2.     QUALITATIVE AND QUANTITATIVE COMPOSITION

For a full list of excipients, see section 6.1.

4.1 Therapeutic indications

Vascace is indicated in for the treatment of all grades of essential hypertension. 

Vascace is also indicated in for the treatment of chronic heart failure, usually as an adjunctive therapy with digitalis and/or diuretics 
4.2 Posology and method of administration

Special Dosage Instructions:

Essential hypertension

Hypertension: The recommended initial dosage is a 1mg tablet once a daydose is 1 mg/day.  Blood pressure should be assessed, and dosage adjusted individually in accordance with the blood pressure response.  The usual dose range of Vascace is 2.5 to 5.0 mg once daily.Dosage should be adjusted individually in accordance with the blood pressure response until control is achieved.  Most patients can be maintained on 1.0 - 2.5mg/day.  If the blood pressure is not adequately controlled with 5mg Vascace once daily, a low dose of a non-potassium-sparing diuretic may be administered concomitantly to enhance the anti-hypertensive effect.

Renovascular hypertension

Safety and efficacy of Vascace in the treatment of renovascular hypertension have not been established to date and therefore its use is not recommended in this patient group.

Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, salt and/or volume depletion, cardiac decompensation or severe hypertension) may experience an excessive drop in blood pressure following the initial dose. A lower starting dose of 0.5 mg once daily is recommended in such patients and the initiation of treatment should take place under medical supervision.

Hypertensive patients receiving diuretics

Hypertensive patients receiving diuretics:  If possible, Tthe diuretic should be discontinued 2 to - 3 days before beginning therapy with Vascace to reduce the likelihood of symptomatic hypotension.  It may be resumed later if required.  The recommended starting dose in these patients is 0.5 mg once daily.

Chronic heart failure

Chronic heart failure:  Vascace can be used as adjunctive therapy with digitalis and/or diuretics in patients with chronic heart failure.  Therapy with Vascace should be initiated with at a recommended starting dose of 0.5 mg once daily under close medical supervision.  This dose should be maintained for about 1 week. If this dose has been well tolerated it may be increased in weekly intervals and according to the clinical status of the patient to 1.0 mg or 2.5 mg. The maximum daily dose for these patients is 5.0 mg. The posology recommendation for cilazapril in chronic heart failure is based on effects on symptomatic improvement, rather than on data showing that cilazapril reduces morbidity and mortality in this patient group (see section 5.1).The dose should be increased to the lowest maintenance dose of 1mg daily according to tolerability and clinical status.  Further titration within the usual maintenance dose of 1mg to 2.5mg daily should be carried out based on patient's response, clinical status and tolerability.  The usual maximum dose is 5mg once daily.

Results from clinical trials showed that clearance of cilazaprilat in patients with chronic heart failure is correlated with creatinine clearance.  Thus in patients with chronic heart failure and impaired renal function special dosage recommendation as given under "Impaired Renal Function" should be followed.

Impaired renal function

Patients with renal impairment: Reduced dosages may beare required for patients with renal impairment, depending on their creatinine clearance (see section 4.4Special warnings and precautions for use).

The following dosage schedules are recommended:

Table 1:  Recommended dosage schedule for patients with renal impairment

In patients requiring haemodialysis, Vascace should be administered on days when dialysis is not performed and the dosage should be adjusted according to blood pressure response.

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, they should be discontinued and renal function should be monitored during the first weeks of Vascace therapy.

Results from clinical trials showed that clearance of cilazapril was correlated with creatinine clearance in patients with chronic heart failure.  The special dosage recommendation should thus be followed in chronic heart failure patients with impaired renal function.

Liver cirrhosis

Liver cirrhosis:  In the unlikely event that patients with liver cirrhosis (but without ascites) should who require therapy for hypertension, treatment with cilazapril, it should be dosedinitiated with great caution not exceeding at a dose of 0.5 mg/day accompanied by careful monitoring of the blood pressure, or 0.25mg once daily, because significant hypotension may occur (see Pharmacokinetic properties).

Vascace is contraindicated in patients with ascites (see Contraindications).

