Lisinopril

Registered South African indications:

• Mild to moderate hypertension
  - Alone or in combination with other antihypertensives
• Congestive heart failure
  - As an adjunctive therapy with diuretics and, where appropriate, digitalis
• Acute myocardial infarction
  - When admin. within 24hrs to haemodynamically stable patients to reduce the risk of left ventricular dysfunction or heart failure and improve survival

Should a woman become pregnant while receiving an ACE-inhibitor, the treatment must be stopped promptly and changed to a different class of antihypertensive medicine. If a woman is contemplating pregnancy, a different class of medicine should be used.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• History of angioedema related to previous ACE-inhibitor therapy or angiotensin receptor blocker. These patients must never again be given these medicines
• Hereditary or idiopathic angioedema
• Aortic stenosis
• Renal artery stenosis in patients with a single kidney
• Bilateral renal artery stenosis
• Hypertrophic obstructive cardiomyopathy
• Severe renal function impairment (CrCl<30ml/min)
• Porphyria
• Coadministration with potassium sparing diuretics such as spironolactone, triamterene, amiloride
• Lithium therapy: Coadministration with lisinopril may lead to toxic blood concentrations of lithium
• Coadministration with aliskiren-containing products
• Coadministration of fluoroquinolones with ACE inhibitors/renin-angiotensin blockers is contraindicated in patients with moderate to severe renal impairment
• Coadministration with sacubitril/ valsartan therapy and lisinopril must not be initiated earlier than 36 hours after the last dose of

South African recommendations

Caution in the following patient groups

• Mild to moderate renal impairment
• Hepatic impairment
• Elderly

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
• Patients at increased risk, including those with heart failure, ischaemic heart, or cerebrovascular disease, require close monitoring during initiation and dose adjustment

Hypotension in acute myocardial infarction

• Treatment must not be initiated in patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These include patients with a systolic blood pressure of 100mmHg or lower or cardiogenic shock
• The dose should be reduced to 5mg or temporarily to 2.5mg if systolic blood pressure is 100mmHg or lower. Withdraw lisinopril if hypotension persists (systolic blood pressure less than 90mmHg for more than 1 hour)

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

• The combined use of lisinopril with angiotensin II receptor blockers (ARBs) or aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including acute renal failure). Dual blockade is contraindicated with aliskiren-containing products. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy

Renal function impairment

• Decreased elimination of lisinopril (CrCl<80ml/min) results in an increased risk of hyperkalaemia, requiring lower doses. Patients with renal artery stenosis (bilateral or in one kidney) or a renal transplant have an increased risk of renal function impairment (increased blood urea and serum creatinine)
• Treatment should not be initiated in acute myocardial infarction patients with evidence of renal dysfunction (serum creatinine concentrations exceeding 177 micromol/L or proteinuria exceeding 500mg/24 hours, and the drug may need to be withdrawn if dysfunction develops during treatment (serum creatinine concentrations exceeding 177 micromol/L or doubling of the pretreatment value)

Neutropenia/agranulocytosis

• Lisinopril should be used with extreme caution in patients with collagen vascular disease, those on immunosuppressant therapy, or those treated with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Periodic monitoring of white blood cell counts is advised for such patients
• Bone marrow depression, increases the risk of agranulocytosis and neutropenia

Diabetic patients

• Diabetes mellitus increases the risk of hyperkalaemia. 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 due to the risk of hypoglycaemia

Hyperkalaemia

• Lisinopril may cause an increase in serum potassium levels. Patients with impaired renal function, diabetes mellitus, and/or those taking potassium-sparing diuretics (such as spironolactone, triamterene, and amiloride) are at high risk of severe hyperkalaemia, which can lead to cardiac conduction abnormalities, dysrhythmias, and cardiac arrest

Renovascular disease

• Lisinopril should not be used in patients with renovascular disease or suspected renovascular disease, but it may be used cautiously in severe resistant hypertension in such patients, only under specialist supervision
• The elderly, patients with peripheral vascular diseases or generalised atherosclerosis may have asymptomatic renovascular disease

Hypersensitivity/angioedema

• If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx is observed, lisinopril should be discontinued promptly. Angioedema associated with laryngeal oedema may be fatal and requires appropriate emergency therapy (e.g., administration of adrenaline and/or maintenance of a patent airway)
• Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk. Concomitant use with sacubitril/valsartan is contraindicated and a wash-out period of 36 hours is required before starting either medicine. Caution should be used when starting racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in a patient already taking an ACE inhibitor, due to the increased risk of angioedema

Desensitisation

• Anaphylactoid reactions have occurred in patients using ACE-inhibitors during desensitising protocols (e.g., hymenoptera venom); these reactions were avoided when ACE inhibitors were temporarily withheld

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.

