LISINOPRIL 1 MG / ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Lisinopril 1 mg/ml oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of oral solution contains 1 mg lisinopril (as lisinopril dihydrate).

Excipients with known effect

Each ml contains 0.24 mg of sodium and 1.5 mg of benzoate salt

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution.

The oral solution is clear and colourless with a sweet taste

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hypertension

Treatment of hypertension.

Treatment of symptomatic heart failure.

Short-term (6 weeks) treatment of haemodynamically stable patients within 24 hours of an acute myocardial infarction.

Treatment of renal disease in hypertensive patients with Type 2 diabetes mellitus and incipient nephropathy (see section 5.1).

4.2 Posology and method of administration

Lisinopril 1 mg/ml oral solution should be administered orally in a single daily dose. As with all other medication taken once daily, Lisinopril 1 mg/ml oral solution should be taken at approximately the same time each day. The absorption of Lisinopril 1 mg/ml oral solution is not affected by food.

Mixing with food or drinks has not been studied, and any mixing with food and drinks is therefore the responsibility of the health care professional or the user.

The dose should be individualised according to patient profile and blood pressure response (see section 4.4).

Lisinopril 1 mg/ml oral solution may be used as monotherapy or in combination with other classes of antihypertensive therapy (see sections 4.3, 4.4, 4.5 and 5.1).

Starting dose

In patients with hypertension the usual recommended starting dose is 10 mg. Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation, or severe hypertension) may experience an excessive blood pressure fall following the initial dose. A starting dose of 2.5–5 mg is recommended in such patients and the initiation of treatment should take place under medical supervision. A lower starting dose is required in the presence of renal impairment (see Table 1 below).

Maintenance dose

The usual effective maintenance dosage is 20 mg administered in a single daily dose. In general, if the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks on a certain dose level, the dose can be further increased. The maximum dose used in long-term, controlled clinical trials was 80 mg/day.

Diuretic-treated patients

Symptomatic hypotension may occur following initiation of therapy with Lisinopril 1 mg/ml oral solution. This is more likely in patients who are being treated currently with diuretics. Caution is recommended therefore, since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with Lisinopril 1 mg/ml oral solution. In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Lisinopril 1 mg/ml oral solution should be initiated with a 5 mg dose.

Renal function and serum potassium should be monitored. The subsequent dosage of Lisinopril 1 mg/ml oral solution should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed (see section 4.4 and section 4.5).

Dosage adjustment in renal impairment

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

Table 1 Dosage adjustment in renal impairment

* Dosage and/or frequency of administration should be adjusted depending on the blood pressure response.

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

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 5mg 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.

In patients with symptomatic heart failure, Lisinopril 1 mg/ml oral solution should be used as adjunctive therapy to diuretics and, where appropriate, digitalis or beta-blockers. Lisinopril 1 mg/ml oral solution may be initiated at a starting dose of 2.5 mg once a day, which should be administered under medical supervision to determine the initial effect on the blood pressure.

The dose of Lisinopril 1 mg/ml oral solution should be increased:

By increments of no greater than 10 mg

At intervals of no less than 2 weeks

To the highest dose tolerated by the patient up to a maximum of 35 mg once daily.

Dose adjustment should be based on the clinical response of individual patients.

Patients at high risk of symptomatic hypotension, e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with Lisinopril 1 mg/ml oral solution. Renal function and serum potassium should be monitored (see section 4.4).

Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers. Intravenous or transdermal glyceryl trinitrate may be used together with Lisinopril 1 mg/ml oral solution.

Starting dose (first 3 days after infarction)

Treatment with Lisinopril 1 mg/ml oral solution may be started within 24 hours of the onset of symptoms. Treatment should not be started if systolic blood pressure is lower than 100 mm Hg. The first dose of Lisinopril 1 mg/ml oral solution is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily.

Patients with a low systolic blood pressure (120 mm Hg or less) when treatment is started or during the first 3 days after the infarction should be given a lower dose – 2.5 mg orally (see section 4.4).

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

Maintenance dose

The maintenance dose is 10 mg once daily. If hypotension occurs (systolic blood pressure less than or equal to 100 mm Hg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mm Hg for more than1 hour) Lisinopril 1 mg/ml oral solution should be withdrawn.

