Lisinopril tablets and other ACE inhibitors with the following frequencies: Very common (≥1/10), common (≥ane/100 to <1/10), uncommon (≥1/1,000 to <ane/100), rare (≥1/10,000 to <one/ane,000), very rare (<one/10,000), not known (cannot be estimated from the bachelor data).

Blood and the lymphatic organization disorders:

rare:

very rare:

decreases in haemoglobin, decreases in haematocrit.

bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis (meet section 4.iv), haemolytic anaemia, lymphadenopathy, autoimmune affliction

Immune system disorders

not known:

anaphylactic/anaphylactoid reaction

Endocrine Disorders

rare:

syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders

very rare:

hypoglycaemia

Nervous system and psychiatric disorders:

common:

uncommon:

rare:

Not known:

dizziness, headache

mood alterations, paraesthesia, vertigo, taste disturbance, slumber disturbances, hallucinations.

mental confusion, olfactory disturbance

depressive symptoms, syncope.

Cardiac and vascular disorders:

common:

uncommon:

orthostatic effects (including hypotension)

myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in loftier gamble patients (see department 4.iv), palpitations, tachycardia. Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders:

mutual:

uncommon:

very rare:

cough

rhinitis

bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia

Gastrointestinal disorders:

common:

uncommon:

rare:

very rare:

diarrhoea, vomiting

nausea, intestinal pain and indigestion

dry mouth

pancreatitis, intestinal angioedema, hepatitis- either hepatocellular or cholestatic, jaundice and hepatic failure (see section 4.4)

Pare and subcutaneous tissue disorders:

uncommon:

rash, pruritus

rare:

hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, natural language, glottis, and/or larynx (see section iv.four), urticaria, alopecia, psoriasis

very rare:

sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma

A symptom circuitous has been reported which may include one or more than of the post-obit: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated cerise blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.

Renal and urinary disorders:

common:

rare:

very rare:

renal dysfunction

uraemia, acute renal failure

oliguria/anuria

Reproductive system and chest disorders:

uncommon:

rare

impotence

gynaecomastia

General disorders and administration site conditions:

uncommon:

fatigue, asthenia

Investigations:

uncommon:

rare:

increases in claret urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia

increases in serum bilirubin, hyponatraemia.

Condom data from clinical studies propose that lisinopril is generally well tolerated in hypertensive paediatric patients, and that the safe profile in this age group is comparable to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions later authorisation of the medicinal product is important. It allows connected monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Yellowish Card Scheme

Website: www.mhra.gov.united kingdom of great britain and northern ireland/yellowcard or search for MHRA Xanthous Card in the Google Play or Apple App Store

Limited data are available for overdose in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, feet and cough.

The recommended treatment of overdose is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the daze position. If available, treatment with angiotensin Ii infusion and/or intravenous catecholamines may also be considered. If ingestion is recent, accept measures aimed at eliminating Lisinopril tablets (e.one thousand., emesis, gastric lavage, administration of absorbents and sodium sulphate). Lisinopril tablets may be removed from the general circulation by haemodialysis (see department four.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should exist monitored frequently.

Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors, ATC lawmaking: C09A A03

Mechanism of Activeness

Lisinopril tablets is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II likewise stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin Two which results in decreased vasopressor activity and reduced aldosterone secretion. The latter decrease may upshot in an increase in serum potassium concentration.

Pharmacodynamic effects

Whilst the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive fifty-fifty in patients with depression renin hypertension. ACE is identical to kininase Two, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a strong vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to exist elucidated.