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. Patients who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril and receive appropriate medical follow-up

Race

• Lisinopril causes a higher rate of angioedema in black patients than in non-black patients. It may also be less effective in lowering blood pressure in black patients, possibly due to a higher prevalence of low-renin states

Cough

• 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

Surgery/anaesthesia

• In patients undergoing major surgery or anaesthesia with medicines that produce hypotension, lisinopril may block angiotensin II formation, causing hypotension that can be corrected by volume expansion

Concomitant use of fluoroquinolones

• Concomitant use with fluoroquinolones may precipitate acute kidney injury, especially in patients with moderate to severe renal impairment and the elderly. Renal function should be assessed before and monitored during concomitant treatment

Excipient precautions

• The tablets contain mannitol, which may have a laxative effect

Paediatric population

• The safety and effectiveness of lisinopril in children have not been established

Driving and use of machines

• Caution is required when driving or performing tasks requiring alertness because of possible dizziness

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Mild to moderate hypertension
- Alone or in combination with other antihypertensive

• Oral (fct, tab): Initial: 10mg, dly as a single dose; Adjust according to the blood pressure response; Usual effective maintenance dose: 20mg, dly given as a single dose; Max: 40mg/24hrs

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The full therapeutic effect may take several weeks. Therefore, if the desired effect has not been achieved within 2 to 4 weeks, the dose may be increased

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Congestive heart failure
- As an adjunctive therapy with diuretics and, where appropriate, digitalis

• Oral (tab): Initial 2.5mg, dly as a single dose; Adjust according to clinical response; Titrate by up to 10mg at intervals of at least 2 weeks; Maintenance dose range: 5-20mg, dly as a single dose; Max: 35mg/24hrs

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Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers

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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, prior to therapy with lisinopril. The effect of the starting dosage of lisinopril on blood pressure should be monitored carefully

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Acute myocardial infarction
- When admin. within 24hrs to haemodynamically stable patients to reduce the risk of left ventricular dysfunction or heart failure and improve survival

• Oral (tab): Initial: 5mg within 24hrs of onset; Followed by 5mg after 24hrs of the first dose; Then 10mg after 48hrs of the first dose; Then 10mg, dly for 6 weeks

In patients with low systolic blood pressure (≤120mmHg)

• Oral (fct, tab): Initial: 2.5mg should be used during the first 3 days after the infarction

If hypotension occurs (systolic blood pressure ≤100mmHg)

• Oral (fct, tab): Maintenance: 5mg, dly may be given with temporary reductions to 2.5mg if needed

If prolonged hypotension occurs (systolic blood pressure <90mmHg for more than 1 hour)

• Withdraw lisinopril

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Dosing should continue for 6 weeks. The benefit appears to be greatest in patients with large myocardial infarctions and evidence of impaired left ventricular function. Patients who develop symptoms of heart failure should continue with lisinopril

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Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate

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Method of administration
Lisinopril is for oral use and should be administered as a single daily dose at approximately the same time every day. Lisinopril not affected by the presence of food and may be taken with/without meals

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• The use of lisinopril is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take lisinopril during pregnancy
• 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 lisinopril should be stopped immediately and if appropriate, alternative therapy should be started
• Foetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spins bifida) and of kidney malformations
• Lisinopril passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms
• Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of lisinopril during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur

Breastfeeding

South African recommendations

• Contraindicated
• Safety in lactation has not been established

Fertility

South African recommendations

• No information available

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  A lower dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued and in patients who are volume- and/or salt-depleted for any reason
  If creatinine clearance is 31-80 ml/min: Initial: 5-10mg/day; The dose may be increased as needed according to therapeutic response; Max: 20mg/24hrs
• Moderate to severe: Coadministration with fluoroquinolones: Contraindicated
• Severe (CrCl<30ml/min): Contraindicated

South African recommendations

• Caution; no information available

South African recommendations

• Caution; no dose adjustment recommended
  There are no age-related changes in the efficacy or safety profile of the agent
  When advanced age is associated with a decrease in renal function, the guidelines set out in renal impairment above should be used to determine the starting dose of lisinopril
  Thereafter, the dosage should be adjusted according to the blood pressure response

Central Nervous System Disorders

• Dizziness
• Headache
• Mood alterations
• Paraesthesia
• Vertigo
• Sleep disturbances  
• Hallucinations
• Mental confusion
• Depressive symptoms
• Syncope
• Fatigue

Cardiovascular Disorders

• Orthostatic effect
• Hypotension
• Myocardial infarction
• Cerebrovascular accident
• Palpitations
• Tachycardia
• Raynaud's phenomenon

Respiratory Disorders

• Cough
• Rhinitis
• Bronchospasm
• Sinusitis
• Allergic alveolitis/eosinophilic pneumonia

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Indigestion
• Dry mouth
• Intestinal angioedema

Hepatobiliary Disorders

• Hepatocellular or cholestatic hepatitis
• Jaundice
• Hepatic failure
• Increased serum bilirubin
• Increased hepatic enzymes

Genitourinary Disorders

• Renal dysfunction
• Uraemia
• Acute renal failure
• Oliguria/anuria
• Impotence
• Gynaecomastia
• Increased serum creatinine
• Increased blood urea

Endocrine and Metabolic Disorders

• Hypoglycaemia
• Syndrome of inappropriate antidiuretic hormone secretion
• Hyperkalaemia
• Hyponatraemia
• Pancreatitis