Treatment should continue for 6 weeks and then the patient should be reevaluated.

Patients who develop symptoms of heart failure should continue with Lisinopril 1 mg/ml oral solution (see section 4.2).

In hypertensive patients with type 2 diabetes mellitus and incipient nephropathy, the dose is 10 mg Lisinopril 1 mg/ml oral solution once daily which can be increased to 20 mg once daily, if necessary, to achieve a sitting diastolic blood pressure below 90 mm Hg.

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

There is limited efficacy and safety experience in hypertensive children >6 years old, but no experience in other indications (see section 5.1). Lisinopril 1 mg/ml oral solution is not recommended in children in other indications than hypertension.

Lisinopril 1 mg/ml oral solution is not recommended in children below the age of 6, or in children with severe renal impairment (GFR <30 ml/min/1.73m2) (see section 5.2).

In clinical studies, there was no age-related change in the efficacy or safety profile of the drug. When advanced age is associated with decrease in renal function, however, the guidelines set out in Table 1 should be used to determine the starting dose of Lisinopril

1 mg/ml oral solution. Thereafter, the dosage should be adjusted according to the blood pressure response.

There is no experience regarding the administration of Lisinopril 1 mg/ml oral solution in patients with recent kidney transplantation. Treatment with

Lisinopril 1 mg/ml oral solution is therefore not recommended.

4.3 Contraindi­cations

Hypersensitivity to Lisinopril or to any of the excipients listed in section 6.1 or to any other angiotensin converting enzyme (ACE) inhibitor

History of angioedema associated with previous ACE inhibitor therapy

Hereditary or idiopathic angioedema

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

The concomitant use of Lisinopril 1 mg/ml oral solution 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).

Concomitant use with sacubitril/val­sartan therapy. Lisinopril must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see also sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Lisinopril 1 mg/ml oral solution, hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see section 4.5 and section 4.8). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Lisinopril 1 mg/ml oral solution. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Lisinopril 1 mg/ml oral solution may be necessary.

Treatment with Lisinopril 1 mg/ml oral solution must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mm Hg or lower, or those in cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mm Hg or lower. If hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour) then Lisinopril 1 mg/ml oral solution should be withdrawn.

As with other ACE inhibitors, Lisinopril 1 mg/ml oral solution should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.

In cases of renal impairment (creatinine clearance <80 ml/min), the initial Lisinopril 1 mg/ml oral solution dosage should be adjusted according to the patient’s cre­atinine clearance (see Table 1 in section 4.2), and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.

In patients with heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.

In some patients with bilateral renal artery stenosis or with a stenosis of the artery to a solitary kidney, who have been treated with angiotensin-converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration.

Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of Lisinopril

1 mg/ml oral solution therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Lisinopril 1 mg/ml oral solution may be required.

In acute myocardial infarction, treatment with Lisinopril 1 mg/ml oral solution 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 1 mg/ml oral solution (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre-treatment value) then the physician should consider withdrawal of Lisinopril 1 mg/ml oral solution.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin-converting enzyme inhibitors, including lisinopril. This may occur at any time during therapy. In such cases, Lisinopril 1 mg/ml oral solution should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients.

Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angioedema associated with laryngealoedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patient’s airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.

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

Concomitant use of ACE inhibitors with sacubitril/val­sartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/val­sartan must not be initiated earlier than 36 hours after the last dose of lisinopril. Treatment with lisinopril must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see sections 4.3 and 4.5).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or different class of antihypertensi­ve agent.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicinal product.

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 1 mg/ml oral solution who develop jaundice or marked elevations of hepatic enzymes should discontinue Lisinopril 1 mg/ml oral solution and receive appropriate medical followup.

Neutropenia/a­granulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Lisinopril 1 mg/ml oral solution should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Lisinopril 1 mg/ml oral solution is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Dual blockage of the renin-angiotensin-aldosterone system (RAAS) with

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.

Angiotensin-converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients. As with other ACE inhibitors, Lisinopril 1 mg/ml oral solution may be less effective in lowering blood pressure in black patients than in non-blacks, possibly because of a higher prevalence of low renin states in the black hypertensive population.

