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Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
1. NAME OF THE MEDICINAL PRODUCT
LISINOPRIL (Ethics) 5 mg, tablet LISINOPRIL (Ethics) 10 mg, tablet LISINOPRIL (Ethics) 20 mg, tablet
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Lisinopril (Ethics) tablets come in three strengths and contain lisinopril dihydrate equivalent to 5 mg, 10 mg or 20 mg lisinopril.
3. PHARMACEUTICAL FORM
5 mg tablet : A light pink coloured, circular, biconvex uncoated tablet. The tablet has a break line and is embossed with ‘5’ on one side and embossed with ‘BL’ on the other side.
10 mg tablet : A light pink coloured, circular, biconvex uncoated tablet. The tablet is embossed with ‘10’ on one side and embossed with ‘BL’ on the other side.
20 mg tablet : A pink, circular, biconvex uncoated tablet. The tablet is embossed with ‘20’ on one side and embossed with ‘BL’ on the other side.
Lisinopril dihydrate. The chemical name for lisinopril dihydrate is N-[N-[(1S)-1-carboxy-3- phenylpropyl]-L-lysyl]-L-proline dihydrate. Its structural formula is: C21H31N3O5.2H2O, Molecular weight: 441.53, CAS No.: 83915-83-
Lisinopril dihydrate is a white to off-white crystalline powder that is soluble in water, sparingly soluble in methanol and practically insoluble in ethanol.
A synthetic peptide derivative, lisinopril dihydrate is an oral long acting angiotensin converting enzyme inhibitor. It is a lysine analogue of enalaprilat (active metabolite of enalapril).
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Lisinopril is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
Lisinopril is indicated in the management of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis.
Lisinopril is indicated for the treatment of haemodynamically stable patients within 24 hours of an acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blocker.
4.2 Dose and method of administration
Since absorption of lisinopril tablets is not affected by food, the tablets may be administered
before, during or after meals. Lisinopril should be administered in a single daily dose. As with all single daily dose medications, lisinopril should be taken at approximately the same time each day.
Essential Hypertension
In patients with essential hypertension the usual recommended starting dose is 10 mg. The usual effective maintenance dosage is 20 mg administered in a single daily dose. Dosage should be adjusted according to blood pressure response. In some patients, achievement of optimal blood pressure reduction may require two to four weeks of therapy. The maximum dose used in long term, controlled clinical trials was 80 mg/day.
A lower starting dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued, patients who are volume and/or salt-depleted for any reason, and in patients with renovascular hypertension and may be required in some elderly patients.
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. The diuretic should be discontinued 2 to 3 days before beginning therapy with lisinopril (see Warnings and Precautions ). In hypertensive patients in whom the diuretic cannot be discontinued, therapy with lisinopril should be initiated with a 5 mg dose. The subsequent dosage of lisinopril 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:
Creatinine Clearance (mL/min)
Starting Dose (mg/day) < 70 > 30 mL/min 5 mg - 10 mg < 30 > 10 mL/min 2.5 mg - 5 mg < 10 mL/min (including patients on dialysis)**
2.5 mg*
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
Acute Myocardial Infarction
Treatment with lisinopril may be started within 24 hours of the onset of symptoms. The first dose of lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter. Patients with a low systolic blood pressure (120 mm Hg or less) when treatment is started or during the first 3 days after the infarct should be given a lower dose - 2.5 mg orally (see Warnings and Precautions ). If hypotension occurs (systolic blood pressure less than or equal to 100mm 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 90mm Hg for more than 1 hour) lisinopril should be withdrawn. Dosing for patients with acute myocardial infarction should continue for six weeks. (For patients who develop symptoms of heart failure, see Dosage and Administration, Congestive Heart Failure ).
Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate.
