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Drug Details

ZESTRIL

• Drug Class Description
  ACE inhibitors.
• Generic Name
  Lisinopril - hypertension
• Presentation
  Tablets, lisinopril 2.5mg , 5mg , 10mg , 20mg .
• Description
  2.5 mg white tablets marked with heart shape and strength; 5 mg pink scored tablets marked with heart shape and strength; 10 mg pink tablets marked with heart shape, strength and trade mark; 20 mg pink tablets marked with heart shape, strength and trade mark.
• Indications
  

  All grades of essential and renovascular hypertension. Renal complications of diabetes in normotensive type I and hypertensive type II patients who have incipient nephropathy characterised by microalbuminuria.

• Adult Dosage
  

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

  The dose should be individualised according to patient profile and blood pressure response.

  Hypertension

  Zestril may be used as monotherapy or in combination with other classes of antihypertensive therapy.

  Starting dose

  In patients with hypertension the usual recommended starting dose is 10 mg. 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 2.55 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 impairment (see Table 1 below).

  Maintenance dose

  The usual effective maintenance dosage is 20 mg 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 80 mg/day.

  Diuretic-treated patients

  Symptomatic hypotension may occur following initiation of therapy with Zestril. 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 Zestril. In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Zestril should be initiated with a 5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Zestril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.

  Dosage adjustment in renal impairment

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

  Table 1 Dosage adjustment in renal impairment

  Creatinine Clearance (ml/min)	Starting Dose (mg/day)
  Less than 10 ml/min (including patients on dialysis)	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.

  Heart failure

  In patients with symptomatic heart failure, Zestril should be used as adjunctive therapy to diuretics and, where appropriate, digitalis or beta-blockers. Zestril may be initiated at a starting dose of 2.5 mg once a day, which should be administered under medical supervision to determine the initial effect on the blood pressure. The dose of Zestril 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 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 Zestril. 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 Zestril.

  Starting dose (first 3 days after infarction)

  Treatment with Zestril may be started within 24 hours of the onset of symptoms. Treatment should not be started if systolic blood pressure is lower than 100 mm Hg. The first dose of Zestril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily. Patients with a low systolic blood pressure (120 mm Hg or less) when treatment is started or during the first 3 days after the infarction should be given a lower dose - 2.5 mg orally.

  In cases of renal impairment (creatinine clearance <80 ml/min), the initial Zestril dosage should be adjusted according to the patient's creatinine clearance (see Table 1).

  Maintenance dose

  The maintenance dose is 10 mg once daily. If hypotension occurs (systolic blood pressure less than or equal to 100 mm Hg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mm Hg for more than 1 hour) Zestril 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 Zestril.

  Renal complications of diabetes mellitus

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

  In cases of renal impairment (creatinine clearance <80 ml/min), the initial Zestril dosage should be adjusted according to the patient's creatinine clearance (see Table 1).

  Paediatric use

  Efficacy and safety of use in children has not been fully established. Therefore, use in children is not recommended.

  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 Zestril. 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 Zestril in patients with recent kidney transplantation. Treatment with Zestril is therefore not recommended.

• Child Dosage
  Not recommended.
• Contra Indications
  

  • Hypersensitivity to Zestril, to any of the excipients or any other angiotensin converting enzyme (ACE) inhibitor

  • History of angioedema associated with previous ACE inhibitor therapy

  • Hereditary or idiopathic angioedema

  • Second and third trimesters of pregnancy

• Special Precautions
  

  Symptomatic hypotension

  Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Zestril, 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. 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 Zestril. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Zestril may be necessary.

  Hypotension in acute myocardial infarction

  Treatment with Zestril 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 mm Hg 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 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mm Hg or lower. If hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour) then Zestril should be withdrawn.

  Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

  As with other ACE inhibitors, Zestril 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 Zestril dosage should be adjusted according to the patient's creatinine clearance, 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 Zestril 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 Zestril 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 Zestril may be required.

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

  Hypersensitivity/Angioedema

  Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported uncommonly in patients treated with angiotensin-converting enzyme inhibitors, including Zestril. This may occur at any time during therapy. In such cases, Zestril 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 patent 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 and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving Zestril who develop jaundice or marked elevations of hepatic enzymes should discontinue Zestril 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. Zestril 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 Zestril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

  Race

  Angiotensin-converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.

  As with other ACE inhibitors, Zestril 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, Zestril 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 Zestril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). 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 Zestril is generally not recommended.

   

  Pregnancy and lactation

  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.

  Use of lisinopril is not recommended during breast-feeding.

• Interactions
  

  Diuretics

  When a diuretic is added to the therapy of a patient receiving Zestril 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 Zestril is added. The possibility of symptomatic hypotension with Zestril can be minimised by discontinuing the diuretic prior to initiation of treatment with Zestril.

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

  Although in clinical trials, serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients. Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassiumcontaining salt substitutes. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. If Zestril is given with a potassium-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 Zestril 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 3 g/day

  Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor. NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.

  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.

  Other antihypertensive agents

  Concomitant use of these agents may increase the hypotensive effects of Zestril. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.

  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 medicines (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.

  Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

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

• Adverse Drug Reactions
  

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

  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.

  Metabolism and nutrition disorders

  very rare: hypoglycaemia.

  Nervous system and psychiatric disorders

  common: dizziness, headache

  uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances

  rare: mental confusion

  frequency 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, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx

  rare: urticaria, alopecia, psoriasis

  very rare: diaphoresis, 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, 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.