Therapeutic Indications
• Arterial hypertension.
•Heart failure, as a supplementary therapy together with potassiumunretentative diuretics and, when its applicable, together with heartglycosides.
• Acute myocardial infarction in haemodynamically stable patients.
• Diabetic nephropathy in normotensive insulin-dependent and hypertensive insulin-independent diabetes mellitus patients
Posology and Methods of Administration
Tabletsare taken orally regardless of any dietary pattern. The daily dose isusually taken once per day, preferably at the same time.
Hypertension.
Forpatients with hypertension who do not take other hypotensive drugs andwithout significant kidney functions disorders the initial dose is 2,5- 10 mg once a day. Dose can be adjusted according to the reduction ofblood pressure. The supportive dose is usually 10 –
20 mg per day,maximal dose is 40 mg per day. To achieve the effect 2 – 4 week oftreatment may be needed. Necessity for combined therapy should beevaluated in case of need.
Patients who take diuretics shoulddiscontinue treatment with diuretics 2 – 3 days before the beginning oftherapy, to avoid risk of symptomatic hypotension. If the use ofdiuretics may not be discontinued, the initial dose of lisinopril is 5mg. As sensitive patients might experience rapid decrease of bloodpressure at the beginning of therapy, it is preferable to take thefirst dose before bed.
After the first administration and afterincrease of dose of lisinopril or diuretic, medical monitoring isadvisable, to reduce the risk of uncontrolled symptomatic hypotension.Monitoring should continue until the blood pressure has become stable.
Renovascular hypertension.
Incase of renovascular hypertension exaggerated response to initial doseof lisinopril is possible. Recommended initial dose is 2.5 – 5 mg,careful monitoring is recommended (blood pressure, renal function,se-K). Under medical monitoring supportive dose may be graduallyincreased. In cases when there is elevated activity of renine –angiotensine – aldosterone system (patients with salt deficiency, withor without hyponatraemia, hypovolaemic patients), special attentionshould be paid during the administration of initial dose.
Renal failure
As lisinopril is eliminated through kidneys, dose for patients with renal failure should be adjusted to creatinine clearance.
| Creatinine clearance (ml/min) | Initial dose (mg per day) |
| ≤ 70 > 30 | 5 – 10 |
| ≤ 30 ≥ 10 | 2.5 – 5 |
| < 10 (The same for patients who are on dialysis therapy) | 2.5 |
Dose can be elevated, considering the decrease of blood pressure, but it should no exceed maximum dose 40 mg.
Heart failure.
Lisinopril can be used additionally to diuretic or heart glycosides therapy.
Theinitial dose is 2.5 mg in the morning. The initial dose may beincreased up to supportive dose — 5– 10 mg per day. Doses above 20 mgper day usually are not recommended.
Before the treatment andduring the therapy it is advisable to regularly control blood pressure,kidney functions, levels of potassium and sodium, because of thepossibility of hypotension and simultaneous decrease in renal functions.
Acute myocardial infarction.
Lisinoprilcan be prescribed additionally to standard MI therapy, includingacetylsalicylic acid, thrombolytic agents, beta blockers andsymptomatic treatment with nitrates.
Treatment with lisinopril canbe initiated within 24 hours after the symptoms have appeared, if thepatient is haemodynamically stable. Initial does is 5 mg of medicine,followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg oflisinopril once daily.
Patients with low systolic blood pressure (120 mmHg) when treatment is started or during the first 3 days afterinfarction should be given a lower 2.5 mg dose.
If hypotension occurs (systolic blood pressure 100 mmHg), a daily maintenance dose of
5mg may be given with reduction to 2.5 mg if needed. If prolongedhypotension occurs (systolic blood pressure 90 mmHg for more than 1hour), the administration of lisinopril must be discontinued. Thetreatment should continue for 6 weeks. Minimal supportive dose is 5 mgper day. Patients with heart failure symptoms should continue therapywith lisinopril.
Diabetic nephropathy.
For normotensive patients with insulin-dependent diabetes mellitus lisinopril daily dose is
10mg which can be elevated up to 20mg in order to lower the bloodpressure under the purpose diastolic level – 75 mmHg in a sittingposition.
Patients with insulin-independent diabetes mellitus andhypertension should use the same dose in order to lower blood pressureunder the purpose diastolic level – 90 mmHg in a sitting position.
Elderly patients.
Themedicine should be used with precautions, i.e., smaller dosages, asblood levels of active substance are higher in older patients than inyounger patients; they have renal disorders more often as well.
