AGIMLISIN®20

Composition: Each tablet contains:
Lisinopril. . . . . . . . . . . . . . . . . . . . . . . . . 20 mg
Presentation:
Blister of 10 tablets, box of 3 blisters.
Indications:
Treatment of hypertension: Lisinopril is used alone or in combination with other antihypertensives such as thiazide diuretics, alpha blockers or calcium channel blockers.
Treatment of heart failure: Lisinopril is used in combination with cardiac glycosides and diuretics for the treatment of congestive heart failure in patients who are not responding adequately to diuretics and digitalis.
Acute myocardial infarction in hemodynamically stable patients: Short-term (6 weeks) treatment lisinopril is combined with thrombolytics, aspirin and/or beta blockers to improve survival of hemodynamically stable patients with acute myocardial infarction. Lisinopril is used within 24 hours of the onset of acute myocardial infarction.
Treatment of renal disease in hypertensive patients with type 2 diabetes mellitus and incipient nephropathy.

Additional information

Dosage and administration

Dosage:
Hypertension:
Agimlisin 20 may be used as monotherapy or in combination with other classes of antihypertensive medicinal products.
Starting dose:
In patients with hypertension the usual recommended starting dose is 10mg. Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation, or severe hypertension) may experience an excessive blood pressure fall following the initial dose. A starting dose of 2.5-5mg 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 impairment.
Maintenance dose:
The usual effective maintenance dosage is 20mg administered in a single daily dose. In general, if the desired therapeutic effect cannot be achieved in a period 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 80mg/day.
Diuretic-treated patients:
Symptomatic hypotension may occur following initiation of therapy with lisinopril. This is more likely in patients who are being treated currently with diuretics. Caution is recommended therefore, since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with lisinopril. In hypertensive patients in whom the diuretic cannot be discontinued, therapy with lisinopril should be initiated with a 5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of lisinopril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.
Dosage adiustment in renal impairment:
Dosage in patients with renal impairment should be based on creatinine clearance as outlined below.
Creatinine clearance (ml/min) ~ Starting Dose (mg/day):
– 10 ml/min ~ 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 depending on the blood pressure response.
The dosage may be titrated upward until blood pressure 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 20 to <50 kg, and 5 mg once daily in patients ≥50 kg. The dosage should be individually adjusted to a maximum of 20 mg daily in patients weighing 20 to <50 kg, and 40 mg in patients ≥50kg. Doses above 0.61 mg/kg (or in excess of 40 mg) have not been studied in paediatric patients.
In children with decreased renal function, a lower starting dose or increased dosing interval should be considered.
Heart failure:
In patients with symptomatic heart failure, lisinopril should be used as adjunctive therapy to diuretics and, where appropriate, digitalis or beta-blockers. Lisinopril may be initiated at a starting dose of 2.5mg once a day, which should be administered under medical supervision to determine the initial effect on the blood pressure. The dose of lisinopril should be increased:
By increments of no greater than 10mg
At intervals of no less than 2 weeks.
The highest dose tolerated by the patient up to a maximum of 35mg once daily.
Dose adjustment should be based on the clinical response of individual patients.
Patients at high risk of symptomatic hypotension e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with lisinopril. Renal function and serum potassium should be monitored.
Acute myocardial infarction:
Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers. Intravenous or transdermal glyceryl trinitrate may be used together with lisinopril.
Starting dose (first 3 days after infarction):
Treatment with lisinopril may be started within 24 hours of the onset of symptoms. Treatment should not be started if systolic blood pressure is lower than 100mm Hg. The first dose of lisinopril is 5mg given orally, followed by 5mg after 24 hours, 10mg after 48 hours and then 10mg once daily. Patients with a low systolic blood pressure (120mm Hg or less) when treatment is started or during the first 3 days after the infarction should be given a lower dose – 2.5mg orally.
In cases of renal impairment (creatinine clearance <80 ml/min), the initial lisinopril dosage should be adjusted according to the patient's creatinine clearance.
Maintenance dose:
The maintenance dose is 10mg once daily. If hypotension occurs (systolic blood pressure less than or equal to 100mm Hg) a daily maintenance dose of 5mg may be given with temporary reductions to 2.5mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour) lisinopril should be withdrawn.
Treatment should continue for 6 weeks and then the patient should be re-evaluated. Patients who develop symptoms of heart failure should continue with lisinopril.
Renal complications of diabetes mellitus:
In hypertensive patients with type 2 diabetes and incipient nephropathy, the dose is 10mg lisinopril once daily which can be increased to 20mg once daily, if necessary, to achieve a sitting diastolic blood pressure below 90mmHg.
In cases of renal impairment (creatinine clearance <80 ml/min), the initial lisinopril dosage should be adjusted according to the patient's creatinine clearance.
Paediatric population:
There is limited efficacy and safety experience in hypertensive children >6 years old, but no experience in other indications. 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 impairment (GFR <30ml/min/1.73m2).
Use in the elderly:
In clinical studies, there was no age-related change in the efficacy or safety profile of the drug. When advanced age is associated with decrease in renal function, however, the guidelines set out in Table 1 should be used to determine the starting dose of lisinopril. Thereafter, the dosage should be adjusted according to the blood pressure response.
Use in kidney transplant patients:
There is no experience regarding the administration of lisinopril in patients with recent kidney transplantation. Treatment with lisinopril is therefore not recommended.
Administration:
Agimlisin 20 (lisinopril) should be administered orally in a single daily dose. As with all other medication taken once daily, Agimlisin 20 should be taken at approximately the same time each day. The absorption of Agimlisin 20 is not affected by food.
The dose should be individualised according to patient profile and blood pressure response.

