SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

[nationally completed name] 5 mg film-coated tablets [nationally completed name] 10 mg film-coated tablets [nationally completed name] 20 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 5/10/20 mg Benazepril hydrochloride. For the full list of excipients see section 6.1

3. PHARMACEUTICAL FORM

Film-coated tablet

[nationally completed name] 5 mg film-coated tablets: Oval (4 x 8 mm), light yellow film-coated tablets with score on both sides. [nationally completed name] 10 mg film-coated tablets: Oval (11 x 5.5 mm) yellow film-coated tablets with score on both sides. [nationally completed name] 20 mg film-coated tablets: Oval (11 x 5.5 mm) light red film-coated tablet with score on both sides.

The tablet can be divided into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Essential hypertension, congestive heart failure - in addition to diuretics and especially to digitalis glycosides in cases of severe congestive heart failure

4.2 Posology and method of administration

Posology

Paediatric population [nationally completed name] is not recommended for use in children due to insufficient data on safety and efficacy (see section 4.4).

Essential hypertension 10 to 20 mg daily divided in one or two doses. Maximum daily dose is 40 mg.

Congestive heart failure Initially 2.5 mg daily. After 2-4 weeks the dosage can be increased to 5 mg daily. Maximum dose is 20 mg daily.

Dosage at renal impairment For the treatment of essential hypertension the dose should be reduced if creatinine clearance is below 30 ml/min. At renal impairment as well as in patients with heart failure a dose of 10 mg should not be exceeded.

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Method of administration: The tablets can be taken with or without food with a sufficient amount of fluid (e.g. a glass of water). The daily dose of [nationally completed name] should be taken in the morning as a single dose; however it can be divided into two single doses to be taken in the morning and in the evening.

4.3 Contraindications

 Hypersensitivity to benazepril hydrochloride, other ACE-inhibitors or to any of the other excipients.  history of angioneurotic oedema associated with previous ACE inhibitor therapy  hereditary/idiopathic angioneurotic oedema  bilateral renal artery stenosis  kidney transplantation  hemodynamic relevant aortic and mitral valve stenosis / hypertrophic cardiomyopathy  primary hyperaldosteronism  Second and third trimesters of pregnancy (see sections 4.4 and 4.6).  The concomitant use of [nationally completed name] with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Anaphylactoid and related reactions Because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril) may experience a variety of anaphylactoid and related reactions, some of them serious.

Angioedema Angioneurotic oedema has been reported rarely with ACE inhibitors including benazepril. Angioedema may occur during the first weeks of treatment. In rare cases, however, angioedema may occur after long-term use. In some cases symptoms have been observed up to 2 years after initiation of treatment.

Such reactions should be regarded as an indication to discontinue therapy immediately and the patient closely monitored. If antihypertensive treatment is necessary, therapy should be continued using a non-ACE- inhibitor drug.

Where swelling is confined to the face, lips and mouth, the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airways obstruction, appropriate therapy such as subcutaneous adrenaline (0.5mil 1:1000) should be administered promptly when indicated.

Angioedema with laryngeal oedema can be fatal.

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). Other hypersensitivity reactions have been reported.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black patients of African origin than in non-black patients. Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)

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Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).

Anaphylactoid reactions during desensitisation Two patients undergoing desensitising treatment with Hymenoptera venom while receiving ACE inhibitors had life-threatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure / Dialysis Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes while receiving an ACE inhibitor. Symptoms can be facial swelling, flushing, hypotension and dyspnoea and can occur within a few minutes after initiation of the dialysis. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulphate absorption.

Symptomatic hypotension Benazepril may cause a profound fall in blood pressure, especially after the first dose. As with other ACE inhibitors, symptomatic hypotension has been observed in rare cases, typically in patients with volume or salt depletion as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. Volume and/or salt depletion should be corrected before starting therapy with benazepril. If hypotension occurs, the patient should be placed in the supine position and if necessary given physiological saline iv.

Treatment with benazepril can be continued once blood pressure and volume have returned to normal. In patients with severe congestive heart failure, ACE inhibitor therapy can cause excessive hypotension which may be associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure. In such patients, therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased.

Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

Blood pressure and laboratory parameters should be carefully monitored, especially in patients with  sodium depletion or hypovolaemia  severe cardiac decompensation  renal dysfunction  patients older than 65 years  severe hypertension

Ethnic differences As with other ACE inhibitors, benazepril 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.

Patients with renovascular hypertension There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with benazepril. Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis. In these patients the treatment

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should be initiated at hospital under close medical supervision and with low doses and careful dose titration. Diuretic treatment should be discontinued and renal function should be monitored during the first weeks of the treatment.

Impaired renal function Changes in renal function may occur in susceptible patients. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin- aldosterone system, treatment with ACE inhibitors may be associated with oliguria and/or progressive azotaemia and (rarely) acute renal failure. In a small study of hypertensive patients with renal artery stenosis in one kidney or bilateral renal artery stenosis, treatment with benazepril was associated with increases in blood urea nitrogen, and serum creatinine; these increases were reversible on discontinuation of benazepril or diuretic therapy, or both. If such patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed elevated blood urea nitrogen and serum creatinine levels (usually minor and transient), especially when benazepril was given with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of benazepril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see section 4.2).

Agranulocytosis/Neutropenia Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors.

Another ACE inhibitor, Captopril, has been shown to cause agranulocytosis and bone marrow depression; such effects occur more frequently in patients with renal impairment, especially if they also have a collagenvascular disease such as systemic lupus erythematosus or scleroderma. Not enough data are available from clinical trials of benazepril to show whether or not it causes a similar incidence of agranulocytosis. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

Benazepril must 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 benazepril is used in such patients, regular monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Hepatitis and hepatic failure There have been rare reports of predominantly cholestatic hepatitis and isolated cases of acute liver failure, some of them fatal, in patients on ACE inhibitors. The mechanism of this syndrome is not known.

Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue ACE inhibitors and be kept under medical surveillance.

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).

Cough

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Persistent non-productive cough has been reported with ACE inhibitors, presumably due to inhibited degradation of endogenous bradykinin. This cough always resolves after discontinuation of therapy. ACEinhibitor-induced cough must be considered in the differential diagnosis of cough.

Hyperkalaemia Hyperkalaemia may occur during treatment with an ACE inhibitor. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, hypoaldosteronism or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or in patients taking other active substances associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Surgery/Anaesthesia Benazepril may cause hypotension and even hypotensive shock in patients undergoing major surgery or during anaesthesia through the enhancement of other hypotensive potentials. Before surgery the anaesthetist should be informed that the patient is receiving an ACE inhibitor. If it is not possible to withdraw benazepril, volume management should be handled with care. During anaesthesia with agents that induce hypotension, ACE inhibitors may block angiotensin II formation secondary to compensatory renin release. Hypotension occurring by this mechanism should be corrected by volume expansion.

Proteinuria It may occur particularly in patients with existing impairment of renal function or on relatively high doses of benazepril.

Diabetic patients In diabetic patients treated with oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first months of treatment with an ACE inhibitor.

Children and adolescents (< 18 years) Efficacy and safety has not been established.

Aortic or mitral stenosis As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE- inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Galactose intolerance This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

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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).

Diuretics Patients in diuretic treatment and especially those who are volume- and/or salt depleted, may occasionally experience an excessive reduction in blood pressure when therapy with an ACE inhibitor is started. The possibility of hypotensive effects in such patients can be minimised by discontinuing diuretic therapy (for at least three days before treatment with benazepril), by increasing salt intake prior to intake and by initiation of therapy with lower doses of the ACE inhibitor. Further increases in dosage should be made with caution. (See sections 4.2 and 4.4)

Antihypertensive agents, tricyclic antidepressants, antipsychotics, anaesthetics The antihypertensive effect is usually additive and excessive symptomatic hypotension may occur. Concomitant use of glycerol trinitrate and other nitrates, or other vasodilators may lower the blood pressure further.

Potassium-sparing diuretics Concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride, eplerenone), potassium supplements, or salt substitutes containing potassium is not recommended in patients receiving ACE inhibitors, since this may lead to significant increase in serum potassium (especially in patients with impaired renal function). However, if co- medication is considered necessary, frequent monitoring of serum potassium is advisable.

Sympathomimetics Reduction of the antihypertensive effect.