Lisinopril is indicated in the management of patients with acute myocardial infarction to prevent the subsequent development of left ventricular dysfunction (as defined by an ejection fraction less than or equal to 35%) or heart failure and to improve survival, based on the outcome of the Gruppo Italiano per lo Studio della Sporavvienza nell'Infarto Miocardico (GISSI-3) trial. The GISSI-3 study was a multicentre, controlled, randomised, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-term (six week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (six week) mortality and on longer-term death and markedly impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who were haemodynamically stable were randomised, in a 2 x 2 factorial design, to six weeks of either lisinopril alone (n = 4,841), nitrates alone (n = 4,869), lisinopril plus nitrates (n = 4,841) or open control (n = 4,843). All patients received routine therapies, including thrombolytics (72%), aspirin (84%) and a beta-blocker (31%), as appropriate, normally utilised in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure less than or equal to 100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine
2 mg/dL and/or proteinuria > 500 mg/24 hours). Doses of lisinopril were adjusted as necessary according to protocol (see Dosage and Administration).
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined endpoint at six months after the myocardial infarction, consisting of a number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction less than or equal to 35% or an akinetic-dyskinetic (A-D) score greater than or equal to 45%. Patients receiving lisinopril (n = 9,646), alone or with nitrates, had an 11% lower risk of death at six weeks (2p (two tailed) = 0.04) compared to patients receiving no lisinopril (n = 9,672) (6.4 versus 7.2%, respectively). The reduction in mortality at six months was not significant, but this was not a primary outcome measure. Although patients randomised to receive lisinopril for up to six weeks also fared numerically better on the combined endpoint at six months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of lisinopril between six weeks and six months in the group randomised to six weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction treated with lisinopril had a higher (9.0 versus 3.7%) incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more than
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
one hour) and renal dysfunction (2.4 versus 1.1%) in hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration).
Use in children
Not recommended for children. Safety and effectiveness of lisinopril in children have not been established.
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 (see Dosage and Administration, Dosage Adjustment in Renal Impairment ) should be used to determine the starting dose of lisinopril. Thereafter the dosage should be adjusted according to the blood pressure response.
4.3 Contraindications
- Hypersensitivity to lisinopril or any other component of lisinopril.
- History of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor.
- Patients with hereditary or idiopathic angioedema.
- Pregnancy (see Warnings and Precautions , Use in pregnancy ).
- Patients undergoing haemodialysis with polyacrylonitrile metalylsulfonate high flux membranes. There is a risk of anaphylactoid reaction (hypersensitivity reactions which may be severe, e.g. shock) with the simultaneous use of an ACE inhibitor and polyacrylonitrile metalylsulfonate high flux dialysis membranes (e.g. AN69) or during low-density lipoproteins (LDL) apharesis with dextran sulphate within the framework of dialysis treatment. This combination thus needs to be avoided, either by using other medical products to control high blood pressure or cardiac insufficiency or by using other membranes during dialysis.
- Lisinopril should not be administered with aliskiren in patients with diabetes (see Interactions ).
4.4 Special warnings and precautions for use
Dual blockade of the renin-angiotensin-aldosterone system
As a consequence of inhibiting the renin-angiotensin-aldosterone system, hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of the renin-angiotensin-aldosterone system (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) is therefore not recommended in patients with already controlled blood pressure and should be limited to individually defined cases with close monitoring of renal function.
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident, respectively. In all high-risk patients, it is advisable to initiate treatment at lower dosages than those usually recommended for uncomplicated patients.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can usually be given without difficulty once the blood pressure, has increased.
Patients should be cautioned to report light-headedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing doctor.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion, e.g. vomiting or diarrhoea, may also lead to a fall in blood pressure; patients should be advised to consult with their doctor.
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, i.e. patients with a systolic blood pressure of 100 mmHg or lower or cardiogenic shock. During the first three 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 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure < 90 mmHg for more than one hour), lisinopril should be withdrawn.
Aortic Stenosis/Hypertrophic Cardiomyopathy
As with other vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
Neutropenia/agranulocytosis: Another ACE inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia and neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to lisinopril cannot be excluded.
It is recommended that periodic haematological monitoring be considered in patients with diseases known to affect bone marrow function (e.g. renal dysfunction, collagen vascular disease) and/or who are taking concomitant therapy known to be associated with bone marrow depression.
