Sandoz Business use only Page 1 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Summary of Product Characteristics
Benazepril hydrochloride 5/10/20 mg film-coated tablets
1 NAME OF THE MEDICINAL PRODUCT [Nationally completed name]
2 QUALITATIVE AND QUANTITATIVE COMPOSITION [Benazepril hydrochloride 5 mg film-coated tablets] One tablet contains 5 mg Benazepril hydrochloride. [Benazepril hydrochloride 10 mg film-coated tablets] One tablet contains 10 mg of Benazepril hydrochloride. [Benazepril hydrochloride 20 mg film-coated tablets] One tablet contains 20 mg of Benazepril hydrochloride.
For the a full list of excipients see section 6.1List of excipients.
3 PHARMACEUTICAL FORM filmcoated tablet
5 mg: slightly yellow to cream-coloured round film-coated tablets with a breaking notch 10 mg: slightly yellow coloured round film-coated tablets with a breaking notch 20 mg: white to off-white coloured round film-coated tablets with a cross-breaking notch
4 CLINICAL PARTICULARS
4.1 Therapeutic Indications
Treatment of essential hypertension
Adjuvant treatment of congestive heart failure (New York Heart Association (NYHA) class II-IV)
Essential hypertension, congestive heart failure - in addition to diuretics and especially to digitalis glykosides in cases of severe congestive heart failure
Sandoz Business use only Page 2 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
4.34.2 Posology and Method of Administration
Dosage in general target population Hypertension Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. The recommended initial dose for patients not receiving thiazide diuretics is 10 mg once daily. The dosage may be increased to 20 mg daily. The dosage should be adjusted according to blood pressure response, generally at intervals of 1 to 2 weeks. In some patients, the antihypertensive effect may diminish towards the end of the dosing interval. The total daily dosage should then be divided into two equal doses. The maximum recommended daily dose of benazepril in hypertensive patients is 40 mg, given as a single dose or two doses.
If benazepril alone does not produce a sufficient fall in blood pressure, another antihypertensive drug, e.g. a thiazide-type diuretic or a calcium antagonist (initially in a low dose), may be administered concomitantly. A cautious dosage schedule or dose reduction should be considered when benazepril is initiated in patients on pre- existing diuretic treatment particularly in severely sodium-depleted and/or volume depleted patients. This may include temporary dose reduction or suspension of diuretic treatment (e.g. 2-3 days) prior to benazepril initiation or a reduction of the initial dose of benazepril to 5 mg (instead of 10 mg) in order to avoid excessive hypotension. Volume and/or salt depletion should be corrected before starting therapy with benazepril (see section 4.4 Special warnings and precautions for use).
The usual dose of benazepril is recommended in patients with a creatinine clearance of ≥ 30 mL/min.
Patients with a creatinine clearance of < 30 mL/min The initial dose is 5 mg. The dosage may be increased to up to 10 mg daily. For any further reduction in blood pressure a non-thiazide diuretic or another antihypertensive drug should be added. Essential hypertension 10 to 20 mg daily to be taken in one or two doses. Maximum daily dose 40 mg.
Congestive heart failure (CHF) Formatiert: Schriftart: Nicht Kursiv The recommended initial dose is 2.5 mg once daily. Owing to the risk of a steep fall in blood pressure in response to the first dose, patients taking benazepril for the first time should be closely monitored (see section 4.4 Special warnings and precautions for use). The dose may be increased to 5 mg once daily after 2-4 weeks if the symptoms of heart failure have not been adequately relieved, provided the patient has not developed symptomatic hypotension or other unacceptable adverse effects. Depending on the clinical response, the dose may be increased further to 10 mg and eventually to 20 mg once daily at appropriate intervals.
Once-daily dosing is generally effective. Some patients may respond better to a twice-daily regimen. Controlled clinical trials show that patients with more severe heart failure (NYHA class IV) usually require smaller doses of benazepril than patients with mild to moderate heart failure (NYHA classes II and III).
Sandoz Business use only Page 3 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Particular caution in dosing and surveillance is recommended when benazepril is added to pre-existing diuretic treatment especially in severely sodium-depleted and/or volume depleted patients. Depending on the clinical situation a dose reduction or temporary suspension of diuretic treatment prior to benazepril initiation may be considered. Volume and/or salt depletion should be corrected before starting therapy with benazepril.