Elderly

Elderly with hypertension: In the tTreatment of hypertension,with Vascace should be initiated with a dose between 0.5mg and 1.0 mg oncetablet daily.  Thereafter, the maintenance dose must be adapted to individual tolerability, response and clinical status.

In the treatment of chronic heart failure, Vascace should be initiated with a dose of 0.5mg daily. The maintenance dose of 1mg to 2.5mg must be adapted to individual tolerability, response and clinical status.

Elderly with chronic heart failure: In elderly patients with chronic heart failure on high diuretic dosage tThe recommended starting dose of Vascace 0.5 mg must be strictly followed.

Children

Children: Safety and efficacy in children have not been established. tTherefore, there is no recommendation for administration of cilazapril to children.

4.3 Contraindications

Hypersensitivity to cilazapril or any components of the product, or to other ACE inhibitors

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)

Vascace is contraindicated in patients who are hypersensitive to cilazapril, other ACE-inhibitors or any of the product excipients, in patients with ascites and in the second and third trimesters of pregnancy (see Special warnings and precautions for use and Pregnancy and lactation).

Vascace should not be used in patients with aortic stenosis, hypertrophic cardiomyopathy, outflow obstruction, or bilateral renal artery stenosis.

Vascace is also contraindicated in patients with a history of angioedema after treatment with other ACE-inhibitors.

4.4 Special warnings and precautions for use

(See also Special Dosage Instructions under Posology and method of administration.)

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).

Haemodyalysis/anaphylaxis

Although the mechanism involved has not been definitely established, there is clinical evidence that haemodialysis with polyacrylonitrile methallyl sulphate high-flux membranes (e.g. AN69), haemofiltration or LDL-apheresis, if performed in patients being treated with ACE-inhibitors, including cilazapril, can lead to the provocation of anaphylaxis/anaphylactoid reactions including life-threatening shock.  The above-mentioned procedures must therefore be avoided in such patients.

Hypersensitivity/angioneurotic oedema

Angioneurotic oedema has been reported rarely with ACE-inhibitors including Vascace.  In some cases symptoms have been observed up to 2 years after initiation of treatment.

Angioedema involving the tongue, glottis or larynx is likely to cause airways obstruction, and may be fatal.   If involvement of the face, lips, tongue, glottis and/or larynx occurs Vascace should be discontinued, replaced by an agent belonging to another class of drugs and appropriate therapy instituted without delay.  Emergency therapy should be given including, but not necessarily limited to, immediate intramuscular adrenalin (epinephrine) solution 1:1000 (0.3 to 0.5ml) or slow intravenous adrenalin 1mg/ml (observing dilution instructions) with control of ECG and blood pressure.  The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.

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.

Hypotension

ACE inhibitors may cause severe hypotension, especially when starting treatment. First-dose hypotension is most likely to occur in patients whose renin-angiotensin-aldosterone system is activated, such as in renovascular hypertension or other causes of renal hypoperfusion, sodium or volume depletion, or previous treatment with other vasodilators. These conditions can co-exist, particularly in severe heart failure.

Hypotension should be treated by placing the patient supine and volume expansion. Cilazapril may be continued once the patient is volume replete, but should be given at a lower dose or discontinued if hypotension persists.

At-risk patients should start treatment with cilazapril under medical supervision, with a low initial dose and careful titration. If possible, diuretic therapy should be discontinued temporarily.

Similar caution should be taken for patients with angina pectoris or cerebrovascular disease, in whom hypotension can cause myocardial or cerebral ischaemia.

Symptomatic hypotension

Occasionally, symptomatic hypotension has been reported with ACE-inhibitor therapy, particularly in patients with sodium or volume depletion in connection with conditions such as vomiting, diarrhoea, pre-treatment with diuretics, low sodium diet or after dialysis.

Patients with chronic heart failure, especially those taking high doses of loop diuretics, may experience a pronounced blood pressure decrease in response to ACE-inhibitors.  This should be treated by having the patient rest in the supine position and may require infusion of normal saline or volume expanders.  After volume repletion, Vascace therapy may be continued.  However, if symptoms persist, the dosage should be reduced or the drug discontinued.

Renal impairment

In patients with renal impairment, the dosage of cilazapril should be adjusted according to creatinine clearance (see section 4.2). Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.

