Lisinopril 10mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lisinopril 10mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Lisinopril 10mg as Lisinopril dihydrate.
For excipients see section 6.1
3 PHARMACEUTICAL FORM
Tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension: all grades of essential and renovascular hypertension. Lisinopril Tablets may be used alone or with other antihypertensives (see sections 4.3, 4.4, 4.5 and 5.1).
Congestive heart failure: Lisinopril may be taken as an additional treatment with non-potassium-sparing diuretics and, where appropriate digoxin or digitoxin. Commencement of Lisinopril treatment should be under close medical supervision. Severe heart failure should be treated in hospital.
Acute myocardial infarction: Lisinopril may be used to treat haemodynamically stable patients (ie who are not in cardiogenic shock and who have a systolic blood pressure greater than 100 mmHg). Lisinopril can be given within 24 hours of acute myocardial infarction to prevent left ventricular dysfunction, heart failure, and to increase survival prospects. Patients should also receive the standard recommended treatments for this condition, ie aspirin, a beta-blocker and thrombolytics.
4.2 Posology and method of administration
Lisinopril Tablets are for oral administration only.
Lisinopril Tablets should be taken as a single daily dose at approximately the same time each day. As absorption of Lisinopril Tablets in unaffected by food, the tablets may be taken before, during or after meals.
Adults and the elderly
Hypertension
Blood pressure should be measured just before the next dose to determine whether or not the dosage needs to be titrated.
Patients taking diuretics for hypertension should have the diuretic discontinued if possible, or the dose reduced, 2 to 3 days before beginning treatment with Lisinopril. If required, treatment with the diuretic may be resumed again later. See also section 4.4 Special Warnings and Precautions for Use.
Essential and renovascular hypertension: the initial recommended dose is 2.5mg once daily. This should be adjusted to achieve optimal blood pressure control. If the required therapeutic effect cannot be achieved in 2-4 weeks on a particular dose level, the dose may be further increased.
The initial 2.5mg dose rarely achieves a satisfactory therapeutics response. The usually effective dose range is 10-20mg once daily. The maximum recommended dose is 40mg once daily.
Use in the elderly: as age does not appear to affect the safety or efficacy of Lisinopril, the normal starting dose is recommended.
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.
Congestive Heart Failure:
Lisinopril may be used as an adjunct with non-potassium sparing diuretics, with or without digoxin or digitoxin. If possible, the dose of diuretic should be reduced before starting treatment with Lisinopril.
Blood pressure and renal function should be monitored closely before starting and during treatment with Lisinopril as severe hypotension and, more rarely, consequent renal failure have been reported with angiotensina-converting enzyme (ACE) inhibitors. If hypotension becomes evident after the first dose of Lisinopril, this does not preclude subsequent careful dose adjustment with the drug following effective treatment of the hypotension.
Treatment should be started under close medical supervision. Patients with severe or unstable congestive heart failure, or patients at high risk should have their treatment started in hospital under close medical supervision. High risk patients are those on high dose loop diuretics (e.g. >80mg Frusemide), those on multiple diuretic therapy, patients with hypovolaemia, hyponatraemia (serum sodium <130mmol/1), or systolic blood pressure <90 mmHg, patients on high dose vasodilators, patients with renal impairment, ie with a serum creatinine >150micromol/1, or elderly patients aged 70 years +.
The recommended starting dose is 2.5mg with subsequent dose titration. Maintenance dose: the dose should be gradually increased, depending on the patient’s response, to the usual maintenance dose (5-20mg). Dose adjustment should be based on the clinical response of the patient and may be made at 2-4 weekly intervals.
Acute myocardial infarction:
Treatment with Lisinopril may be started within 24 hours of the onset of symptoms of acute myocardial infarction. Treatment must not be initiated in patients at risk of further serious haemodynamic deterioration after treatment with a vasodilator, ie patients with a systolic blood pressure of 100 mmHg or less, or patients with cardiogenic shock.
The usual dosing is as follows. The first dose is 5mg given orally, followed by 5mg after 24 hours, 10mg after 48 hours and then 10mg once daily thereafter.
During the first 3 days following an acute myocardial infarction, patients with a low systolic blood pressure (120 mmHg or less) should be given a lower dose of 2.5mg orally. If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg), a daily maintenance dose of 5mg may be given with temporary reductions to 2.5mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour), treatment with Lisinopril should be withdrawn.
Dosing should continue for 6 weeks.
The benefit seems 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 taking Lisinopril (see Congestive heart failure above).
Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate.
Patients with impaired renal function:
Lisinopril should be used with caution in patients with renal insufficiency as the drug is excreted via the kidneys. A full evaluation of the patient including assessment of renal function should be made prior to initiation of therapy and during treatment.
Dose titration should be done carefully and patients may require lower or less frequent doses.
Lisinopril is dialyzable. 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
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).
Method of administration: oral.
4.3 Contraindications
Lisinopril is contra-indicated in the following circumstances:
- second and third trimesters of pregnancy (see sections 4.4 and 4.6).