Clinical efficacy and condom

The effect of Lisinopril tablets on mortality and morbidity in heart failure has been studied by comparing a loftier dose (32.5 mg or 35 mg one time daily) with a low dose (ii.5 mg or five mg in one case daily). In a report of 3164 patients, with a median follow up menstruum of 46 months for surviving patients, loftier dose Lisinopril tablets produced a 12% gamble reduction in the combined endpoint of all-cause mortality and all-cause hospitalisation (p = 0.002) and an 8% risk reduction in all-cause bloodshed and cardiovascular hospitalisation (p = 0.036) compared with low dose. Take a chance reductions for all-crusade mortality (8%; p = 0.128) and cardiovascular mortality (10%; p = 0.073) were observed. In a postal service-hoc assay, the number of hospitalisations for centre failure was reduced by 24% (p=0.002) in patients treated with high-dose Lisinopril tablets compared with low dose. Symptomatic benefits were similar in patients treated with high and low doses of Lisinopril tablets.

The results of the study showed that the overall adverse issue profiles for patients treated with high or low dose Lisinopril tablets were similar in both nature and number. 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 tablets compared with depression dose.

In the GISSI-3 trial, which used a 2x2 factorial design to compare the effects of Lisinopril tablets and glyceryl trinitrate given alone or in combination for six weeks versus control in 19,394, patients who were administered the handling inside 24 hours of an acute myocardial infarction, Lisinopril tablets produced a statistically meaning risk reduction in mortality of xi% versus control (2p=0.03). The run a risk reduction with glyceryl trinitrate was not pregnant but the combination of Lisinopril tablets and glyceryl trinitrate produced a meaning risk reduction in mortality of 17% versus control (2p=0.02). In the sub-groups of elderly (historic period > 70 years) and females, pre-defined equally patients at high risk of mortality, significant benefit was observed for a combined endpoint of mortality and cardiac role. The combined endpoint for all patients, as well as the loftier-risk sub-groups, at half dozen months also showed significant benefit for those treated with Lisinopril tablets or Lisinopril tablets plus glyceryl trinitrate for half-dozen weeks, indicating a prevention result for Lisinopril tablets. As would be expected from any vasodilator handling, increased incidences of hypotension and renal dysfunction were associated with Lisinopril tablets treatment but these were not associated with a proportional increase in mortality.

In a double-blind, randomised, multicentre trial which compared Lisinopril tablets with a calcium channel blocker in 335 hypertensive Type two diabetes mellitus subjects with incipient nephropathy characterised by microalbuminuria, Lisinopril tablets 10 mg to 20 mg administered once daily for 12 months, reduced systolic/diastolic claret pressure by 13/ten mmHg and urinary albumin excretion rate by 40%. When compared with the calcium channel blocker, which produced a like reduction in blood pressure, those treated with Lisinopril tablets showed a significantly greater reduction in urinary albumin excretion charge per unit, providing evidence that the ACE inhibitory activity of Lisinopril tablets reduced microalbuminuria by a direct mechanism on renal tissues in improver to its blood force per unit area lowering effect.

Lisinopril handling does not touch on glycaemic control as shown by a lack of pregnant effect on levels of glycated haemoglobin (HbA1c).

Renin-angiotensin system (RAS)-acting agents

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

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular illness, or type two diabetes mellitus accompanied by prove of end-organ harm. VA NEPHRON-D was a written report in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial result on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension equally compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin Two receptor blockers.

ACE-inhibitors and angiotensin Two receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type ii Diabetes Using Cardiovascular and Renal Illness Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin Ii receptor blocker in patients with type 2 diabetes mellitus and chronic kidney illness, cardiovascular illness, or both. The study was terminated early considering of an increased hazard of agin outcomes. Cardiovascular expiry and stroke were both numerically more than frequent in the aliskiren group than in the placebo grouping and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more often reported in the aliskiren group than in the placebo group.

Paediatric population

In a clinical report involving 115 paediatric patients with hypertension, anile half dozen-16 years, patients who weighed less than 50 kg received either 0.625 mg, ii.5 mg or 20 mg of lisinopril one time a day, and patients who weighed 50 kg or more received either ane.25 mg, v mg or forty mg of lisinopril once a 24-hour interval. At the end of 2 weeks, lisinopril administered once daily lowered trough blood pressure level in a dose-dependent fashion with a consistent antihypertensive efficacy demonstrated at doses greater than 1.25 mg.

