Vascace

One film coated tablet 0.5mg contains:

Cilazapril, anhydrous 0.5mg, in the form of the monohydrate (cilazapril 0.522mg).

Excipients include lactose monohydrate 82.028 mg.

One film coated tablet 1.0mg contains:

Cilazapril, anhydrous 1.0mg, in the form of the monohydrate (cilazapril 1.044mg).

Excipients include lactose monohydrate 81.506 mg.

One film coated tablet 2.5mg contains:

Cilazapril, anhydrous 2.5mg, in the form of the monohydrate (cilazapril 2.61mg).

Excipients include lactose monohydrate 124.39 mg.

One film coated tablet 5.0mg contains:

Cilazapril, anhydrous 5.0mg, in the form of the monohydrate (cilazapril 5.22mg).

Excipients include lactose monohydrate 121.78 mg.

For warnings related to lactose monohydrate, see section 4.4 Special warnings and precautions for use.

For full list of excipients, see section 6.1.

Tablets.

Vascace is indicated in treatment of all grades of essential hypertension. Vascace is also indicated in the treatment of chronic heart failure, usually as an adjunctive therapy with digitalis and/or diuretics.

Vascace should be administered once-daily. As food intake has no clinically significant influence on absorption, Vascace can be administered before or after a meal. The dose should always be taken at about the same time of day.

Special Dosage Instructions:

Essential hypertension

The recommended initial dosage is 1mg once a day. Dosage should be adjusted individually in accordance with the blood pressure response until control is achieved. Most patients can be maintained on between 2.5 and 5.0mg/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.

Hypertensive patients receiving diuretics

The diuretic should be discontinued two to three 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 0.5mg once daily.

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 a recommended starting dose of 0.5mg once daily under close medical supervision. 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 patients 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

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

The following dose schedules are recommended:

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.

Impaired hepatic function

In the unlikely event that a patient with liver cirrhosis should require treatment with cilazapril, it should be initiated with caution, at a dose of 0.5 mg or less once daily, because significant hypotension may occur (see section 4.4 Special warnings and precautions for use).

Vascace is contraindicated in patients with ascites (see section 4.3 Contraindications).

Elderly

In the treatment of hypertension, Vascace should be initiated with between 0.5mg and 1mg once daily. Thereafter, the maintenance dose must be adapted to individual response.

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.

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

Children

Safety and efficacy in children have not been established therefore there is no recommendation for administration of cilazapril to children.

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 section 4.4 Special warnings and precautions for use and section 4.6 Pregnancy and lactation).

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

(See also Special Dosage Instructions under section 4.2 Posology and method of administration)

Vascace should be used with caution in patients with aortic stenosis, hypertrophic cardiomyopathy or outflow obstruction.

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

Hypersensitivity/angioneurotic oedema

Angioneurotic oedema has been reported in patients being treated with ACE-inhibitors (see section 4.8 Undesirable effects).

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.

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. In patients with angina pectoris or cerebrovascular disease, treatment with ACE-inhibitors should be started under close medical supervision, as excessive hypotension could result in myocardial infarction or cerebrovascular accident.

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

Reduced dosages may be required for patients with renal impairment, depending on their creatinine clearance (see section 4.2 Special dosage instruc-tions). Treatment with ACE-inhibitors may produce increases in blood urea nitrogen and/or serum creatinine. 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 special precautions for use.

Hepatic impairment

In patients with severe liver function impairment, hypotension may occur.

Hepatic failure

Rarely, ACE-inhibitors have been associated with hepatotoxicity including cholestatic and hepatocellular hepatitis. More severe reactions such as fulminant hepatic necrosis have also been reported. Patients receiving ACE-inhibitors who develop jaundice or elevations of hepatic enzymes should discontinue the ACE-inhibitor and receive appropriate medical follow-up.

Serum potassium

Concomitant administration of potassium-sparing diuretics, potassium supplements or potassium containing salt substitutes may lead to increases in serum potassium, particularly in patients with renal impairment (see section 4.5 Interaction with other medicinal products and other forms of interaction and section 5.1 Pharmacodynamic properties). Therefore, if concomitant use for such agents is indicated, their dosage should be reduced when Vascace is initiated and serum potassium and renal function should be monitored carefully.

Surgery anaesthesia

The use of ACE-inhibitors in combination with anaesthetic drugs in surgery 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

Neutropenia and agranulocytosis have been rarely reported with ACE-inhibitors. 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 receiving immunosuppressive therapy, 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 section 4.3 Contraindications and section 4.6 Pregnancy and lactation).