Contraindications

Patients with hypersensitivity to lisinopril or to other angiotensin converting enzyme (ACE) inhibitors or to any excipient of the drug.
Patients with history of angioedema associated with previous ACE inhibitor therapy, hereditary or idiopathic angioedema.
Co-administration of lisinopril with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60ml /min /1.73 m2).
Patients dialysed with polyacrylonitrile metalylsulfonate high flux dialysis membranes due to the risk of anaphylactoid reaction.
Pregnant women.

Warnings and precautions for use

Symptomatic hypotension:
Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving lisinopril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin dependent hypertension (see section “Interactions” and section “Undesirable effects”). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use 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 heart or cerebrovascular disease in whom an excessive fall in blood pressure could result 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 not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with lisinopril. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of lisinopril may be necessary.
Hypotension in acute myocardial infarction:
Treatment with lisinopril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mmHg or lower or those in cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mmHg or lower. Maintenance doses should be reduced to 5mg or temporarily to 2.5mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than 1 hour) then lisinopril should be withdrawn.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy:
As with other ACE inhibitors, lisinopril should be 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 dosage should be adjusted according to the patient's creatinine clearance (see Table 1 in section “Dosage and administration”) and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.
In patients with heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
In some patients with bilateral renal artery 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, there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under 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 function should be monitored during the first weeks of lisinopril therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or lisinopril may be required.
In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/l and/or proteinuria exceeding 500 mg/24h. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre-treatment value) then the physician should consider withdrawal of lisinopril.
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 time during therapy. In such cases, lisinopril tablets should be discontinued promptly, and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.
Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patient's airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Angiotensin converting enzyme inhibitors cause a higher 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.
Anaphylactoid reactions in haemodialysis patients:
Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g. 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 have 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 treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicinal product.
Hepatic failure:
Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving lisinopril who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril 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 after discontinuation of the ACE inhibitor. Lisinopril tablets should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Lisinopril tablets are used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Race:
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
As with other ACE inhibitors, Lisinopril tablets may be less effective in lowering blood pressure in black patients than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Cough:
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Surgery/Anaesthesia:
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to 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 lisinopril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics (e.g. 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, cotrimoxazole). If concomitant use of the above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.
Diabetic patients:
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor.
Lithium:
The combination of lithium and lisinopril is generally not recommended.
Pregnancy:
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which 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.
Others:
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This product contains sunset yellow. It has risk to cause allergic reactions. Caution should be exercised in patients with atopic allergy.

Recommendation for pregnancy and breastfeeding

Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which 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 trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). 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.
Breast-feeding:
Because no information is available regarding the use of lisinopril during breastfeeding. Lisinopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Effects on ability to drive and use machines

Lisinopril has no known influence on the ability to drive and use machines. However, patients who drive and use machines should use lisinopril with caution because it may occasionally cause headache, fatigue.

Interactions, incompatibilities of medicine

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 II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
Diuretics:
When a diuretic is added to the therapy of a patient receiving lisinopril tablets the antihypertensive effect is usually additive.
Patients already on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when lisinopril is added. The possibility of symptomatic hypotension with lisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with lisinopril.
Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes and 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 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 be undertaken as appropriate. If lisinopril is given with a potassium losing diuretic, diuretic induced hypokalaemia may be ameliorated.
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of lisinopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.
Non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid ≥ 3g/day:
When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 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, especially in patients with poor pre-existing renal function. These effects are usually reversible. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Gold:
Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.
Tricyclic antidepressants / Antipsychotics /Anaesthetics:
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure.
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 effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Tissue plasminogen activators:
Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.
Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates:
Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates.
Inform the doctor about other medicines that are being used while using lisinopril.