Impaired renal function
Changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin- angiotensin aldosterone system, treatment with ACE inhibitors may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
In patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed. These increases are usually reversible upon discontinuation of ACE treatment. ACE inhibitors should be avoided in patients with known or suspected bilateral renal artery stenosis.
When an ACE inhibitor is given to a patient with stenosis of the renal artery supplying a solitary kidney or with bilateral renal artery stenosis, acute renal insufficiency may occur. ACE inhibition may also cause a decrease in renal function in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces glomerular filtration pressure. Under these circumstances, renal function is dependent on angiotensin II-induced vasoconstriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration decreases, and renal failure may result. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors.
Some patients with no apparent pre-existing renovascular disease have developed increases in blood urea nitrogen and serum creatinine which is usually minor and transient. This is more likely to occur in patients with pre-existing renal impairment or in those on diuretics.
Dosage reduction of the ACE inhibitor and/or discontinuation of the diuretic 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 μmol/L and/or proteinuria exceeding 500 mg/24h. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 265 μmol/L or a doubling from the pre-treatment value) then the physician should consider withdrawal of lisinopril. Evaluation of the hypertensive patient should always include assessment of renal function (see Dosage and Administration). In patients with renal artery stenosis, if deterioration in renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by another and in these patients usage of another class of antihypertensive agent would be preferable. Patients with unilateral renal artery stenosis present a special problem as deterioration of function may not be apparent from measurement of blood urea and serum creatinine.
It is possible that in patients with compromised renal function who are being treated with NSAIDS, the co-administration of lisinopril may result in a further deterioration of renal function. This may result in an increase in serum potassium, but it appears that these effects are usually reversible.
Impaired hepatic function
Hepatitis (hepatocellular and/or cholestatic) and elevations of hepatic enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in-patients with or without pre-existing hepatic abnormalities. In most cases the changes were reversed on discontinuation of the drug. There are no adequate studies in-patients with cirrhosis and/or hepatic dysfunction. Lisinopril should be used with particular caution in-patients with pre-existing hepatic abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.
Hyperkalaemia
Because the ACE inhibitors decrease the formation of angiotensin II and the subsequent production of aldosterone, serum potassium concentrations exceeding 5.5 mEq/L may occur. Hyperkalaemia is more likely in-patients with some degree of renal impairment, those treated with potassium sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride)
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day and showed no evidence of carcinogenicity.
At least one other ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential for lisinopril to cause a similar effect is unknown.
Neutropenia
Patients should be told to report promptly any indication of infection (e.g. sore throat, fever) which may be a sign of neutropenia.
Note: As with many other drugs, certain advice to patients being treated with lisinopril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
Renal complication of diabetes
EUCLID (EURODIAB controlled trial of lisinopril in insulin dependent diabetes mellitus) was an 18 centre, multinational, randomised, double blind, placebo controlled trial. It investigated the effects of lisinopril on the urinary albumin excretion rate (AER) in 530 normotensive men and women aged 20 to 59 years with insulin dependent diabetes mellitus (IDDM) and normoalbuminuria or microalbuminuria. The study recruited patients with a diastolic blood pressure in the range of 75 to 90 mmHg inclusive provided that the systolic blood pressure was less than or equal to 155 mmHg. Patients received either lisinopril 10 mg once daily or matching placebo for two years. Titration up to 20 mg once daily of lisinopril or two placebo tablets was permitted if sitting diastolic blood pressure had not reached the target value of less than 75 mmHg after three months of treatment. Nifedipine treatment (20 mg twice daily) was initiated if the blood pressure remained inadequately controlled (systolic blood pressure > 160 mmHg, diastolic blood pressure > 95 mmHg).