Cough 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.

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Lisinopril 1 mg/ml oral solution may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

ACE inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole also known as trimethoprim/sul­famethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalaemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5).

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 section 4.5).

Lithium

The combination of lithium and Lisinopril 1 mg/ml oral solution is generally not recommended (see section 4.5).

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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).

This medicinal product contains less than 1 mmol sodium (23 mg) per ml oral solution, that is so to say essentially ‘sodium-free’.

This medicinal product contains 1.5 mg benzoate salt in each ml oral solution.

Increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus (non-conjungated bilirubin deposits in the brain tissue).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of ACE inhibitors with sacubitril/val­sartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).

When Lisinopril 1 mg/ml oral solution is combined with other antihypertensive agents (e.g. glyceryl trinitrate and other nitrates, or other vasodilators), additive falls in blood pressure may occur.

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).

When a diuretic is added to the therapy of a patient receiving Lisinopril 1 mg/ml oral solution 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 1 mg/ml oral solution is added. The possibility of symptomatic hypotension with Lisinopril 1 mg/ml oral solution can be minimised by discontinuing the diuretic prior to initiation of treatment with Lisinopril 1 mg/ml oral solution (see section 4.4 and section 4.2).

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with lisinopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when lisinopril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sul­famethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of lisinopril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

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.

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 may reduce the antihypertensive effects of ACE inhibitors.

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.

Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.

Lisinopril 1 mg/ml oral solution may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates.

Patients taking concomitant co-trimoxazole (trimethoprim/sul­famethoxazole) may be at increased risk for hyperkalaemia (see section 4.4).

4.6 Fertility, 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 contra-indicated 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 inhibitors therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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, skullossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to ACE inhibitors 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).

Because no information is available regarding the use of lisinopril during breast-feeding, Lisinopril 1 mg/ml oral solution is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

There are no data available regarding potential effects of lisinopril on human fertility.

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 lisinopril 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).

Rare:         decreases in haemoglobin, decreases in haematocrit.

Very rare:    bone marrow depression, anaemia, thrombocytopenia,

leukopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia, lymphadenopathy, autoimmune disease.

Very rare:    hypoglycaemia.

Common:    dizziness, headache.

Uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances, hallucinations.

Rare:         mental confusion, olfactory disturbance.

Frequency

not known:   depressive symptoms, syncope.

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.

Common:    cough.

Uncommon: rhinitis.

Very rare:    bronchospasm, sinusitis, allergic alveolitis/eo­sinophilic

pneumonia.

Common:    diarrhoea, vomiting.

Uncommon:  nausea, abdominal pain and indigestion.

Rare:        dry mouth.

Very rare:    pancreatitis, intestinal angioedema, hepatitis – either

hepatocellular orcholestatic, jaundice and hepatic failure (see section 4.4).

Uncommon: rash, pruritus.

Rare:          urticaria, alopecia, psoriasis, hypersensitivi­ty/angioneuro­tic

oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see section 4.4).

Very rare: sweating, 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 anti-nuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.

Common:    renal dysfunction.

Rare:         uraemia, acute renal failure.

Very rare:     oliguria/a­nuria.

Rare:         syndrome of inappropriate antidiuretic hormone secretion

(SIADH).

Uncommon: impotence.

Rare:         gynae­comastia.

General disorders and administration site conditions Uncommon: fatigue, asthenia.

Uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia.

Rare:         increases in serum bilirubin, hyponatraemia.

5   PHARMACOLOGICAL PROPERTIES

6.1 List of excipients

Glycerol (E 422)

Hydroxyethylce­llulose

Sodium benzoate (E 211)

Citric acid monohydrate (E 330)

Purified water

6.2 Incompati­bilities

Not applicable.

6.3 Shelf life

3 years

Use within 30 days of opening.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

150 ml amber (type III) glass bottle with a tamper-evident PP/LDPE closure and a double-ended 5 ml/2.5ml measuring spoon (PS).

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Essential Pharmaceuticals Limited,

7 Egham Business Village,

Crabtree Road, Egham,

Surrey, TW20 8RB,

United Kingdom