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Urticaria
• Alopecia
• Psoriasis
• Hypersensitivity reaction
• Angioneurotic oedema (of the face, extremities, lips, tongue, glottis, and/or larynx)
• Sweating
• Pemphigus
• Toxic epidermal necrolysis
• Stevens-Johnson Syndrome
• Erythema multiforme
• Cutaneous pseudolymphoma
• Symptom complex
  - Fever
  - Vasculitis
  - Myalgia
  - Arthralgia/arthritis
  - A positive antinuclear antibodies (ANA)
  - Elevated red blood cell sedimentation rate (ESR)
  - Eosinophilia
  - Leucocytosis
  - Photosensitivity
  - Other dermatological manifestations

Immune, Blood and Lymphatic System Disorders

• Decreased haemoglobin
• Decreased haematocrit
• Bone marrow depression
• Anaemia
• Haemolytic anaemia
• Thrombocytopenia
• Leucopenia
• Neutropenia
• Agranulocytosis
• Lymphadenopathy
• Autoimmune disease
• Anaphylactic/anaphylactoid reaction

Sensory Disorders

• Taste disturbance
• Olfactory disturbance

• Potassium-sparing diuretics
• Spironolactone
• Triamterene
• Amiloride
• Lithium
• Aliskiren-containing products
• Fluoroquinolones
• Sacubitril/valsartan
• Allopurinol
• Procainamide
• Other agents that act on the renin-angiotensin-aldosterone system
• ACE-inhibitors
• Angiotensin II receptor blockers
• Agents that increase serum potassium
• Potassium supplements
• Potassium-containing salt substitutes
• Trimethoprim
• Cotrimoxazole
• Ciclosporin
• Heparin
• Antihypertensive agents
• Glyceryl trinitrate
• Nitrates
• Vasodilators
• Diuretics
• Immunosuppressant therapy
• Non-steroidal anti-inflammatory drugs
• Acetylsalicylic acid (≥3g/day)
• COX-2 inhibitors
• Gold
• Sodium aurothiomalate
• Tricyclic antidepressants
• Antipsychotics
• Anaesthetic agents  
• Sympathomimetics
• Antidiabetic agents
• Insulins  
• Oral hypoglycaemic antidiabetics
• Tissue plasminogen activators  
• Thrombolytics
• Beta-blockers
• Racecadotril
• mTOR inhibitors
• Sirolimus
• Everolimus
• Temsirolimus
• Vildagliptin

• Blood pressure

None routine. Specific cases may require

• Hepatic function
• Full blood count
• Renal function
• Electrolytes
• Blood glucose
• Heart rate

Lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, inhibits ACE that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion. The latter decrease may result in an increase in serum potassium concentration.

Tablet 5mg

• Adco-Zetomax (Adcock Ingram)
• Cipla-Lisinopril (Cipla Medpro)
• Hexal-Lisinopril (Sandoz)
• Liso (Pharma Dynamics)
• Lizro (Novagen)
• Lysin (Ranbaxy)
• Simayla Lisinopril (Zydus)
• Sinopren (Ranbaxy)
• Zestril (AstraZeneca) originator

Tablet 10mg

• Adco-Zetomax (Adcock Ingram)
• Austell-Lisinopril (Austell)
• Cipla-Lisinopril (Cipla Medpro)
• Hexal-Lisinopril (Sandoz)
• Liso (Pharma Dynamics)
• Lizro (Novagen)
• Simayla Lisinopril (Ranbaxy)
• Sinopren (Ranbaxy)
• Zestril (AstraZeneca) originator

Tablet 20mg

• Adco-Zetomax (Adcock Ingram)
• Apex-Lisinopril (Camox)
• Austell-Lisinopril (Austell)
• Hexal-Lisinopril (Sandoz)
• Liso (Pharma Dynamics)
• Lizro (Novagen)
• Lysin (Ranbaxy)
• Simayla Lisinopril (Ranbaxy)
• Sinopren (Ranbaxy)
• Zestril (AstraZeneca) originator

COMBINATION PREPARATIONS

Lisinopril/ Hydrochlorothiazide

Tablet 10mg/12.5mg 

• Adco-Zetomax Co (Adcock Ingram)
• Auro Lisinopril Co (Actor)
• Hexal-Lisinopril Co (Sandoz)
• Lisinopril Co Unicorn (Unicorn)
• Lisinozide (Novagen)
• Lisoretic (Pharma Dynamics)
• Lisozide (Austell)
• Zestoretic (AstraZeneca) originator

Tablet 20mg/12.5mg

• Adco-Zetomax Co (Adcock Ingram)
• Auro Lisinopril Co (Actor)
• Diace Co (Zydus)
• Hexal-Lisinopril Co (Sandoz)
• Lisinopril Co Unicorn (Unicorn)
• Lisinozide (Novagen)
• Lisoretic (Pharma Dynamics)
• Lisozide (Austell)
• Zestoretic (AstraZeneca) originator
• Zestozide (Xixia)