Allopurinol, procainamide, cytostatics, immunosuppressive agents, systemic corticosteroids and other medicinal products changing the blood picture Increased risk of haematological reactions, especially leukocytosis, leukopenia.

Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Anti-diabetic agents 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

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including acetylsalicylic acid used as an anti-inflammatory agent When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs, 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.

Ciclosporin and heparin

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Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin and with heparin. Monitoring of serum potassium is recommended. mTOR inhibitors (e.g. temsirolimus, sirolimus, everolimus) Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see section 4.4).

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

Alcohol Increased hypertensive effect and increased effect of alcohol.

Sodium chloride Decreased antihypertensive effect.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see section 4.3 and 4.4).

ACE inhibitors have been reported to cause foetal and neonatal death when given to pregnant women.

Breastfeeding Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of [nationally completed name] in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of [nationally completed name] in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

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4.7 Effects on ability to drive and use machines

As with other antihypertensive drugs, it is advisable to exercise caution when driving or operating machines. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.

4.8 Undesirable effects

Benazepril has been found to be well tolerated. Adverse reactions associated with benazepril and other ACE inhibitors are listed below. The adverse experience profile for paediatric patients appears to be similar to that seen in adult patients. There is no information about the long-term administration to paediatric patients and its effects on growth, puberty and general development. The pharmacokinetic data were derived from a limited number of patients.

The following undesirable effects have been observed and reported during treatment with [nationally completed name] and other ACE inhibitors with the following frequencies:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Blood and lymphatic system common decreases in haemoglobin, disorders haematocrit, leukocytes and thrombocytes uncommon anaemia, aplastic anaemia, thrombocytopenia (see also section 4.4), leukopenia, neutropenia, agranulocytosis very rare haemolytic anaemia Immune system disorders rare hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx (see also section 4.4) Psychiatric disorders uncommon insomnia, nervousness and paraesthesia Nervous system disorders common headache, dizziness, balance disorders, somnolence, apathy uncommon mood alterations, vertigo, taste disturbances, sleep disturbances, mental confusion, impotence, blurred vision very rare dysgeusia Ear and labyrinth disorders very rare tinnitus Cardiac disorders common severe hypotension with orthostatic effects, especially in high risk groups, syncope, impaired vision, palpitations rare symptomatic hypotension, chest pain, angina pectoris, arrhythmias very rare myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, tachycardia Vascular disorders common flushing Respiratory, thoracic and common cough, bronchitis, symptoms of upper mediastinal disorders respiratory tract infection

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uncommon dyspnoea, sinusitis, rhinitis very rare bronchospasm, glossitis, xerostomia Gastrointestinal disorders common nausea, abdominal pain, indigestion, non-specific gastrointestinal disorders uncommon vomiting, diarrhoea, constipation, anorexia, intestinal oedema and cholelithiasis, especially with existing cholecystitis very rare pancreatitis, ileus Hepatobiliary disorders rare hepatitis (predominantly cholestatic), cholestatic jaundice (see section 4.4) Skin and subcutaneous tissue common photosensitivity reactions, rash, disorders pruritus rare urticaria, pemphigus, Stevens- Johnson’s syndrome very rare alopecia, psoriasis, Raynaud’s phenomenon Musculoskeletal and connective rare arthralgia, arthritis, myalgia. tissue disorders Renal and urinary disorders common renal impairment (see section 4.4), pollakiuria uncommon proteinuria, progression of renal dysfunction rare acute renal failure, increase in blood urea nitrogen, increase in serum creatinine General disorders common fatigue

The following events of unknown frequency have been reported during post marketing use of benazepril: small bowel angioedema, anaphylactoid reactions, hyperkalaemia, agranulocytosis and neutropenia (see section 4.4).

Laboratory findings: As with other ACE inhibitors, minor increases in blood urea nitrogen (BUN) and serum creatinine, which were reversible on discontinuation of therapy have been observed in 0.1% of patients with essential hypertension treated with benazepril alone. Increases are more likely to occur in patients also receiving diuretics or in patients with renal artery stenosis (see section 4.4).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Symptoms: Although there is limited experience of overdosage with benazepril, the main sign to be expected is marked hypotension, which can be associated with electrolyte disturbances and renal failure. Possible symptoms of an overdose include also shock, stupor, bradycardia, electrolyte disturbances, dehydration, and renal failure. Serum electrolytes and creatinine should be monitored frequently.