ACE inhibitors have established renoprotective effects, but can cause reversible impairment of renal function in the setting of reduced renal perfusion, whether due to bilateral renal artery stenosis, severe congestive heart failure, volume depletion, hyponatraemia or high dosages of diuretics, and in those receiving treatment with NSAIDs. Preventive measures include withdrawing or temporarily withholding diuretics, beginning therapy with very small doses of ACE inhibitors, and cautious dose titration.

In patients with renal artery stenosis, activation of the renin-angiotensin-aldosterone system helps to maintain renal perfusion by causing constriction of the efferent arteriole. Hence, blockade of angiotensin II formation, and possibly also an increase in the formation of bradykinin, causes efferent arteriolar vasodilation resulting in a reduction in glomerular filtration pressure. Hypotension contributes further to a reduction in renal perfusion (see section 4.4 ‘Hypotension’).  As with other agents acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with cilazapril. Therefore, caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.

Reduced dosages may be required for patients with renal impairment, depending on their creatinine clearance (see Special Dosage Instruc­tions).    Treatment with ACE-inhibitors may produce increases in blood urea nitrogen and/or serum creatinine.   Such changes have also occasionally been observed in patients with normal renal function, particularly in those receiving concomitant diuretics.  Although these alterations are usually reversible upon discontinuation of Vascace and/or diuretic therapy, cases of severe renal dysfunction and, rarely, acute renal failure have been reported.

In this patient population, renal function should be monitored during the first weeks of therapy.

For haemodialysis using high-flux polyacrylonitrile (AN69) membranes please see above statement under the heading of Special warnings and precautions for use.

Hypersensitivity/angioedema

Angioedema has been associated with ACE inhibitors, with a reported incidence of 0.1-0.5%. Angioedema due to ACE inhibitors can present as recurrent episodes of facial swelling, which resolves on withdrawal, or as acute oropharyngeal edema and airways obstruction, which requires emergency treatment, and may be life-threatening. A variant form is angioedema of the intestine, which tends to occur within the first 24-48 hours of treatment. The risk of angioedema appears to be greater in black-skinned than non black-skinned patients. Patients with a history of angioedema unrelated to ACE inhibitors may be at greater risk.

Anaphylaxis

Haemodialysis: Anaphylaxis has occurred in patients dialysed with high flux membranes (e.g. AN 69) receiving ACE inhibitors. Consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent in such patients.

Low-density lipoproteins (LDL) apheresis: Patients receiving ACE inhibitors during LDL apheresis with dextran sulphate have experienced life-threatening anaphylaxis. This can be avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Desensitization: Anaphylactic reactions can occur in patients undergoing desensitization therapy with wasp or bee venom while receiving an ACE inhibitor. Cilazapril must be stopped before the start of desensitization therapy, and should not be replaced by a β- blocker.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death.  The mechanism of this syndrome is not understood.  Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Hepatic disorders

Single cases of liver function disorders, such as increased values of liver function tests (transaminases, bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis with or without necrosis have been reported. Patients receiving cilazapril who develop jaundice or marked elevations of hepatic enzymes should discontinue cilazapril and receive appropriate medical follow-up. In patients with liver cirrhosis (but without ascites) who require therapy for hypertension, cilazapril should be initiated at a lower dose and with great caution because significant hypotension may occur (see section 4.2). In patients with ascites, cilazapril administration is not recommended.

Serum potassium

Since serum potassium may increase in some patients with renal impairment, during ACE-inhibitor treatment, potassium levels should be monitored frequently at regular intervals, depending on renal function.  Potassium sparing diuretics should only be used with great caution during cilazapril therapy (see Interaction with other medicinal products and other forms of interaction and Pharmacodynamic properties).

Surgery/anaesthesia

The use of ACE-inhibitors in combination with anaesthetic drugs that also have blood-pressure-lowering effects, can produce arterial hypotension.  If this occurs, volume expansion by means of intravenous infusion or, if resistant to these measures - angiotensin II infusion is indicated.