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.

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, potassium supplements or potassium containing salt substitutes administered together with Vascace can lead to increases in serum potassium, particularly in patients with renal impairment (see section 4.4 Special warnings and precautions for use and section 5.1 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 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.

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). Should exposure to an 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 section 4.3 Contraindications and section 4.4 Special warnings and precautions for use).

Lactation

Because no information is available regarding the use of Vascace during breast-feeding, Vascace is not recommended, and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

There are no studies on the effect of Vascace on the ability to drive. When driving vehicles or operating machinery it should be taken into account that occasionally dizziness or fatigue may occur (see section 4.8 Undesirable effects). These effects may be enhanced by the concomitant use of alcohol (see section 4.5 Interaction with other medicinal products and other forms of interaction).

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

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.

Cardiac disorders

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. Other cardiovascular effects that have occurred include tachycardia, palpitations and chest pain.

Hepatobiliary disorders

Single cases of liver function disorders, such as increased liver function tests (transaminases, bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis with or without necrosis, have been reported.

Immune system disorders

ACE-inhibitors have been documented to induce cough in a substantial number of patients. Rarely dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have been reported.

As with other ACE-inhibitors, angioneurotic oedema has been reported, although rarely, in patients receiving Vascace. Angioedema involving the tongue, glottis or larynx 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 adrenaline (epinephrine) solution 1:1000 (0.3 to 0.5ml) or slow intravenous adrenaline 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.

Gastrointestinal disorders

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

Skin and subcutaneous tissue disorders

Skin rashes (including erythema multiforme and toxic epidermal necrolysis) may occur; photosensitivity, alopecia and other hypersensitivity reactions have also been reported.

Laboratory test findings

Clinically relevant changes in laboratory test values possibly or probably related to Vascace treatment have been observed only rarely.

Minor, mostly reversible increases in serum creatinine/urea have been observed in patients treated with Vascace. Such changes are likely to occur in patients with renal artery stenosis or with renal impairment (see section 4.4 Special warnings and precautions for use), but they have also occasionally been observed in patients with normal renal function, particularly in those receiving concomitant diuretics.

Renal and urinary disorders

Isolated cases of acute renal failure have been reported in patients with severe heart failure, renal artery stenosis or renal disorders (see section 4.4 Special warnings and precautions for use).

While single doses of up to 160mg Vascace have been administered to normal healthy volunteers without untoward effects on blood pressure, only a few data on overdose are available in patients.

The most likely symptoms of overdosage are hypotension, which may be severe, shock, stupor, bradycardia, hyperkalaemia, hyponatraemia and renal impairment with metabolic acidosis.

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.

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

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 section 4.4 Special warnings and precautions for use and section 4.5 Interaction with other medicinal products and other forms of interaction).

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 seven 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 toward 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 remained in general unchanged with Vascace despite a clinically significant blood pressure reduction.

As with other ACE-inhibitors, the blood pressure-lowering effect of Vascace in black patients may be less pronounced than in non-blacks. However, racial differences in response are no longer evident when Vascace is administered in combination with hydrochlorothiazide.

Chronic 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.

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 two hours after administration and are directly related to dosage.

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

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.

Hepatic impairment

In patients with liver cirrhosis, increased plasma concentrations and reduced plasma and renal clearance were observed, with a greater effect on cilazapril than on its active metabolite cilazaprilat.

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 4.2 Special Dosage Instructions) should not be necessary.

Teratogenicity

Foetotoxicity has been observed for ACE-inhibitors in animals.

In the tablet core:

Lactose monohydrate

Maize starch

Hypromellose 3cp

Talc

Sodium stearyl fumarate

In the film coat:

Hypromellose 6cp

Talc

Titanium dioxide E171

Iron oxide red E172 (2.5mg and 5.0mg only)

Iron oxide yellow E172 (1.0mg and 2.5mg only)

Not applicable.

3 years.

Do not store above 25°C.

Glass Bottles and Aluminium Blisters

0.5mg: 2, 28, 30 or 100 tablets

1.0mg: 2, 28, 30 or 100 tablets

2.5mg: 4, 28, 30, 98 or 100 tablets

5.0mg: 28, 30, 98 or 100 tablets

Not all pack sizes may be marketed.

None stated.

Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom.

26 October 1990/7 December 2001

March 2009

Vascace is a registered trade mark