The primary efficacy variable was the rate of change in the urinary albumin excretion rate (AER) measured from two consecutive overnight urine collections at six monthly intervals from baseline to 24 months in the whole patient group (i.e. normoalbuminuric and microalbuminuric at baseline). After 24 months treatment the AER was 18.8% (95% CI: 2.0, 32.7) lower in the lisinopril group (n = 230) compared to the placebo group (n = 226) with a between group difference of 2.2 microgram/minute (p = 0.03) when adjusted for baseline AER and centre. After adjustment for diastolic blood pressure reduction produced by lisinopril, the between group relative difference in AER was reduced to 17.3% (95% CI: 0.2, 31.5, p = 0.05). There were no statistically significant differences in AER between lisinopril and placebo in patients with good baseline glycaemic control (HbA1C < 7%) or with a baseline diastolic blood pressure > 80 mmHg.
In patients with baseline microalbuminuria the AER was 49.7% (95% CI: 14.5, 77.9) lower in the lisinopril group (n = 39) compared to placebo (n = 34), p = 0.1. Only 15% (n = 79) of the randomised patients had baseline microalbuminuria compared to 40% anticipated by the protocol. This may have left the study underpowered to detect a statistically significant difference in the AER between treatments in patients with baseline microalbuminuria. In a nonprotocol specified subgroup analysis in patients with baseline microalbuminuria (AER 20 to 200 microgram/minute) and endpoint AER the absolute difference in mean AER between the lisinopril group (n = 39) and the placebo group (n = 34) was 38.5 microgram/minute (p = 0.001).
The results also show that lisinopril does not increase the risk of hypoglycaemic events in IDDM as there was no treatment difference in hypoglycaemic events or glycaemic control throughout the study.
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
4.5 Interaction with other medicines and other forms of interaction
Diuretics
When a diuretic is added to the therapy of a patient receiving an ACE inhibitor, the antihypertensive effect is usually additive. Patients receiving diuretics, especially those in whom diuretic therapy was recently instituted or those with intravascular volume depletion, may sometimes experience an excessive reduction of blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects may be minimised by discontinuing the diuretic and ensuring adequate hydration and salt intake prior to commencing ACE inhibitor therapy.
If it is not possible to discontinue the diuretic, the starting dose of the ACE inhibitor should be reduced and the patient closely observed for several hours following the initial dose of the ACE inhibitor and until the blood pressure has stabilised. The combination of Lisinopril with other antihypertensive drugs may increase the antihypertensive effect, especially in combination with diuretics.
Lithium
Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
Non-steroidal anti-inflammatory drugs (NSAIDS)
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase- inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non- steroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors, the co- administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible renal failure. These effects are usually reversible.
These interactions should be considered in patients taking NSAIDs including selective COX- 2 inhibitors concomitantly with diuretics and ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly.
Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics: The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed- combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
There were no adverse events on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril.
Use in pregnancy (Category D)
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. As with all ACE inhibitors, lisinopril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with lisinopril and avoided during the treatment. If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment. If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management. There are no adequate and well-controlled studies of ACE inhibitors in pregnant women, but foetotoxicity is well documented in animal models. Data, however, show that ACE inhibitors cross the human placenta. Post marketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero. When ACE inhibitors have been used during the second and third trimesters of pregnancy, there have been reports of foetal hypotension, renal failure, hyperkalaemia, skull hypoplasia and death. A historical cohort study in over 29,000 infants born to non-diabetic mothers has shown 2. times higher risk for congenital malformations in infants exposed to any ACE inhibitor during the first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4. times (95% confidence interval 1.37 to 14.02) respectively compared to no exposure. Oligohydramnios has been reported, presumably resulting from decreased fetal renal function; oligohydramnios has been associated with fetal limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation. Prematurity and patent ductus arteriosus have been reported, however it is not clear whether these events were due to ACE inhibitor exposure. Infants exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia. If such complications arise, appropriate medical treatment should be initiated to support blood pressure and renal perfusion. Lisinopril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and theoretically may be removed by exchange transfusion.
Use in lactation
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known whether this drug is secreted in human milk. Because the possibility exists that lisinopril may be secreted in human milk, lisinopril should not be given to a breastfeeding mother.