Neutropenia

Rarely, Nneutropenia and agranulocytosis have been rarely reportedassociated with ACE -inhibitors, especially in patients with renal failure or.   Periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease and renal disease such as systemic lupus erythematosus and scleroderma, or in patients those receiving immunosuppressive therapy.  Periodic monitoring of leukocyte count is recommended in such patients., especially when they also have impaired renal function.

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 Contraindications and Pregnancy and lactation).

Serum potassium

ACE inhibitors can cause hyperkalemia 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) or potassium-sparing diuretics, and especially aldosterone antagonists, hyperkalemia can occur. Potassium-sparing diuretics should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored.

Diabetes

Administration of ACE inhibitors to patients with diabetes may potentiate the blood glucose-lowering effect of oral hypoglycaemic agents or insulin, especially in patients with renal impairment. In such patients, glucose levels should be carefully monitored during initiation of treatment with an ACE inhibitor.

Surgery/anaesthesia

Anaesthetic agents with blood pressure lowering effects can cause hypotension in patients receiving ACE inhibitors. Hypotension in this setting can be corrected with volume expansion.

Aortic stenosis/hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in patients with obstructive cardiac disorders (e.g. mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy), since cardiac output cannot increase to compensate for systemic vasodilation, and there is a risk of severe hypotension.

Lactose intolerance

Owing to the presence of lactose monohydrate, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ethnicity

ACE inhibitors are less effective as antihypertensives in patients with black skin colour. These patients also have a higher risk of angioedema.

 4.5 Interaction with other medicinal products and other forms of interaction

There was no increase in plasma digoxin concentrations when Vascace was administered concomitantly with digoxin.  No clinically significant drug interactions were observed when Vascace was administered concomitantly with nitrates, oral antidiabetics, H2-receptor blockers and coumarin anticoagulants.  No significant pharmacokinetic drug interactions between Vascace and furosemide or thiazides were noted.  An additive effect may be observed when Vascace is administered in combination with other blood-pressure-lowering agents.

Potassium-sparing diuretics administered together with Vascace can lead to increases in serum potassium, particularly in patients with renal impairment (see Special warnings and precautions for use and Pharmacodynamic properties).

As with other ACE-inhibitors, use of Vascace concomitantly with a non-steroidal anti-inflammatory drug (NSAID) may diminish the anti-hypertensive effect of Vascace.

Anaphylactic reactions can occur in patients undergoing desensitisation therapy with wasp or bee venom while receiving an ACE-inhibitor.  Cilazapril must therefore be interrupted before the start of desensitisation therapy.  Additionally, in this situation, cilazapril must not be replaced by a beta blocker.

Concomitant administration of ACE-inhibitors and anti-diabetic medicines (insulin, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with the risk of hypoglycaemia.  This phenomenon may be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

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 risk of lithium toxicity with ACE inhibitors.

Use of cilazapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.

Lithium should generally not be given with ACE-inhibitors.  ACE-inhibitors reduce the renal clearance of lithium and add a risk of lithium toxicity

Concomitant administration of allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide with ACE-inhibitors may lead to an increased risk of leucopenia.

Alcohol can enhance the hypotensive effect of ACE-inhibitors.

Other antihypertensive agents

An additive effect may be observed when cilazapril is administered in combination with other antihypertensive agents.

Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with cilazapril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, the combination of cilazapril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.

Diuretics (thiazide or loop diuretics)

Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with cilazapril (see section 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of cilazapril.

Tricyclic antidepressants/antipsychotics/anesthetics/narcotics

Concomitant use of certain anesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including aspirin ³ 3 g/day

When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

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 hypoglycemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.

Others

No clinically significant interactions were observed when cilazapril and digoxin, nitrates, coumarin anticoagulants, and H₂ receptor blockers were concomitantly administered.
4.6 Pregnancy and lactation

The use of ACE -inhibitors such as cilazapril is not recommended during the first trimester of pregnancy (see section 4.4Special warnings and precautions for use).   The use of ACE -inhibitors such as cilazapril is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4Contraindications and Special warnings and precautions for use).

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 also Preclinical safety data).   Should exposure to an ACE -inhibitors have occurred from the second trimester of pregnancy, ultrasound check examination 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 4.4Contraindications and Special warnings and precautions for use).

