Lisinopril 20mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lisinopril 20 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 21.78 mg lisinopril dihydrate equivalent to 20 mg lisinopril. For full list of excipients see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Lisinopril 20 mg Tablets: Ochre pink, round, biconvex tablets, with ‘scoreline’ line on one side.
The scoreline is only to facilitate swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension
Lisinopril may be used, for all grades of essential hypertension and renovascular hypertension, alone or with other antihypertensive agents.
Heart Failure
In heart failure, Lisinopril is indicated as an adjunctive therapy with non-potassiumsparing diuretics and, where appropriate, digitalis.
Severe Heart Failure
Treatment with Lisinopril should always be initiated in hospital under close medical supervision.
Mild to Moderate Heart Failure
Treatment with Lisinopril should always be initiated under close medical supervision. Acute Myocardial Infarction
Lisinopril is indicated for the treatment of haemodynamically stable patients, defined as patients not in cardiogenic shock and who have a systolic blood pressure greater than 100mmHg. Lisinopril may be initiated within 24 hours of 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 Posology and method of administration
Route of administration: oral. Lisinopril 20 mg tablets are only suitable for doses of 20 mg or higher. The absorption of Lisinopril is not affected by food. 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.
Hypertension
Use in Hypertensive Paediatric Patients aged 6-16 years
The recommended initial dose is 2.5 mg once daily in patients 20 to <50 kg, and 5 mg once daily in patients >50 kg. The dosage should be individually adjusted to a maximum of 20 mg daily in patients weighing 20 to <50 kg, and 40 mg in patients >50 kg. Doses above 0.61 mg/kg (or in excess of 40 mg) have not been studied in paediatric patients (see section 5.1).
In children with decreased renal function, a lower starting dose or increased dosing interval should be considered.
The need for dosage titration should be determined by measurement of the blood pressure just before the next dose
Essential and renovascular hypertension
Treatment should be started with 2.5 mg once daily, and titrated upwards to achieve optimal blood pressure control. For essential hypertension, 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.
A 2.5 mg dose seldom achieves a therapeutic response. The usual effective dose range is 1020 mg once daily.
The maximum recommended dose is 40 mg daily.
Diuretic-treated patients
Symptomatic hypotension can occur following the initial dose of Lisinopril; this is more likely when Lisinopril is added to previous diuretic therapy. Caution is recommended, therefore, since these patients may be volume or salt depleted.
If possible, the diuretic should be discontinued, or the dose reduced, two to three days before beginning therapy with Lisinopril (see ‘Special Warnings and Precautions’) and may be resumed later if required.
Lisinopril reduces the development of thiazide-induced hypokalaemia and hyperuricaemia. Use in the elderly
Age alone does not appear to affect the efficacy or safety profile of Lisinopril. Thus, elderly patients should start treatment with ‘Lisinopril’ as directed above.
Congestive heart failure
Lisinopril may be used as adjunctive therapy with non-potassium-sparing diuretics with or without digitalis.
Initial dosage: Therapy with Lisinopril should be initiated under close medical supervision (in hospital for severe heart failure) with a recommended starting dose of 2.5 mg once daily. If possible, the dose of diuretic should be reduced before beginning treatment.
Blood pressure and renal function should be monitored closely both before and during treatment because severe hypotension and, more rarely, consequent renal failure has been reported with angiotensin-converting enzyme (ACE) inhibitors (see ‘Special Warnings and Precautions’).
The appearance of hypotension after the initial dose of Lisinopril does not preclude subsequent careful dose adjustment with the drug, following effective treatment of the hypotension.
Some patients, other than those with severe heart failure, are considered to be at higher risk when started on an ACE inhibitor and are recommended for initiation of therapy in hospital. Research data have shown such patients to be: those on multiple or high-dose diuretics (e.g. >80 mg frusemide); patients with hypovolaemia; hyponatraemia (serum sodium <130 mEq/l); pre-existing hypotension (systolic blood pressure <90 mm Hg); patients with unstable cardiac failure; renal impairment (serum creatinine >150 micromol/l); those on high-dose vasodilator therapy; patients aged 70 years or over.