In CHF patients with a creatinine clearance of < 30 mL/min the daily dose may be increased to 10 mg, but the initial low dose given (2.5 mg once daily) may prove to be optimal (see section 5.2 Pharmacokinetic properties).Congestive heart failure Initial 2.5 mg daily. Possibly the dosage can be increased to 5 mg daily after two to four weeks. The maximum dose is 20 mg daily.
Special population Formatiert: Schriftart: Nicht Kursiv Paediatric patients The antihypertensive effects of benazepril have been evaluated in a double-blind study in paediatric patients 7 to 16 years of age. The usual starting dose was 0.2 mg/kg (up to a maximum dose of 10 mg/d). The dosage was adjusted according to blood pressure response up to a maximum dose of 0.6 mg/kg (or a maximum daily dose of 40 mg) (see section 5.1 Pharmacodynamic properties). The pharmacokinetics of benazepril have been evaluated in paediatric patients 6 to 16 years of age (see section 5.2 Pharmacokinetic properties).
Treatment with benazepril is not recommended in paediatric patients less than 67 Formatiert: Schriftart: Nicht Kursiv years of age (body weight < 25 kg), and in children with glomerular filtration rate < 30 mL/min as there are insufficient data available to support a dosing recommendation in these groups.
Children who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths should not receive benazepril tablets. The safety and efficacy have not been established in children with CHF.and Formatiert: Schriftart: Nicht Kursiv progressive chronic renal insufficiency.
There is no information about the long-term administration to paediatric patients (see sections 4.8 Undesirable effects and 5.1 Pharmacodynamic properties).
Elderly: The usual initial dose in hypertension is 5mg once daily which may be titrated to 10mg.Geriatric patients Formatiert: Schriftart: Nicht Kursiv Dosage recommendation and special precautions for the elderly are the same as in adults (see also section 5.2 Pharmacokinetic properties).Dosage in renal impairment For the treatment of essential hypertension the dose should be reduced if creatinine clearance is below 30 ml/min. Renal impairment to the same extent in patients with heart failure a dose of 10 mg should not be exceeded.
For the dosage regimens which can not realised with this strength other appropriate strengths are available.
Sandoz Business use only Page 4 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
4.44.3 Contraindications
hypersensitivity to the active substance, to any other ACE inhibitor, or to any of the excipients listed in section 6.1 history of angioneurotic oedema associated with or without 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)during pregnancy (see section 4.6 “Pregnancy and lactation”) Benazepril must not be used with aliskiren-containing medicines in patients with diabetes mellitus or with moderate to severe renal impairment (eGFR < 60 ml/min/1.73 m2).
4.54.4 Special Warnings and Precautions for Use Formatiert: Schriftart: Fett Pregnancy Formatiert: Schriftart: Fett 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).
Anaphylactoid and related reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism Formatiert: Schriftart: Nicht Fett of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril) may experience a variety of adverse reactions, some of them serious.
Angioedema Angioedema of the face, lips, tongue, glottis, and larynx has been reported in Formatiert: Schriftart: Nicht Fett patients treated with ACE inhibitors, including benazepril. In such cases benazepril should be immediately discontinued and appropriate therapy and monitoring be provided until complete and sustained resolution of signs and symptoms. Where swelling is confined to the face and lips, the condition generally resolves either without treatment or with antihistamines. Angioedema with laryngeal oedema can be fatal. Where the tongue, glottis or larynx are involved, appropriate therapy should be given immediately, e.g. subcutaneous adrenaline injection 1:1000 (0.3-0.5 mL) and/or measures to ensure a patent airway.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angiodema while receiving an ACE inhibitor (see Contraindications). Other hypersensitivity reactions have been reported.
Sandoz Business use only Page 5 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Formatiert: Schriftart: Nicht Fett The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black patients of African heritage than in non-black patients.