Undesirable effects (ADRs)

The following undesirable effects have been observed and reported during treatment with Lisinopril tablets and other ACE inhibitors with the following frequencies:
Very common, ADR ≥ 1/10
Common, 1/100 ≤ ADR < 1/10
Uncommon, 1/1000 < ADR < 1/100
Rare, 1/10000 < ADR < 1/1000
Very rare, < 1/10000
Blood and the lymphatic system disorders:
– Rare: Decreases in haemoglobin, decreases in haematocrit.
– Very rare: Bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis, haemolytic anaemia, lymphadenopathy, autoimmune disease
Endocrine Disorders
– Rare: Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders
– Rare: Hypoglycaemia
Nervous system and psychiatric disorders:
– Common: Dizziness, headache
– Uncommon: Mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances, hallucinations.
– Rare: Mental confusion, olfactory disturbance
– Not known: Depressive symptoms, syncope.
Cardiac and vascular disorders:
– Common: Orthostatic effects (including hypotension)
– Uncommon: Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, 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: Diarrhoea, vomiting
– Uncommon: Nausea, abdominal pain and indigestion
– Rare: Dry mouth
– Very rare: Pancreatitis, intestinal angioedema, hepatitis- either hepatocellular or cholestatic, jaundice and hepatic failure.
Skin and subcutaneous tissue disorders:
– Uncommon: Rash, pruritus
– Rare: Hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx, urticaria, alopecia, psoriasis
– 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, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.
Renal and urinary disorders:
– Common: Renal dysfunction
– Rare: uraemia, acute renal failure
– Very rare: oliguria/anuria
Reproductive system and breast disorders:
– Uncommon: Impotence
– Rare: Gynaecomastia
General disorders and administration site conditions:
– Uncommon: Fatigue, asthenia
Investigations:
– Uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia
– Rare: Increases in serum bilirubin, hyponatraemia.
Safety data from clinical studies suggest that lisinopril is generally well tolerated in hypertensive paediatric patients, and that the safety profile in this age group is comparable to that seen in adults.
Guidelines for ADR manangement:
Cough: (5 to 20% of patients) Cough usually develops in the first week of treatment and persists throughout the therapy. Sometimes the treatment must be stopped. This unwanted effect may be due to accumulation of bradykinin, substance P and/or prostaglandin in the lungs, indirectly caused by lisinopril. After withdrawal of the lisinopril, cough will resolve usually within a few days.
Angioedema: (0.1 to 0.2% of patients) ACEIs induce rapid swelling in the nose, throat, mouth, glottis, lips, larynx, and /or toungue. This unwanted effect, called angioneurotic edema, apparently is not dose-related and nearly always develops within the first week of therapy, usually within the first few hours after the initial dose. Angioedema can cause airway obstruction and respiratory distress which may lead to death. Although the mechanism of angioneurotic edema is unknown, it may involve accumulation of bradykinin, induction of tissue-specific autoantibodies, or inhibition of complement-1-esterase inactivator. If symptoms of angioedema occur the treatment with lisinopril must be discontinued immediately, these adverse reactions will disappear within hours. In cases of emergency, adrenaline, antihistamines, and/or corticosteroids should be administered.
Chest pain is often associated with severe hypotension.
Hypotension: Hypotension usually occurs after the initial dose of lisinopril in patients with increased plasma renin activity. Due to this effect, lisinopril should be given with caution to patients with limited salt intake, patients simultaneously treated with antihypertensives and patients with congestive heart failure. In these patients the lowest start dose or increased salt intake and discontinuation of diuretics 2-3 days before starting therapy should be advised.
Hyperkalemia: Lisinopril causes hyperkalemia in patients with renal impairment, in patients taking potassium sparing diuretics, potassium supplements, beta blockers or nonsteroidal anti-inflammatory drugs.
Proteinuria often occurs in patients with renal insufficiency.
Rash (burning, hives) usually disappear after dose reduction or discontinuation of lisinopril, in severe cases an antihistamine is recommended.
Neutropenia and agranulocytosis is commonly observed in patients with renal failure or collagen vascular disease. Neutropenia appears to be dose-related and may occur within 3 months after starting the treatment.
Discontinue this medicine and inform your doctor about adverse reactions encountered while using this medicine.
Inform your doctor about adverse reactions encountered while using this medicine.

Overdose and management

Symptom of overdose can be hypotension.
The recommended treatment of overdose is intravenous infusion of normal saline solution. Lisinopril may be removed from the general circulation by haemodialysis.
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, anxiety and cough.
The recommended treatment of overdose is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. If ingestion is recent, take measures aimed at eliminating lisinopril (e.g., emesis, gastric lavage, administration of absorbents and sodium sulphate). Lisinopril may be removed from the general circulation by haemodialysis. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.