Maintenance dosage: The dose should be gradually increased, depending on the patient's response, to the usual maintenance dose (5-20 mg). This dose adjustment may be performed over a two- to four-week period, or more rapidly if clinically indicated.
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 mmHg or less) should be given a lower dose - 2.5 mg orally (see 'Special Warnings and Precautions'). If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg) 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 mmHg for more than 1 hour) Lisinopril should be withdrawn.
Dosing for patients with acute myocardial infarction should continue for six weeks.
The benefit appears to be greatest in patients with large myocardial infarctions and evidence of impaired left ventricular function. For patients who develop symptoms of heart failure, see ‘Posology and Method of Administration’, congestive heart failure.
Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate.
Impaired renal function
Lisinopril is excreted by the kidney, and should be used with caution in patients with renal insufficiency. The dose should be titrated against the response and should be kept. Lisinopril
is dialysable. Dialysis patients may be given the usual dose of Lisinopril on dialysis days. On the days when patients are not on dialysis the dosage should be tailored to the blood pressure response.
Paediatric use
Lisinopril has not been studied for use in children.
There is limited efficacy and safety experience in hypertensive children >6 years old, but no experience in other indications (see section 5.1). Lisinopril is not recommended in children in other indications than hypertension.
Lisinopril is not recommended in children below the age of 6, or in children with severe renal impairment (GFR <30ml/min/1.73m2) (see section 5.2).
4.3 Contraindications
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Hypersensitivity to Lisinopril, and in patients with a history of angioneurotic oedema relating to previous treatment with an ACE inhibitor and in patients with hereditary or idiopathic angioedema.
4.4 Special warnings and precautions for use
Assessment of renal function: Evaluation of the patient should include assessment of renal function prior to initiation of therapy, and during treatment.
Impaired renal function: Lisinopril should be used with caution in patients with renal insufficiency, as they may require reduced or less frequent doses (see ‘Posology’). Close monitoring of renal function during therapy should be performed as deemed appropriate in those with renal insufficiency. In the majority, renal function will not alter, or may improve.
Renal failure has been reported in association with ACE inhibitors and has been mainly in patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure is usually reversible.
Some hypertensive patients, with no apparent pre-existing renal disease, have developed increases in blood urea and creatinine when Lisinopril has been given concurrently with a diuretic. Dosage reduction of Lisinopril and/or discontinuation of the diuretic may be required. This situation should raise the possibility of underlying renal artery stenosis (see ‘Renovascular hypertension’).
Symptomatic hypotension was seen rarely in uncomplicated hypertensive patients. It is more likely to occur in patients who have been volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhoea, or vomiting. In these patients, by discontinuing diuretic therapy or significantly reducing the diuretic dose for two to three days prior to initiating Lisinopril, the possibility of this occurrence is reduced.
Similar caution and close supervision may apply also to patients with ischaemic heart or cerebrovascular disease in whom severe hypotension could result in a myocardial infarct or cerebrovascular accident. (See 'Undesirable Effects').
Severe hypotension has been reported with ACE inhibitors, mainly in patients with severe heart failure. Many of these patients were on high doses of loop diuretics, and some had hyponatraemia or functional renal impairment. If hypotension develops, the patient should be placed in a supine position. Volume repletion with oral fluids or intravenous normal saline may be required. Intravenous atropine may be necessary if there is associated bradycardia. Treatment with Lisinopril may be restarted with careful dose titration following restoration of effective blood volume and pressure.
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Lisinopril. This effect is anticipated and usually is not a reason to discontinue therapy. If such hypotension becomes symptomatic, a reduction of dose or discontinuation of Lisinopril may become necessary.
Hypotension in Acute Myocardial Infarction
Treatment with lisinopril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mmHg or lower or cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mmHg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than 1 hour) then Lisinopril should be withdrawn.