Lactation

Because no information is available regarding the use safety of Vascace cilazapril during breast-feeding, Vascace cilazapril 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

There are no studies on the effect of Vascace on the ability to drive.   When driving and vehicles or operating machines,machinery it should be taken into account that occasionally dizziness or and fatigue may occur, especially when starting therapy (see sections 4.4 and 4.8Undesirable effects). 

 4.8 Undesirable effects

(a) Summary of the safety profile

The most frequent drug-attributable adverse events observed in patients taking ACE inhibitors are cough, skin rash and renal dysfunction. Cough is more common in women and non-smokers. Where the patient can tolerate the cough, it may be reasonable to continue treatment. In some cases, reducing the dose may help.

Treatment-related adverse events severe enough to stop treatment occur in less than 5% of patients receiving ACE inhibitors.

(b) Tabulated list of adverse reactions

The following list of adverse reactions is derived from clinical trials and post-marketing data in association with cilazapril and/or other ACE inhibitors. Estimates of frequency are based on the proportion of patients reporting each adverse reaction during cilazapril clinical trials that included a total combined population of 7171 patients. Adverse reactions that were not observed during cilazapril clinical trials but have been reported in association with other ACE inhibitors or derived from post-marketing case reports are classified as ‘rare’.

Frequency categories are as follows:

Very common   ≥ 1/10

Common          ≥ 1/100 and < 1/10

Uncommon       ≥ 1/1,000 and < 1/100

Rare                 < 1/1,000

In most cases, undesirable effects are transient, mild or moderate in degree, and do not require discontinuation of therapy.   The most common adverse effects include dry cough, rash, hypotension, dizziness, fatigue, headache and nausea, dyspepsia and other gastrointestinal disturbances.

Blood and lymphatic system disorders:

RareVery rare (<1/10,000):

Neutropenia, agranulocytosisAgranulocytosis, neutropenia, thrombocytopenia, anaemia.

Immune system disorders

Uncommon

Angioedema (may involve the face, lips, tongue, larynx or gastrointestinal tract) (see section 4.4)

Rare

Anaphylaxis (see section 4.4)

Lupus-like syndrome (symptoms may include vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies, increased erythrocyte sedimentation rate, eosinophilia and leukocytosis)

Nervous system disorders

Very common (>1/10): Dizziness.

Common (>1/100, <1/10):

Headache.

Uncommon

Dysgeusia

Rare

Cerebral ischaemia, transient ischaemic attack, ischaemic stroke

Peripheral neuropathy

Cardiac disorders:

Uncommon

Very rare (<1/10,000): Myocardial infarction ischaemia, angina pectoris, tachycardia, palpitations

Rare

Myocardial infarction, arrhythmia

Vascular disorders:

Common (>1/100, <1/10):

Dizziness

Uncommon

Hypotension., postural hypotension (see section 4.4). Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.

Very rare (<1/10,000): Stroke.

Respiratory, thoracic and mediastinal disorders:

Common (>1/100, <1/10):

Cough

UncommonRare (>1/10,000, <1/1,000):

Sinusitis, rhinitis, dDyspnoea, bronchitis and bronchospasm, rhinitis

Rare

Interstitial lung disease, bronchitis, sinusitis

Gastrointestinal disorders:

Common (>1/100, <1/10):

Nausea, dyspepsia.

Uncommon

Dry mouth, aphthous stomatitis, decreased appetite, diarrhoea, vomiting

Rare (>1/10,000, <1/1,000):

Pancreatitis, glossitisGlossitis, pancreatitis

Hepatobiliary disorders

:

Very rare (<1/10,000): Cholestatic hepatitis with or without jaundice, transaminases increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma glutamyltransferase increased.

Rare

Abnormal liver function test (including transaminases, bilirubin, alkaline phosphatase, gamma GT)

Cholestatic hepatitis with or without necrosis

Skin and subcutaneous tissue disorders:

UncommonCommon (>1/100, <1/10):

Rash, maculopapular rash.