- in patients hypersensitive to Lisinopril or any of the other ingredients;
- in patients who have previously had angioneurotic oedema following treatment with ACE inhibitors; and
- in patients with hereditary or idiopathic angioedema.
The concomitant use of lisinopril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).
4.4 Special warnings and precautions for use
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).
Use of lisinopril is not recommended during breast-feeding.
Evaluation of the patient should include assessment of renal function prior to commencement of and during treatment.
Afro-Caribbean patients may show a reduced therapeutic response where Lisinopril is used alone for treatment of hypertension.
Lisinopril should not be used in patients with aortic stenosis, outflow tract obstruction, or cor pulmonale. If Lisinopril is used in hypertrophic cardiomyopathy, extreme caution should be used.
Angioneurotic oedema in association with Lisinopril treatment has been rarely reported. If this occurs treatment should be withdrawn immediately. If the swelling is limited to the lips, mouth and face, it will usually settle without the need for intervention, although symptomatic relief may be obtained with antihistamines. Laryngeal oedema may be fatal. If the tongue, glottis or larynx swells, obstruction of the airways is likely and emergency treatment should be instituted immediately. It is important to maintain a patient airway and treatment may include adrenaline/epinepherin. The patient should be observed closely until all symptoms have totally subsided.
There is a greater frequency of angioedema cases in black patients then in nonblack patients when taken ACE inhibitors.
Surgery/anaesthesia: Lisinopril blocks angiotensin II formation secondary to compensatory renin release in patients undergoing major surgery or having anaesthesia with hypotension producing agents. Resulting hypotension may be corrected by volume expansion.
Impaired renal function: Lisinopril should be used cautiously in patients with renal dysfunction, as they may require reduced or less frequent does. Routine close monitoring of renal function should be performed in this patient group. In most patients renal function will not change, or may get better (see also section 4.8 Undesirable Effects).
Kidney failure has been documented after ACE inhibitor treatment. However it appears to have been reported principally in those who have severe congestive heart failure or underlying kidney disease (including renal artery stenosis). Renal failure can usually be reversed if it is recognised early and appropriate treatment is given.
An increase in blood urea and serum creatinine have been reported in some of those treated with ACE inhibitors and who also have bilateral renal artery stenosis or stenosis of the artery to a single kidney, particularly in patients with renal insufficiency. These effects often disappear once treatment has stopped. In patients with renovascular hypertension there is an increased risk of severe hypotension and renal insufficiency. Therefore, such patients should be monitored closely at the start of treatment and begin on a low dose with gradual dose increases. As diuretics may contribute to the risk, they should be withdrawn and kidney function should be checked during the first few weeks of Lisinopril treatment.
Increases in blood urea and creatinine have occurred in some hypertensive patients without pre-existing kidney disease taking Lisinopril with a diuretic. If this occurs, the dosage of Lisinopril should be reduced and/or the diuretic discontinued. The possibility of underlying renal artery stenosis should be considered.
In acute myocardial infarction: Lisinopril treatment should not be started in patients with evidence of renal dysfunction, ie serum creatinine concentration greater than 177 micromol/l and/or proteinuria exceeding 500mg/24 hours. If renal dysfunction develops during treatment with Lisinopril (serum creatinine > 265 micromol/l or a doubling from the pre-treatment value) then the clinician should consider withdrawing Lisinopril.
Lisinopril treatment must not be started in acute myocardial infarction patients at risk of further serious haemodynamic deterioration following treatment with a vasodilator (ie patients with a systolic blood pressure of < 100 mmHg or cardiogenic shock).
Dialysis patients: Use of high flux dialysis membranes (eg. AN69) should be avoided because there have been reports of patients experiencing anaphylactoid reactions when also treated with an ACE inhibitor.
Hypotension: Rare cases of symptomatic hypotension have been observed in uncomplicated hypertensive patients. This is more likely to occur in patients who have been volume-depleted as a result of taking diuretics, restricting dietary salt, being on dialysis, or vomiting and diarrhoea. Discontinuance of or reduction in the dosage of diuretics, where used, 2 to 3 days before start of treatment with Lisinopril will reduce the possibility of this happening.
Reports of severe hypotension have been made 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. Initiation of treatment and dose adjustment should be monitored under close clinical supervision in patients at risk. If hypotension develops, treatment with Lisinopril should be stopped, and patients should be placed supine. Oral fluids or normal saline IV may be necessary to replenish fluid volumes. Associated bradycardia may require administration of intravenous atropine. Treatment with Lisinopril may be restarted with careful dose titration when effective blood volume and pressure has been restored.
Additional lowering of systemic blood pressure may occur with Lisinopril in some patients with congestive heart failure with normal or low blood pressure. If the hypotension becomes symptomatic, the dose may need to be reduced or discontinued.
If hypotension becomes manifest after the initial dose of Lisinopril, this does that preclude subsequent careful dose adjustment with the drug after the hypotension has become effectively managed.
Caution and close supervision many also apply to patients with ischaemic heart and cerebrovascular disease as severe hypotension in these patients could result in a heart attack or cerebrovascular accident.