Renovascular hypertension
Lisinopril can be used when surgery is not indicated, or prior to surgery. In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases of blood urea and creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients treated with diuretics and/or those with renal insufficiency.
In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding
177 micromol/l and/or proteinuria exceeding 500 mg/24 h. If renal dysfunction develops during treatment with ‘Lisinopril’ (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre-treatment value) then the physician should consider withdrawal of Lisinopril.
Angioneurotic oedema: It has been reported with angiotensin-converting enzyme inhibitors, including Lisinopril. This may occur at any time during treatment. In such cases, Lisinopril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Where swelling is confined to the face, lips and mouth, the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx likely to cause airways obstruction, appropriate therapy (which may include subcutaneous epinephrine (adrenaline) (0.5 ml 1:1,000) and/or measures to ensure a patent airway) should be administered promptly.
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 Lisinopril who develop jaundice or marked elevations of hepatic enzymes should discontinue Lisinopril and receive appropriate medical follow-up.
Race
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 (see also ‘Contraindications’).
Other hypersensitivity reactions have been reported.
As with other ACE inhibitors, Lisinopril 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.
Anaphylactoid reactions during hymenoptera desensitisation: Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom (e.g. Bee or Wasp venom) have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.
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, it is recommended that a different type of dialysis membrane or different class of antihypertensive agent is used.
Anaphylactoid reactions during LDL apheresis: Rarely, patients receiving ACE inhibitors during low-density lipoprotein (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.
Cough: Cough has been reported with the use of ACE-inhibitors. Characteristically, the cough is non-productive, persistent, and resolves after discontinuation of therapy. ACE-inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Surgery/anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Lisinopril blocks angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.
Aortic stenosis/Hypertrophic cardiomyopathy: As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded. These cases generally involved patients with collagen vascular disease and renal disease.
Hyperkalaemia
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Lisinopril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, 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 (see section 4.5).
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 (see 4.5 Interaction with other medicinal products and other forms of interaction)
Lithium
The combination of lithium and Lisinopril is generally not recommended (see section 4.5).
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
General
Lisinopril should not be used in patients with aortic stenosis, cor pulmonale or outflow tract obstruction.
Where Lisinopril is used as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response.
4.5 Interaction with other medicinal products and other forms of interaction
When Lisinopril is combined with other antihypertensive agents such as beta-blockers and diuretics, the antihypertensive effect is usually additive.
Lisinopril reduces the development of thiazide induced hypokalaemia and hyperuricaemia.
Lisinopril has been used with nitrates without significant clinical interaction.
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.
As Lisinopril may reduce the elimination of lithium, serum levels of lithium should be monitored if lithium salts are administered.
Plasma potassium usually remains within normal limits, although a few cases of hyperkalaemia have occurred. If Lisinopril is given with a diuretic, the likelihood of diuretic-induced hypokalaemia may be lessened. Lisinopril may elevate plasma potassium levels in patients with renal failure. Potassium supplements, potassiumsparing diuretics and potassium-containing salt substitutes are not recommended.
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. Long term controlled clinical trials with lisinopril have not confirmed these findings and do not preclude the use of lisinopril in diabetic patients. It is advised, however that these patients be monitored.
Alcohol may enhance the hypotensive effect of any antihypertensive.
Narcotic drugs/antipsychotics: Postural hypotension may occur with ACE inhibitors.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids, or procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia.
Antacids: induce decreased bioavailability of ACE inhibitors.
Sympathomimetics: may reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.
Ciclosporin: increase the risk of hyperkalaemia with ACE inhibitors.
4.6 Pregnancy and lactation
Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (See section 5.3.). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Lactation
Because no information is available regarding the use of Lisinopril during breastfeeding, Lisinopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects on ability to drive and use machines
Lisinopril can cause dizziness which could potentially affect the patient’s ability to drive or use machines.