Rare

Psoriaform dermatitis, psoriasis (exacerbation), lichen planus, exfoliative dermatitis, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous pemphigoid, pemphigus, Karposi’s sarcoma, vasculitis/purpura, photosensitivity reactions, alopecia, onycholysis

Rare (>1/10,000, <1/1,000): Angioneurotic oedema (see Special warnings and precautions for use).

Very rare (<1/10,000): Erythema multiforme, toxic epidermal necrolysis, photosensitivity, alopecia.

Musculoskeletal and connective tissue disorders

Uncommon

Muscle cramps, myalgia, arthralgia

Renal and urinary disorders:

RareVery rare (<1/10,000):

Renal impairment, Aacute renal failure (see section 4.4Special warnings and precautions for use), blood creatinine increased, blood urea increased.

Hyperkalaemia, hyponatraemia, proteinuria, nephrotic syndrome, nephritis

Reproductive and breast disorders

Uncommon

Impotence

Rare

Gynaecomastia

General disorders and administration site conditions :

Common (>1/100, <1/10):

Fatigue.

Uncommon

Excess sweating, flushing, asthenia, sleep disorder

Very rare (<1/10,000): Chest pain.

(c) Description of selected adverse events

Hypotension and postural hypotension may occur when starting treatment or increasing dose, especially in at-risk patients (see section 4.4).

Renal impairment and acute renal failure are more likely in patients with severe heart failure, renal artery stenosis, pre-existing renal disorders or volume depletion (see section 4.4).

Hyperkalaemia is most likely to occur in patients with renal impairment and those taking potassium sparing diuretics or potassium supplements.

The events of cerebral ischaemia, transient ischaemic attack and ischaemic stroke reported rarely in association with ACE inhibitors may be related to hypotension in patients with underlying cerebrovascular disease. Similarly, myocardial ischaemia may be related to hypotension in patients with underlying ischaemic heart disease.

Headache is a commonly reported adverse event, although the incidence of headache is greater in patients receiving placebo than in those receiving ACE inhibitors.

Investigations:

Rare (>1/10,000, <1/1,000): Increased serum creatinine, serum urea increased (see Special warnings and precautions for use).

Angioneurotic oedema involving the tongue, glottis or larynx may be fatal:  Vascace should be discontinued, replaced by an agent belonging to another class of drugs and appropriate therapy instituted without delay (see Special warnings and precautions for use).

Pancreatitis has been reported rarely in patients treated with ACE-inhibitors (including Vascace); in some cases this has proved fatal.

Blood disorders have been reported with ACE-inhibitors and include neutropenia and agranulocytosis (especially in patients with renal failure and those with collagen vascular disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia and anaemia.

Pronounced hypotension may occur at the start of therapy with ACE-inhibitors, particularly in patients with heart failure and in sodium- or volume-depleted patients.   Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischaemic heart disease or cerbrovascular disease.
4.9 Overdose

Limited data are available for overdosage in humans.  Symptoms of associated with overdosage of ACE inhibitors are may include hypotension, which may be severe, circulatory shock, stupor, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and coughhyperkalaemia, hyponatraemia and renal impairment with metabolic acidosis.

The recommended treatment of overdosage is intravenous infusion of sodium chloride 9 mg/ml (0.9%) 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.

Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

If indicated, cilazaprilat, the active form of cilazapril, may be removed from the general circulation by haemodialysis (see section 4.4).

Treatment should be mainly symptomatic and supportive.

After ingestion of an overdose, the patient should be kept under close supervision, preferably in an intensive care unit.  Serum electrolytes and creatinine should be monitored frequently.  Therapeutic measures depend on the nature and severity of the symptoms.  Measurements to prevent absorption such as gastric lavage, administration of adsorbents and sodium sulphate within 30 minutes after intake, and to hasten elimination should be applied if ingestion is recent.  If hypotension occurs, the patient should be placed in the shock position and salt and volume supplementation should be given, rapidly.  Treatment with angiotensin II may be considered if conventional therapy is ineffective.  Bradycardia or extensive vagal reactions should be treated by administering atropine.  The use of a pacemaker may be considered.  ACE-inhibitors may be removed from the circulation by haemodialysis.  The use of high-flux polyacrylonitrile membranes should be avoided.
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors, plain, ATC code: C09AA08.