Children.
Effectiveness and safety of lisinopril have not been studied in children, therefore lisinopril is not recommended in children.
Contraindications
• Hypersensitivity to lisinopril or any of the excipients.
• Angioedema in history related to previous treatment with ACE inhibitors; hereditary/idiopathic angioedema.
• Haemodinamically significant aortal or mitral stenosis or hypertrofic cardiomyopathy.
• Bilateral stenosis of renal arteries or unilateral stenosis of renal artery in patients with one kidney,
• Pregnancy.
For contraindications after acute myocardial infarction see Special Warnings and Special Precaution for Use.
Special Warnings and Special Precautions for Use
Rarelyangioedema of the face, lips, tongue and larynx has been reported inpatients treated with ACE inhibitors, including lisinopril. In suchcase the use of medicine should be discontinued. If angioedemainvolves the tongue, glottis or larynx, subcutaneous 0.1% adrenalinehydrochloride (epinephrine) solution (0.3 to 0.5 ml) or a slowintravenous epinephrine injection (0.1 mg) should be provided, andsimultaneously ECG and blood pressure should be monitored. Patient must be hospitalized and should be monitored for 12 – 24 hours.
Hypotension.Lisinopril can cause severe decrease in blood pressure, especiallyafter the initial dose. Symptomatic hypotension without complicationsis rare in hypertensive patients. More often it is observed in patientson diuretic therapy, with massive deficiency of electrolytes and fluid,because of dialysis, diarrhoea, vomiting or limited consumption ofsalts. Symptomatic hypotension is mainly observed in patients withsevere heart failure alone or together with renal failure. More oftenit can develop in patients who take a high doses of loop diuretics, inpatients with hyponatraemia or functional renal disorders. Thesepatients should begin the therapy under close supervision, advisably inhospital with low doses, simultaneously renal functions and potassiumlevel should be controlled and doses adjusted. If possible, use ofdiuretics should be discontinued temporary. These warnings refer alsoto patients with angina pectoris or cerebrovascular disease, wheresevere hypotension can cause myocardial infarction or acutecerebrovascular disturbances. If excessive hypotension occurs, thepatient should be placed in the supine position, if necessary receivean intravenous infusion of normal saline. A transient hypotension afterinitial dose is not contraindication to further doses of lisinopril,effective therapy is possible if doses are carefully adjusted. Ifsymptomatic hypotension develops in patients with heart failure, a dosereduction or discontinuation of lisinopril and/or concomitant diureticmay be necessary. If it is possible use of diuretic should bediscontinued 2 – 3 days before initiation of lisinopril therapy.
Hypotension in case of myocardial infarction.
Therapywith lisinopril should not be started in acute myocardial infarctionpatients, if there is risk of severe haemodynamic exacerbation aftertreatment with vasodilator. In such patients systolic blood pressure is100 mmHg or lower or they have cardiogenic shock. If systolic bloodpressure is 100 mmHg or lower, maintenance dose should be reduced to 5mg or temporarily even until 2.5 mg. Use of lisinopril can cause severehypotension in patients with acute myocardial infarction. Ifhypotension does not disappear (systolic blood pressure
<90mmHg for more than 1 hour), lisinopril therapy should be discontinued.Patients with severe hear failure after myocardial infarction may uselisinopril only if they are haemodynamically stable. Therapy withlisinopril should be discontinued if impairment of renal functionsappears (serum creatinine level increases more than twice compared toinitial level).
Renovascular hypertension/stenosis of renal artery (see Contraindications).If patients with renovascular hypertension and pre-existing unilateralor bilateral renal artery stenosis are taking lisinopril, risk ofsevere hypotension and renal failure is increased. Concomitant use ofdiuretics may increase the risk. In case of unilateral renal arterystenosis, renal functions may worsen following even insignificantchanges in serum creatinine level. These patients should start thetherapy with small doses under medical supervision and carefully adjustdoses. During first weeks of therapy diuretics should not be used andrenal functions must be controlled regularly.
Impaired renal function.Lisinopril should be taken with special caution in patients with renalinsufficiency, lower doses or longer period between doses may berequired. Renal insufficiency during lisinopril therapy is observedmainly in patients with severe heart failure or pre-existing kidneydisease, including renal artery stenosis. Lisinopril caused renalfailure is reversible if it is diagnosed immediately and treatedadequately. Some hypertensive patients without pre-existing renaldisease blood urea and serum creatinine level increases, if lisinoprilis used concomitantly with diuretic agents. In such case use oflisinopril/diuretic should be discontinued or doses reduced and patientshould be monitored up to assure that there is no renal arterystenosis.