4.7 Effects on ability to drive and use machines
When driving vehicles or operating machines, patients may experience dizziness or tiredness.
4.8 Undesirable effects
Lisinopril has been found to be generally well tolerated in controlled clinical trials. For the most part, adverse experiences were mild and transient in nature. In patients with congestive heart failure high doses of lisinopril may predispose to symptoms related to hypotension
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
(dizziness, syncope) and biochemical changes related to impaired renal function (hyperkalaemia and increased serum creatinine), as would be expected with ACE inhibitor therapy.
The adverse events that occurred in controlled clinical trials with lisinopril are taken from the case reports of 3,702 patients (2,633 patients with hypertension and 636 patients with congestive cardiac failure and 433 diabetic patients).
Hypertension
Adverse reactions reported in 2,633 patients with hypertension follow.
More common reactions (3 to 10%)
Nervous system. Dizziness, headache.
Less common reactions (1 to 3%)
Body as a whole. Asthenia/ fatigue.
Cardiovascular. Chest pain.
Gastrointestinal. Diarrhoea, nausea, vomiting.
Respiratory. Cough.
Dermatological. Rash.
Rare reactions (< 1%)
Cardiovascular Hypotension, orthostatic effects, angina, oedema, palpitation, rhythm disturbances.
Gastrointestinal Dyspepsia, anorexia, constipation, flatulence.
Nervous system. Paraesthesia, depression, somnolence, insomnia, vertigo.
Respiratory. Dyspnoea, orthopnoea.
Dermatological. Pruritus.
Musculoskeletal. Muscle cramps, back pain, leg pain, shoulder pain.
Other. Blurred vision, fever, flushing, gout, decreased libido, malaise.
Congestive cardiac failure. Adverse reactions reported in 636 patients with congestive cardiac failure. The most common adverse reaction occurring in this patient population was dizziness (14.2%). The other adverse reactions follow.
More common reactions (3 to 10%)
Nervous system. Headache.
Cardiovascular. Hypotension, chest pain, angina.
Gastrointestinal. Diarrhoea, nausea.
Respiratory. Cough, dyspnoea.
Dermatological. Rash.
Body as a whole. Asthenia/ fatigue.
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
Cardiovascular. Angina pectoris, cerebral ischaemia, hypertension, palpitations.
Gastrointestinal. Constipation, flatulence, gastritis, vomiting.
Dermatological. Eczema.
Metabolic. Hyperlipidaemia, hypoglycaemic reaction, peripheral oedema.
Musculoskeletal. Arthrosis, bursitis, pathological fracture, tendon disorder.
Nervous system. Anxiety, depression, hypertonia, paraesthesia.
Special senses. Ear disorder, taste perversion.
Genitourinary. Dysuria, haematuria, kidney pain.
General
Hypersensitivity/ angioneurotic oedema. Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely (see Precautions and Warnings ). In very rare cases, intestinal angioedema has been reported.
Additional adverse reactions, which occurred rarely, either during, controlled clinical trials or after the drug was marketed, include the following:
Cardiovascular. Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Precautions and Warnings ); tachycardia.
Gastrointestinal. Abdominal pain, dry mouth, hepatitis (hepatocellular and cholestatic, very rarely this may progress to hepatic failure), jaundice, pancreatitis, taste disturbance.
Musculoskeletal. Joint pain.
Nervous system. Mood alterations, mental confusion, stroke, sleep disturbances.
Respiratory. Bronchitis, bronchospasm, nasal congestion, pharyngeal pain, sinusitis, rhinitis.
Dermatological. Alopecia, urticaria, diaphoresis, psoriasis and severe skin disorders have been reported, including pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme.
Genitourinary. Uraemia, oliguria/ anuria, proteinuria, renal dysfunction, acute renal failure, impotence, urinary tract infection.
Body as a whole. Syncope.
A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/ arthritis, a positive antinuclear antibody (ANA) test, an elevated erythrocyte sedimentation rate (ESR), eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.