Treatment: After intake of an overdose, the patient should be monitored closely preferably at an intensive

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care unit. If the tablets were taken recently, recommended measures include induction of vomiting, administration of activated charcoal and administration of a laxative and/or gastric lavage. Any dehydration, disturbances in the electrolyte balance and hypotension should be treated in an appropriate manner, e .g. plasma-substitution or – if the result is insufficient – with catecholamines.

Although the active metabolite benazeprilat is only slightly dialysable, dialysis might be considered in overdosed patients with severely impaired renal function to support normal elimination. In the case of marked hypotension, give normal saline solution iv.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE-inhibitors, plain ATC-Code: C09 AA07

Benazepril is a potent inhibitor of angiotensin converting enzyme. In patients with hypertension administration of benazepril results in a reduction of supine and standing blood pressure to about the same extent with no compensatory increase in the heart rate. Peripheral arterial resistance is reduced with either no change or an increase in cardiac output.

There is an increase in renal blood flow and the glomerular filtration rate is usually unchanged. Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effect is maintained during long term therapy. Abrupt discontinuation of treatment has not been associated with a rapid increase in blood pressure. ACE inhibitors are effective even in patients with low-renin hypertension. Although antihypertensive effect has been found in the races studied, black hypertensive patients (usually a low-renin hypertensive population) demonstrated a smaller response to ACE inhibitor therapy than non-black patients. This difference disappears when a diuretic is administered concomitantly.

The antihypertensive effect starts 1 hour following oral administration and lasts for 24 hours.

Benazepril treatment relieves symptoms in patients with heart insufficiency. In contrast to other ACE-inhibitors, possible effects of benazepril on mortality have not been examined in placebo- controlled studies.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early

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because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

5.2 Pharmacokinetic properties

Benazepril hydrochloride: The prodrug benazepril hydrochloride is metabolised (hydrolysis, mainly in the liver) into benazeprilat, which is the only active metabolite. Following oral administration at least 37% of the dose is absorbed. The bioavailability is approximately 28 % of orally administered benazepril hydrochloride compared to intravenous administration. Benazeprilat is mainly excreted unchanged into bile and urine. The elimination half-life of benazeprilat is 10 to 11 hours. Plasma protein binding of benazepril hydrochloride is about 95 %.

In patients with severe impaired renal function (creatinine clearance < 30 ml/min) reduced elimination and thus increased accumulation of benazepril hydrochloride occurs. In patients with moderate renal impairment (creatinine clearance > 30 ml/min) only minor changes in pharmacokinetics have been observed, that did not require dose adjustment.

Lactation: In nine women given an oral dose of 20 mg of benazepril daily for 3 days (time postpartum not stated), peak milk levels of 0.9 μg/L of benazepril at 1 hour after the dose and 2 μg/L of its active metabolite benazeprilat at 1.5 hours after the dose were detected. It is estimated that the breastfed infant would receive a daily dose less than 0.14% of the maternal weight-adjusted dose of benazepril.

5.3 Preclinical safety data

No mutagenic or carcinogenic effects were observed in preclinical studies. Reproductive toxicity studies performed in rats, rabbits, and monkeys do not indicate a teratogenic potential of benazepril, but demonstrated embryotoxic effects.

Other ACE inhibitors induced adverse effects on the late fetal development, resulting in fetal death and congenital effects, in particular affecting the skull. Fetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the fetal renin- angiotensin system and partly due to the ischemia resulting from maternal hypotension and decreases in fetal-placental blood flow and oxygen/nutrient delivery to the fetus.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core: Lactose monohydrate Pregelatinised maize starch Croscarmellose sodium Hydrogenated castor oil

Film coat: Hypromellose Macrogol 8000 Talc Titanium dioxide (E 171) Iron oxide, yellow (E172)

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In addition [nationally completed name] 20 mg contains red iron oxide (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

Blister packs (PVC/oPA/Al//Al) and PP-container with LDPE-cap with desiccant (silica gel).

Pack sizes: Blisters: 10, 20, 28, 30, 42, 50, 98 and 100 film-coated tablets. PP-container: 50 and 100 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

[to be completed nationally]

8 MARKETING AUTHORISATION NUMBER(S)

[to be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

03/08/2017

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