Patients with symptoms of renal dysfunction,characterized by serum creatinine concentration ≥ 177 mmol/l (0.2mg/dl) and/ or proteinuria > 500 mg/day, in case of acute myocardialinfarction must not start lisinopril therapy. If renal impairmentoccurs during lisinopril therapy (serum creatinine clearance < 30ml/min or creatinine concentration doubles comparing to the pre-therapyperiod), dose should be reduced to 5-2.5 mg daily (see Posology andMethods of Administration). As there is little experience about use oflisinopril in patients after renal transplantation, it is not advisedto take lisinopril in renal transplant recipients.
Haemodialysis.
Concomitantuse of lisinopril and high-flux poli(acrylonitrile,sodium–2–metilalil-sulfonate) membranes (e.g., AN 69) causes risk ofanaphylactic reactions during dialysis or haemofiltration (fromhypersensitivity reactions to anaphylactic shock). In such cases it isadvised to use different type of dialysis membranes or a differentclass of hypotensive agent.
Hyperkalaemia.Hyperkalaemia is possible during lisinopril therapy, especially inpatients with renal and/or heart failure. Usually potassium supplementsor potassium- sparing agents are not advised, as they lead to asignificant increase in serum potassium. If concomitant use of thesemedicines is deemed appropriate, they should be used with frequentmonitoring of serum potassium.
Primary hyperaldosteronism.Ususally patients with primary hyperaldosteronism do not developresponse to hypotensive medicines, whose action is based on thesuppression of renin-angiotensin system. In this case use of lisinoprilis not recommended.
Proteinuria.Proteinuria is observed rarely, usually in patients with pre-existingrenal impairment or if high doses of lisinopril are administered. Incase of clinically significant proteinuria (more than 1 g daily),lisinopril can be prescribed only after careful analysis of risks andbenefits, clinical and laboratory tests should be monitored regularly.
Children. As effectiveness and safety in children have not been established, lisinopril therapy is not recommended in children.
LDL aferesis/desensitisation therapy.If ACE inhibitors are used during LDL (low density lipoproteins)apheresis with dextrane sulphate, life threatening anaphylacticreactions may occur. Severe anaphylactic reactions may occur also iflisinopril is used during desensitisation therapy against insect poison(e.g., bee, wasp venom). If there is a necessity of LDL apheresis anddesensitisation therapy, lisinopril should be temporarily substitutedwith other medicines to treat hypertension or heart failure (except ACEinhibitors).
Aorta stenosis/hypertrophic cardiomyopathy.ACE inhibitors should be used with special caution in patients withobstruction in the outflow tract of the left ventricle. If obstructionis haemodynamically significant, lisinopril is contraindicated (seeContraindications).
Neutropenia/agranulocytosis.Neutropenia and agranulocytosis is rarely observed in hypertensivepatients treated with ACE inhibitors. These conditions are rare inpatients, who have hypertension without complications; more often theyare observed in patients with renal impairment, especially if patientalso has collagen vascular disease (e.g. systemic lupus erythematosusor sclerodermia) or is taking immunodepressants concomitantly. Periodicmonitoring of white blood cell counts in these patients should beconsidered. Neutropenia and agranulocytosis disappear afterdiscontinuation of use of ACE inhibitors.
Cough.Cough is observed during treatment with ACE inhibitors. Usually it ispersistent unproductive, always resolving after discontinuation oftherapy. It should be considered in the differential diagnosis of cough.
Surgery/anaesthesia.In patient undergoing major surgery or during anaesthesia with agentsthat produce hypotension, lisinopril may block angiotensin II formationto secondary compensatory renin release. Hypotension can be correctedby volume expansion.
Interaction with Other Medicinal Products and Other Forms of Interaction
Diuretics.
Iflisinopril is used simultaneously with diuretics, hypontensive effectis increased. Risk of symptomatic hypotension can be reduced bydiscontinuing the diuretic prior to initiation of treatment withlisinopril.
Potassium-sparing diuretics or potassium – containing medicines.
Whileclinical reports show the normal serum potassium level, in some caseshyperkalaemia occurs. Risk factors of hyperkalaemia are renaldisfunction, diabetes mellitus, and simultaneous use ofpotassium–sparing diuretics (e.g., spironolactone, triamterene, oramiloride), potassium supplements, or potassium-containing saltsubstitutes. Significant increases in serum potassium may occur.