4.8 Undesirable effects
The following undesirable effects have been observed and reported during treatment with Lisinopril and other ACE inhibitors with the following frequencies:
Very common (10%), common (1%, <10%), uncommon (0.1, <1%), rare (0.01, <0.1%), very rare (<0.01%) including isolated reports.
Blood and the lymphatic system disorders
Rare: decreases in haemoglobin, decreases in haematocrit
Very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia, lymphadenopathy, autoimmune disease
Metabolism and nutrition disorders
Very rare: Hypoglycaemia
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
Nervous system and psychiatric disorders
Common: dizziness, headache
Uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances Rare: mental confusion
Cardiac and vascular disorders
Common: orthostatic effects (including hypotension)
Uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see section 4.4), 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 (see section 4.4)
Skin and subcutaneous tissue disorders
Uncommon: rash, pruritus
Rare: hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see section 4.4), urticaria, alopecia, psoriasis Very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme
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
Safety data from clinical studies suggest that lisinopril is generally well tolerated in hypertensive paediatric patients, and that the safety profile in this age group is comparable to that seen in adults.
4.9 Overdose
Limited data are available for overdose in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.
The recommended treatment of overdose is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. If ingestion is recent, take measures aimed at eliminating Lisinopril (e.g. emesis, gastric lavage, administration of absorbents and sodium sulphate). Lisinopril may be removed from the general circulation by haemodialysis (see 4.4 Special warnings and Precautions for use). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors ATC code: C09AA03.
Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (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. While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.
The effect of Lisinopril on mortality and morbidity in heart failure has been studied by comparing a high dose (32.5 mg or 35 mg once daily) with a low dose (2.5 mg or 5 mg once daily). In a study of 3164 patients, with a median follow-up period of 46 months for surviving patients, high dose Lisinopril produced a 12% risk reduction in the combined endpoint of allcause mortality and all-cause hospitalisation (p = 0.002) and an 8% risk reduction in all-cause mortality and cardiovascular hospitalisation (p = 0.036) compared with low dose. Risk reductions for all-cause mortality (8%; p = 0.128) and cardiovascular mortality (10%; p = 0.073) were observed. In a post-hoc analysis, the number of hospitalisations for heart failure was reduced by 24% (p=0.002) in patients treated with high-dose Lisinopril compared with low dose. Symptomatic benefits were similar in patients treated with high and low doses of Lisinopril.
The results of the study showed that the overall adverse event profiles for patients treated with high or low dose Lisinopril were similar in both nature and number. Predictable events resulting from ACE inhibition, such as hypotension or altered renal function, were manageable and rarely led to treatment withdrawal. Cough was less frequent in patients treated with high dose Lisinopril compared with low dose. In the GISSI-3 trial, which used a 2x2 factorial design to compare the effects of Lisinopril and glyceryl trinitrate given alone or in combination for 6 weeks versus control in 19,394 patients who were administered the treatment within 24 hours of an acute myocardial infarction, Lisinopril produced a statistically significant risk reduction in mortality of 11% versus control (2p=0.03). The risk reduction with glyceryl trinitrate was not significant but the combination of Lisinopril and glyceryl trinitrate produced a significant risk reduction in mortality of 17% versus control (2p=0.02).
In the sub-groups of elderly (age > 70 years) and females, pre-defined as patients at high risk of mortality, significant benefit was observed for a combined endpoint of mortality and cardiac function. The combined endpoint for all patients, as well as the high-risk sub-groups at 6 months, also showed significant benefit for those treated with Lisinopril or Lisinopril plus glyceryl trinitrate for 6 weeks, indicating a prevention effect for Lisinopril. As would be expected from any vasodilator treatment, increased incidences of hypotension and renal dysfunction were associated with Lisinopril treatment but these were not associated with a proportional increase in mortality.