Clinical laboratory test findings
Serum electrolytes: Hyperkalaemia (see Precautions and Warnings ) and hyponatraemia have occurred.
Creatinine, blood urea nitrogen: Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in 1.1 and 1.6% of patients, respectively, with essential hypertension treated with lisinopril alone. Increases were more common in-patients receiving concomitant diuretics and in-patients with renal artery stenosis (see Precautions and Warnings ). Reversible minor increases in blood urea nitrogen and serum creatinine were observed in approximately 12% of patients with congestive cardiac
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.
Bone marrow depression: Bone marrow depression, manifest as anaemia, and/or thrombocytopenia and/or leucopenia has been reported. Agranulocytosis has been rarely reported, although a causal relationship has not been established. Rarely, haemolytic anaemia has been reported.
Haemoglobin and haematocrit: Small decreases in haemoglobin and haematocrit, rarely of clinical importance unless another cause of anaemia coexisted, have occurred.
Other (causal relationship unknown): Rarely, elevations of hepatic enzymes and/or serum bilirubin have occurred. Rare cases of bone marrow depression have been reported. Thrombocytopenia and leucopenia have been reported; a causal relationship to therapy with lisinopril cannot be excluded.
4.9 Overdose
There are no data on overdosage in humans. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Lisinopril may be removed from the general circulation by haemodialysis.
5. PHARMACOLOGICAL PROPERTIES
Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of plasma angiotensin II which results in decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mmol/L; however, approximately 15% of patients had increases greater than 0.5 mmol/L and approximately 6% had a decrease greater than 0. mmol/L. In the same study, patients treated with lisinopril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mmol/L; approximately 4% of patients had increases greater than 0.5 mmol/L and approximately 12% had a decrease greater than 0.5 mmol/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin- angiotensin-aldosterone system (RAAS), lisinopril is antihypertensive even in-patients with low renin hypertension. Although lisinopril was antihypertensive in all races studied, black hypertensive patients (usually a low renin hypertensive population) had a smaller average response to monotherapy than non-black patients. Concomitant administration of lisinopril and hydrochlorothiazide further reduced blood pressure in black and non-black patients and any racial difference in blood pressure response was no longer evident.
ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated. When combined with other antihypertensive agents, additive falls in blood pressure may occur.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycaemia. ACE inhibitors,
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
5.2 Pharmacokinetic properties
Following oral administration of lisinopril, peak serum concentrations of lisinopril occur within about seven hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. 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. Lisinopril does not appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with large interpatient variability (6 to 60%) at all doses tested (5 to 80 mg). Lisinopril absorption is not affected by the presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12.6 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease, becomes clinically important only when the glomerular filtration rate (GFR) is below 30 mL/minute. Above this GFR, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have higher (approximately doubled) blood levels and higher values for the area under the plasma concentration time curve (AUC) than younger patients ( see Dosage and Administration ). Lisinopril can be removed by haemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contained radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labelled drug to pregnant rats, but none was found in the fetuses.
5.3 Preclinical safety data
Not applicable
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate dihydrate Magnesium stearate Maize starch Mannitol Ferric oxide red
The tablets are gluten free.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
36 months
Lisinopril (Ethics)
Lisinopril Tablets 5 mg, 10 mg, 20 mg
6.4 Special precautions for storage
Store below 25°C. Protect from light, heat and moisture.
6.5 Nature and contents of container
Lisinopril (Ethics) 5 mg, 10 mg and 20 mg tablets are available in blister packs of 90 tablets each.
6.6 Special precautions for disposal
No special requirements for disposal.
7. MEDICINE SCHEDULE
Prescription medicine
8. SPONSOR
Teva Pharma (New Zealand) Limited PO Box 128 244 Remuera Auckland 1541 Telephone: 0800 800 097
9. DATE OF FIRST APPROVAL
13 September 2007
10. DATE OF REVISION OF THE TEXT
1 July 2021
SUMMARY TABLE OF CHANGES
Section changed Summary of new information
8. Sponsor change