Antihypertensives
Simultaneous use of lisinopril and antihypertensive agents intensify the hypotensive effect.
Anagesic and anti-inflammatory agents (e.g., acetylsalicylic acid, indomethacin)
Use of those medicaments may diminish the hypotensive effect of lisinopril.
Lithium.
Simultaneoususe of lithium and ACE inhibitors increases lithium toxicity becauseelimination of lithium may be reduced (it is recommended periodicmonitoring of lithium serum level).
Lithium toxicity is usually reversible upon discontinuation of lithium and the ACE inhibitors.
Anaesthetics, opiates, narcotics
Ifthose medicaments are used simultaneously with lisinopril, moreremarkable decrease of blood pressure is observed. Anaesthetist shouldbe informed of use of lisinopril.
Sympatomimetics.
Antihypertensive action of ACE inhibitors is reduced.
Peroral antidiabetics (derivatives of sulfonylurea/biguanidines), insulin
ACE inhibitors can increase the hypoglycaemic action of antidiabetics, especially in the first weeks of combined treatment.
Antacids
Bioavailability of ACE inhibitors may be reduced.
Other
Simultaneoususe of allopurinol, cytostatics or immunodepressants, systemiccorticosteroids or procainamide increases risk of leucopenia.
Lisinopril can be used simultaneously with nitrates and/or digoxine, without any signs of clinical important interaction.
Food does not influence the bioavailability of lisinopril.
Alcohol increases the hypotesive effect of the lisinopril.
Pregnancy and Lactation
ACEinhibitors can cause neonatal morbidity and death when administered topregnant woman. When pregnancy is detected, lisinopril should bediscontinued as soon as possible.
Administration of ACE inhibitorsduring the second and third trimesters of pregnancy has been associatedwith fetal and neonatal injury, including hypotension, neonatal skullhypoplasia, anuria, reversible or in renal failure, and death.Oligohydramnios has also been reported, presumably resulting fromdecreased fetal renal function; prematurity and intrauterine growthretardation, and patent ductus arteriousus have also been reported.
Theseadverse effects do not appear to have resulted from intrauterine ACEinhibitors exposure that has been limited to the first trimester.Mothers who have administered lisinopril only during the firsttrimester should be so informed. Nonetheless, when patients becomepregnant, physicians should make every effort to discontinue the use oflisinopril as soon as possible.
Infants with history of in uteroexposure to lisinopril should be closely observed for hypotension,oliguria, and hyperkalaemia. If oliguria occurs, attention should bedirected toward support of blood pressure and renal perfusion. Exchangetransfusion or dialysis may be required as means of reversinghypotension and/or substituting for disordered renal function.Lisinopril, which crosses the placenta, has been removed from neonatalcirculation by peritoneal dialysis with some clinical benefit, andtheoretically may be removed by exchange transfusion.
Lisinopril wasfound in milk of experimental animals (rats). It is not known if it isexcreted with mother milk in humans. Because of the potential forserious reactions in breasts-feed infants, a decision should be madewhether to discontinue breast feeding or to discontinue lisinopril.
Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed.
Duringthe therapy sensitive patients may experience dizziness due tohypotension, especially patients on diuretics therapy after taking thefirst dose of the medicine. In these cases it is not recommended todrive and perform work connected with risk.
Undesirable Effects
Lisinoprilis usually well tolerated. For the most part, adverse experiences weremild and transiet and have not required interruption of treatment.
Body as a whole
Fatigue, asthenia, fever, mantle, anaphylactoid reactions, unpleasant feeling in chest, myalgia, arthalgia, serosite, vasculite.
Cardiovascular
Rarein the beginning of the therapy or after the increase of lisinopriland/or diuretics doses severe hypotension may occur. This is morelikely to happen in risk groups, for example in patients with salt orliquid deficiency after use of diuretics, heart failure and severe orrenal hypertension. Symptoms are vertigo, weakness, impaired vision,sometimes together with unconsciousness. Occasionally hypotensioncaused by ACE inhibitors is related to tachycardia, palpitation,arrhythmia, pain in chest, angina pectoris, myocardial infarction,transient ischemic attacks.
If lisinopril is used in patients withacute myocardial infarction, sometimes, especially in first 24 hours,second or third stage atrioventricular blockade and/or severehypotension and/or renal dysfunction, rarely cardiogenic shock canoccur.