Cough: There have been reports of non productive, persistent cough that resolves on the cessation of treatment when taking ACE inhibitors. This cough should be regarded as part of the differential diagnosis of cough.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
4.5 Interaction with other medicinal products and other forms of interaction
Desensitisation therapy
Patients receiving ACE inhibitors during desensitisation treatment (eg hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they reappeared on inadvertent rechallenge.
Beta-blockers
The antihypertensive effects of Lisinopril may be enhanced if combined with beta-blockers. Lisinopril minimises the development of thiazide-induced hypokalaemia and hyperuricaemia.
Diuretics
When a diuretic is added to the therapy of a patient receiving Lisinopril the antihypertensive effect is usually additive.
Patients already on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when Lisinopril is added. The possibility of symptomatic hypotension with Lisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with Lisinopril (see section 4.4 and section 4.2).
Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes
Although in clinical trials, serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients. Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium - containing salt substitutes. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. If Lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia may be ameliorated.
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of Lisinopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).
Gold
Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.
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.
Other antihypertensive agents
Concomitant use of these agents may increase the hypotensive effects of Lisinopril. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Tricyclic antidepressants / Antipsychotics / Anaesthetics
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Antidiabetics
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates
Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics and/or nitrates.
4.6 Pregnancy and lactation
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
When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.
4.8 Undesirable effects
The following undesirable effects have been observed and reported during treatment with Zestril and other ACE inhibitors with the following frequencies: Very common (> 1/10), common (> 1/100 to <1/10), uncommon (> 1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Blood and the lymphatic system disorders
rare: decreases in haemoglobin, decreases in haematocrit
very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia, lymphadenopathy, autoimmune disease
Metabolism and nutrition disorders
very rare: hypoglycaemia
Nervous system and psychiatric disorders
common: dizziness, headache
uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances
rare: mental confusion
frequency not known: depressive symptoms, syncope
Cardiac and vascular disorders
common: orthostatic effects (including hypotension)
uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (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, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see section 4.4)
rare: urticaria, alopecia, psoriasis
very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma
A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.
Renal and urinary disorders
common: renal dysfunction
rare: uraemia, acute renal failure
very rare: oliguria/anuria
Reproductive system and breast disorders
uncommon: impotence rare: gynaecomastia
General disorders and administration site conditions
uncommon: fatigue, asthenia
Investigations
uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia
rare: increases in serum bilirubin, hyponatraemia
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.
The use of high-flux polyacrylonitrile dialysis membrane should be avoided (see Section 4.4 Special Warning 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
ATC Code: C09A A03 (ACE Inhibitor)
Lisinopril inhibits angiotensin-converting enzyme (ACE) that catalyses the conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor peptide that also stimulates aldosterone secretion by the adrenal cortex. Owing to the inhibition of the angiotensin converting enzyme (ACE) there are lower amounts of angiotensin II that in turn lessens vasopressor activity decreases aldosterone secretion. The reduction of aldosterone may result in a rise in the serum potassium concentration.
The inhibition of the renin-aldosterone system is believed to be the mechanism by which Lisinopril decreases blood pressure, although even in those patients who have low rennin hypertension, Lisinopril lowers blood pressure. ACE is identical to Kinase II that is an enzyme that degrades bradykinin. It is thought that raised levels of bradykinin, a potent vasodilatory peptide, may be a factor in the therapeutic effect of Lisinopril.
ACE inhibitors may have a smaller effect on blood pressure in black hypertensive patients than in non-black hypertensive patients.
In a clinical study involving 115 paediatric patients with hypertension, aged 616 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.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
5.2 Pharmacokinetic properties
After Oral administration, Lisinopril is absorbed slowly, peak plasma levels occurring in approximately 6-8 hours. Absorption and time to peak plasma concentration are unaffected if food is also consumed. Mean absorption is 25% of the administrated dose but this is variable from 6-60%. Lisinopril does not bind significantly to plasma proteins. Following multiple dosing, the normal elimination half-life of Lisinopril is approximately 12 hours. Lisinopril is not metabolised and unchanged drug is excreted in the urine (30%) and faeces (70%).
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/1.73m . 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.
Preclinical safety data
5.3
There are no preclinical safety data of relevance to the prescriber.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol, calcium hydrogen phosphate dihydrate, pregelatinised maize starch, croscarmellose sodium and magnesium stearate.
6.2 Incompatibilities
None Known.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C
6.5 Nature and contents of container
i) Polypropylene container with desiccant and a low density polyethylene snap-on lid. Pack size: 50 tablets; or
ii) Aluminium/PVC blister strips in an outer cardboard box. Pack size: 28 tablets.
6.6
Special precautions for disposal
None.
7
MARKETING AUTHORISATION HOLDER
Momingside Healthcare Ltd 115 Narborough Road Leicester LE30PA UK
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MARKETING AUTHORISATION NUMBER(S)
PL 20117/0072
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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12/11/2001
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DATE OF REVISION OF THE TEXT
12/02/2015