This upshot was confirmed in a withdrawal phase, where the diastolic pressure rose by about ix mm Hg more in patients randomized to placebo than it did in patients who were randomized to remain on the center and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner phase, gender, and race.

Lisinopril is an orally active non-sulphydryl-containing ACE inhibitor.

Absorption

Following oral administration of lisinopril, summit serum concentrations occur within about 7 hours, although at that place was a trend to a minor delay in time taken to reach summit serum concentrations in acute myocardial infarction patients. Based on urinary recovery, the hateful extent of absorption of lisinopril is approximately 25% with inter-patient variability of 6-sixty% over the dose range studied (v-fourscore mg). The absolute bioavailability is reduced approximately sixteen% in patients with center failure. Lisinopril absorption is not afflicted past the presence of nutrient.

Distribution

Lisinopril does not appear to be bound to serum proteins other than to circulating angiotensin converting enzyme (ACE). Studies in rats signal that lisinopril crosses the blood-brain barrier poorly.

Elimination

Lisinopril does not undergo metabolism and is excreted entirely unchanged into the urine. On multiple dosing lisinopril has an effective half-life of accumulation of 12.half dozen hours. The clearance of lisinopril in salubrious subjects is approximately 50 ml/min. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal stage probably represents saturable binding to ACE and is non proportional to dose.

Hepatic impairment

Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril absorption (about xxx% as determined past urinary recovery) but an increment in exposure (approximately 50%) compared to salubrious subjects due to decreased clearance.

Renal impairment

Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this subtract becomes clinically important but when the glomerular filtration charge per unit is beneath xxx ml/min. In mild to moderate renal damage (creatinine clearance 30-lxxx ml/min) mean AUC was increased by 13% only, while a four.5-fold increment in mean AUC was observed in severe renal damage (creatinine clearance five-xxx ml/min).

Lisinopril can exist removed by dialysis. During 4 hours of haemodialysis, plasma lisinopril concentrations decreased on boilerplate by 60%, with a dialysis clearance between twoscore and 55 ml/min.

Centre failure

Patients with heart failure have a greater exposure of lisinopril when compared to good for you subjects (an increase in AUC on average of 125%), simply based on the urinary recovery of lisinopril, there is reduced absorption of approximately 16% compared to good for you subjects.

Paediatric population

The pharmacokinetic contour of lisinopril was studied in 29 paediatric hypertensive patients, aged between 6 and 16 years, with a GFR above 30 ml/min/1.73m2. After doses of 0.1 to 0.2 mg/kg, steady state superlative plasma concentrations of lisinopril occurred within six hours, and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults.

AUC and Cmax values in children in this written report were consistent with those observed in adults.

Elderly

Elderly have higher claret levels and higher values for the expanse under the plasma concentration time bend (increased approximately 60%) compared with younger subjects.

Preclinical information reveal no special gamble for humans based on conventional studies of general pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Angiotensin converting enzyme inhibitors, as a grade, have been shown to induce agin furnishings on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have besides been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal renin-angiotensin organisation and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood catamenia and oxygen/nutrients delivery to the foetus.

Mannitol

Calcium hydrogen phosphate dihydrate

Maize starch

Starch, pregelatinised

Magnesium stearate

Silica, colloidal anhydrous

Not applicable.

ii years.

Do not store above 30°C.

Carton containing 14, 28, 30 or 98 tablets in transparent PVC/PVDC/Aluminium blisters.

Non all pack sizes may be marketed.

The easiest way to break the tablet is illustrated beneath:

- place the tablet with the score on top

- place thumb and index of the aforementioned paw on each side of the score line and press as shown on the drawing.

Whatsoever unused production or waste matter should exist disposed of in accordance with local requirements

Accord Healthcare Limited

319 Pinner Route

N Harrow

Middlesex HA1 4HF

Britain

PL 20075/0133

xviii/09/2008

09/06/2020