Kidneys
Renal failure can occur orpre-existing renal failure can intensify. Acute renal failure isreported in isolated cases. Proteinuria with simultaneous decrease ofrenal functions is observed.
Respiratory
Dry cough,inflammation of throat, hoarseness and bronchitis can occur, raredyspnoea, sinusitis, rhinitis, asthma, bronchospasms and infiltrationof lungs, stomatitis, glositis and dry mouth. In isolated casesangioedema, that involved upper airways, has caused lethal occlusion ofairways. Occasional allergic alveolitis (eozinophilic pneumonia) hasnoted due to lisinopril therapy.
Gastrointestinal/ Liver
Uncommonnausea, abdominal pain and indigestion can occur, rare – vomiting,diarrhoea, constipations, loss of appetite. Rare use of ACE inhibitorsis related with syndrome of cholestatic jaundice, liver necrosis anddeath. Mechanism of this syndrome is not estimated yet. If jaundiceoccurs, use of ACE inhibitors should be stopped and patient should bemedically monitored. In isolated cases liver dysfunction, hepatitis,liver failure, pancreatitis and intestinal obstruction are reported tobe associated with use of ACE inhibitors.
Skin, blood vessels
Allergicskin reactions may occur, for example rash, rare – itch, urticaria,angioedema of face, lips and/or extremities. In very rare cases severeskin reactions are reported, as pemphigus, erythrema multiforme,exfoliative dermatitis, Stevens – Johnson syndrome, toxic epidermalnecrolysis.
Skin reactions may be accompanied with fever,myalgia, arthalgia, vasculitis, eosinophilia, leukocytosis and/orincreased levels of ANA. If there is any suspicion of severe skinreaction, lisinopril therapy must be discontinued. Some cases ofpsoriasis like skin reactions, photosensitivity, flushing, diaphoresis,loss of hair, exacerbation of onycholysis and Rhaynaud's disease areobserved during the use of ACE inhibitors.
Nervous system
Uncommonheadache, tiredness, rare – sleepiness, depression, sleep disorders,impotence, peripheral neuropathy with paresthesia, balancedisturbances, muscle spasm, nervousness, confusion, tinnitus, blurredvision, taste disturbances and temporary loss of taste.
Laboratory test findings
Uncommondecreases in haemoglobin and haematocrite, leukocytes and thrombocytesconts have been reported. Anaemia, thrombocytopenia, neutropenia oreosinophilia are reported. Occasional agranulocytosis or pancytopeniaare observed, especially in patients with reduced renal functions,vascular collagen disease or those simultaneously treated withallopurinol, procainamide or specific immunosupressants. Very rare somehaemolytic anaemia cases are reported in patients with heditaryglucose–6–phosphate dehydrogenase deficiency. Rare creatinine, urea andserum potassium levels can be increased, and serum concentration ofsodium decreased respectively. This is more common in patients withrenal insufficiency, severe heart failure and renovascularhypertension. Hyperkalaemia is reported in diabetes mellitus patients.In some cases intensified proteinuria can occur, sometimes – increasedlevel of liver enzymes and serum bilirubine can be observed.
Special remarks
Beforethe start of lisinopril therapy above mentioned laboratoryinvestigations should be performed. Serum electrolyte and creatinineconcentration and blood count should be controlled, especially at thebeginning of therapy, in high risk groups (patients with renal failureand collagen vascular disease), and if immunosuppressants, cytostatics,allopurinol and procainamide are used. If such symptoms as fever,swelling of lymph nodes and/or inflammation of throat occur, leukocytecount should be monitored immediately.
Overdose
Themost likely features of overdose in humans would be hypotension, shock,bradycardia, electrolyte disturbance and renal failure. Standardtreatment in case of overdose is infusion of physiological solution.Haemodialysis can be used to eliminate lisinopril. After overdosepatient should be carefully monitored, serum electrolytes andcreatinine should be monitored frequently.
If overdose hashappened recently, actions should be taken to prevent resorbtion, forexample, gastric lavage, introduction of adsorbents and sodium sulphatewithin 30 minutes after overdose; stimulation of elimination.
Incase of hypotension, patient should be placed in a shock position andsalts and supplementary solutions should be rapidly administeredthrough intravenous route. Treatment of angiotensine II might beconsidered.
Lisinopril may be removed from the general circulationby haemodialysis. The use of high-flux polyacrylonitrile dialysismembranes should be avoided.