Mechanism of action

Vascace (cilazapril) is a specific, long-acting angiotensin-converting enzyme (ACE) inhibitor which suppresses the renin-angiotensin-aldosterone system and thereby the conversion of the inactive angiotensin I to angiotensin II, which is a potent vasoconstrictor.  At recommended doses, the effect of Vascace in hypertensive patients and in patients with chronic heart failure is maintained for up to 24 hours.

In patients with normal renal function, serum potassium usually remains within the normal range during Vascace treatment.  In patients concomitantly taking potassium-sparing diuretics, potassium levels may rise (see Special warnings and precautions for use and Interaction with other medicinal products and other forms of interaction).

Clinical / efficacy studies

Hypertension

Vascace induces a reduction of both supine and standing systolic and diastolic blood pressure, usually with no orthostatic component.  It is effective in all degrees of essential hypertension as well as in renal hypertension.  The anti-hypertensive effect of Vascace is usually apparent within the first hour after administration, with maximum effect observed between three and seven3 and 7 hours after dosing.  In general, the heart rate remains unchanged.  Reflex tachycardia is not induced, although small, clinically insignificant alterations of heart rate may occur.  In some patients blood pressure reduction may diminish towards the end of the dosage interval.

The initial dosage seldom achieves the desired therapeutic response.  Blood pressure should be assessed and dosage adjusted as required.  Should the effect of Vascace at the top of the recommended dose be insufficient it can be combined with non-potassium-sparing diuretics.

The anti-hypertensive effect of Vascace is maintained during long-term therapy.  No rapid increase in blood pressure has been observed after abrupt withdrawal of Vascace.

In hypertensive patients with moderate to severe renal impairment, the glomerular filtration rate and renal blood flow generally remained in general unchanged with Vascace, despite a clinically significant blood pressure reduction.

Chronic heart failure

No clinical trials have been carried out which prove the effect of cilazapril on morbidity and mortality in heart failure.

In patients with chronic heart failure, the renin-angiotensin-aldosterone and the sympathetic nervous systems are generally activated, leading to enhanced systemic vasoconstriction and to the promotion of sodium and water retention.  By suppressing the renin-angiotensin-aldosterone system, Vascace improves loading conditions in the failing heart by reducing systemic vascular resistance (afterload) and pulmonary capillary wedge pressure (preload) in patients on diuretics and/or digitalis.  Furthermore, the exercise tolerance of these patients increases significantly. showing an improvement in quality of life.  The haemodynamic and clinical effects occur promptly and persist.

5.2 Pharmacokinetic properties

Absorption

Cilazapril is efficiently absorbed and rapidly converted to the active form, cilazaprilat.  Ingestion of food immediately prior to Vascace administration, delays and reduces the absorption to a minor extent which, however, is therapeutically irrelevant.  The bioavailability of cilazaprilat from oral cilazapril approximates 60%, based on urinary recovery data.  Maximum plasma concentrations are reached within 2 hours after administration and are directly related to dosage.

Elimination

Cilazaprilat is eliminated unchanged by the kidneys, with an effective half-life of 9 hours after once- daily dosing with Vascace.

Renal impairment

Pharmacokinetics in special populations

Renal impairment:  In patients with renal impairment, higher plasma concentrations of cilazaprilat are observed than in patients with normal renal function, since drug clearance is reduced when creatinine clearance is lower.  There is no elimination in patients with complete renal failure, but haemodialysis reduces concentrations of both cilazapril and cilazaprilat to a limited extent.

Elderly patients:

In elderly patients whose renal function is normal for age, plasma concentrations of cilazaprilat may be up to 40% higher, and the clearance 20%, lower than in younger patients.

Chronic heart failure:

In patients with chronic heart failure, the clearance of cilazaprilat is correlated with the creatinine clearance.  Thus, dosage adjustments beyond those recommended for patients with impaired renal function (see  section 4.2Special Dosage Instructions) should not be necessary.

5.3 Preclinical safety data

Teratogenicity

Foetotoxicity has been observed for ACE-inhibitors in animals.

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 foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, 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 foetal renin-angiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.

10. DATE OF  REVISION OF THE TEXT

February 2009July 2010