In a double-blind, randomised, multicentre trial which compared Lisinopril with a calcium channel blocker in 335 hypertensive Type 2 diabetes mellitus subjects with incipient nephropathy characterised by microalbuminuria, Lisinopril 10 mg to 20 mg administered once daily for 12 months, reduced systolic/diastolic blood pressure by 13/10 mmHg and urinary albumin excretion rate by 40%. When compared with the calcium channel blocker, which produced a similar reduction in blood pressure, those treated with Lisinopril showed a significantly greater reduction in urinary albumin excretion rate, providing evidence that the ACE inhibitory action of Lisinopril reduced microalbuminuria by a direct mechanism on renal tissues in addition to its blood pressure-lowering effect.
Lisinopril treatment does not affect glycaemic control as shown by a lack of significant effect on levels of glycated haemoglobin (HbA1c).
In a clinical study involving 115 paediatric patients with hypertension, aged 6-16 years, patients who weighed less than 50 kg received either 0.625 mg, 2.5 mg or 20 mg of lisinopril once a day, and patients who weighed 50 kg or more received either 1.25 mg, 5 mg or 40 mg of lisinopril once a day. At the end of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent manner with a consistent antihypertensive efficacy demonstrated at doses greater than 1.25 mg.
This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mm Hg more in patients randomized to placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, and race
5.2 Pharmacokinetic properties
In clinical studies, following oral administration of lisinopril, peak serum concentrations occur within about 6-8 hours. On multiple dosing lisinopril has an effective half-life accumulation of 12.6 hours.
Declining serum concentrations exhibited a prolonged terminal phase which did not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and was not proportional to dose. Lisinopril did not appear to bind to other serum proteins.
The disposition of lisinopril in patients with renal insufficiency was similar to that in patients with normal renal function until the glomercular filtration rate reached 30 ml/min or less.
Peak and trough lisinopril levels then increased, time to peak concentrations was increased and time to steady state was sometimes prolonged. Lisinopril can be removed by dialysis.
In elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations than those seen in young healthy adults given a similar dose. In another study, single daily doses of lisinopril 5 mg were given for 7 consecutive days to young and elderly healthy volunteers and to elderly patients with congestive heart failure. Maximum serum concentrations of lisinopril on Day 7 were higher in the elderly volunteers than in the young and still higher in the elderly patients with congestive heart failure. These findings are consistent with the concept that drugs of low lipid solubility (such as lisinopril) achieve a reduced volume of distribution in the elderly, who have decreased lean body mass/fat ratio: and renal clearance of lisinopril was decreased in the elderly, particularly in the presence of congestive heart failure.
Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25% with interpatient variability (6-60%) at all doses tested (5-80 mg). Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine. Lisinopril absorption is not affected by the presence of food in the gastrointestinal tract.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.
Paediatrics
The pharmacokinetic profile of lisinopril was studied in 29 paediatric hypertensive patients, aged between 6 and 16 years, with a GFR above 30 ml/min/1.73m2. After doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours, and the extent of absorption based on urinary recovery was about 28%.
These values are similar to those obtained previously in adults.
AUC and Cmax values in children in this study were consistent with those observed in adults.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Angiotensin-converting enzyme inhibitors, as a class, have been shown to induce adverse effects on the late fetal development, resulting in fetal death and congenital effects, in particular affecting the skull. Fetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the fetal renin-angiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in fetal-placental blood flow and oxygen/nutrients delivery to the fetus.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate anhydrous
Magnesium stearate
Starch, pregelatinised
Mannitol
Povidone .
Maize starch Iron oxide red (E172)
Iron oxide yellow (E 172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package.
6.5 Nature and contents of container
Polyvinyl chloride/aluminium blister packs of 28 tablets containing 14 tablets on each blister packed in a printed cardboard carton.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
ALKALOID-INT d.o.o.
Slandrova ulica 4, 1231 Ljubljana - Crnuce Slovenia
8 MARKETING AUTHORISATION NUMBER(S)
PL 34088/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18/06/2008
10 DATE OF REVISION OF THE TEXT
06/10/2011