Pharmacodynamic properties

Lisinopril, the lysine analogue of enalapril, is a long-acting angiotensin converting enzyme (ACE) inhibitor. Angiotensin converting enzyme is an endogenous enzyme which plays a role in the conversion of angiotensin I to angiotensin II. Angiotensin I increases in certain diseases such as heart failure and kidney disease, caused by increased response to renin. Angiotensin II has effects on stimulating growth in cardiac myocytes, leading to enlarged heart (hypertrophic cardiomyopathy), and on vasoconstriction, causing hypertension. ACE inhibitors reduce angiotensin II and aldosterone levels, thereby reduce sodium and water retention, dilate peripheral blood vessels, reduce peripheral resistance in both systemic and pulmonary circulation. In addition, lisinopril also affects the kallikrein – kinin system, reduces the degradation of bradykinin, leading to increased level of bradykinin, which is the cause of some unwanted effects such as angioedema and persistent cough due to ACE inhibitors.
In hypertension: The angiotensin converting enzyme inhibitors usually work well to lower blood pressure, except for hypertension caused by by primary hyperaldosteronism. When starting treatment, changes in blood pressure are closely related to pre-existing plasma renin activity and angiotensin II levels. However, after a few weeks of treatment, blood pressure is sharply reduced in most patients and blood pressure – lowering effect at this time is little or not related to plasma renin activity before treatment. The ACE inhibitors are antihypertensives which are widely used in clinical treatment. Lisinopril is used alone or in combination with other antihypertensive drugs to treat hypertension.
In heart failure: The angiotensin converting enzyme inhibitors reduce afterload and systolic wall tension, produce increases in cardiac output and cardiac index, increase the force of myocardial contraction and systolic volume. ACE inhibitors reduce preload and diastolic wall tension; hemodynamic performance is improved, thus, exercise capacity is increased and inhibition of sympathetic nervous system is stronger. Cerebral and coronary blood flow remain stable even if blood pressure is lowered. ACE inhibitors are administered to patients with left ventricular systolic dysfunction to prevent or slow down the progression of heart failure, decrease the incidence of sudden cardiac death and myocardial infarction, or hospitalization and improve quality of life. Except for contraindications, ACE inhibitors may be indicated to all patients with left ventricular dysfunction, with or without apparent symptoms of heart failure. Lisinopril is used in combination with cardiac glycosides and diuretics to treat the symptoms of congestive heart failure.
In myocardial infarction: Lisinopril as well as other ACE inhibitors is the standard drug for the treatment of patients with myocardial infarction to whom these drugs are administered within 24 hours of the onset of acute myocardial infarction. Also, the drug is also effective in prevention of myocardial infarction. Lisinopril is usually combined with antiplatelet drugs and/or beta blockers to increase survival in patients with acute myocardial infarction.
In diabetic nephropathy: Diabetic patients with hypertension will inevitably lead to diabetic nephropathy. This is the primary cause of end-stage renal failure. Lisinopril and ACE inhibitors have proved that they slow the progression of impaired renal function in diabetic nephropathy. ACE inhibitors can retard progressive chronic kidney disease, as in diabetes. Therefore, unless there are contraindications, patients with diabetic nephropathy (despite normal or increased blood pressure) should be treated with ACE inhibitors.

Pharmacokinetic properties

Absorption:
Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients.
Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25% with inter-patient variability of 6-60% over the dose range studied (5-80mg). The absolute bioavailability is reduced approximately 16% in patients with heart failure. Lisinopril absorption is not affected by the presence of food.
Distribution:
Lisinopril does not appear to be bound to serum proteins other than to circulating angiotensin converting enzyme (ACE). Studies in rats indicate 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 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 ml/min. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose.
Hepatic impairment:
Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril absorption (about 30% as determined by urinary recovery) but an increase in exposure (approximately 50%) compared to healthy subjects due to decreased clearance.
Renal impairment:
Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30ml/min. In mild to moderate renal impairment (creatinine clearance 30-80ml/min) mean AUC was increased by 13% only, while a 4.5-fold increase in mean AUC was observed in severe renal impairment (creatinine clearance 5-30 ml/min).
Lisinopril can be removed by dialysis. During 4 hours of haemodialysis, plasma lisinopril concentrations decreased on average by 60%, with a dialysis clearance between 40 and 55 ml/ min.
Heart failure:
Patients with heart failure have a greater exposure of lisinopril when compared to healthy subjects (an increase in AUC on average of 125%), but based on the urinary recovery of lisinopril, there is reduced absorption of approximately 16% compared to healthy subjects.
Elderly:
Older patients have higher blood levels and higher values for the area under the plasma concentration time curve (increased approximately 60%) compared with younger subjects.
Children:
The pharmacokinetic profile 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 peak plasma concentrations of lisinopril occurred within 6 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 study were consistent with those observed in adults.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.