Anaphylactoid reactions during desensitisation Two patients undergoing desensitising treatment with Hymenoptera venom while Formatiert: Schriftart: Nicht Fett 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 Anaphylactoid reactions have been reported in patients dialysed with high-flux Formatiert: Schriftart: Nicht Fett membranes while receiving an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Hypotension Benazepril may cause a profound fall in blood pressure, especially after the first dose. In hypertensive patients receiving benazepril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension. At the beginning of the treatment with benazepril patients at increased risk of symptomatic hypotension should be followed closely for the first two weeks of treatment and after increase on the dose of benazepril. Sodium depletion and hypovolaemia must be corrected before treatment with benazepril can be initiated. 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 supervised, especially in patients with - sodium depletion or hyovolaemia - severe cardiac decompensation - renal dysfunction - patients older than 65 years - severe hypertension
If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required. The appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with benazepril after effective management. Symptomatic hypotension Formatiert: Schriftart: Fett 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
Sandoz Business use only Page 6 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00 necessary given physiological saline i.v.. 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.
Agranulocytosis/neutropenia Formatiert: Schriftart: Fett Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and Formatiert: Einzug: Links: 0 cm bone marrow depression; such effects occur more frequently in patients with renal impairment, especially if they also have a collagen-vascular 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.
Hepatitis and hepatic failure Formatiert: Schriftart: Fett There have been rare reports of predominantly cholestatic hepatitis and isolated Formatiert: Einzug: Hängend: 0,53 cm cases of acute liver failure, some of them fatal, in patients on ACE inhibitors. The Formatiert: Einzug: Links: 0 cm mechanism is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevation of hepatic enzymes should discontinue the ACE inhibitor and be kept under medical surveillance.
Impaired renal function Formatiert: Schriftart: Fett Changes in renal function may occur in susceptible patients. In patients with severe Formatiert: Einzug: Hängend: 0,53 cm congestive heart failure, whose renal function may depend on the activity of the Formatiert: Einzug: Links: 0 cm 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 Posology and method of administration).
Cough Formatiert: Schriftart: Fett Persistent non-productive cough has been reported with ACE inhibitors, presumably Formatiert: Einzug: Hängend: 0,53 cm due to inhibited degradation of endogenous bradykinin. This cough always resolves Formatiert: Einzug: Links: 0 cm
Sandoz Business use only Page 7 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00 after discontinuation of therapy. ACE-inhibitor-induced cough must be considered in the differential diagnosis of cough.
Surgery/anaesthesia Formatiert: Schriftart: Fett Before surgery the anaesthetist should be informed that the patient is receiving an Formatiert: Einzug: Hängend: 0,53 cm ACE inhibitor. During anaesthesia with agents that induce hypotension, ACE Formatiert: Einzug: Links: 0 cm inhibitors may block angiotensin II formation secondary to compensatory renin release. Hypotension occurring by this mechanism should be corrected by volume expansion.
Hyperkalaemia Formatiert: Schriftart: Fett During treatment with ACE inhibitors, elevated serum potassium levels have been Formatiert: Einzug: Hängend: 0,53 cm observed on rare occasions. No discontinuations of benazepril due to hyperkalaemia Formatiert: Einzug: Links: 0 cm have been reported in clinical trials in hypertension. Risk factors for development of hyperkalaemia may include renal insufficiency, diabetes mellitus, and concomitant use of agents to treat hypokalaemia (see section 4.5 Interaction with other medicinal products and other forms of interaction). In a trial involving patients with progressive chronic renal disease, some patients discontinued treatment because of hyperkalaemia. In patients with progressive chronic renal disease serum potassium should be monitored. Formatiert: Einzug: Hängend: 0,53 cm Aortic or mitral stenosis Formatiert: Schriftart: Fett As with all other vasodilators, special caution is indicated in patients suffering from Formatiert: Einzug: Links: 0 cm aortic or mitral stenosis. Formatiert: Englisch (USA)
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 mild changes in serum creatinine even in patients with unilateral renal artery stenosis. In these patients treatment should be started in hospital under close medical supervision with low doses and careful dose titration. Diuretic treatment should be discontinued and renal function should be monitored during the first weeks of therapy.
Patients with renal insufficiency Benazepril should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses. Close monitoring of renal function during therapy should be performed as deemed appropriate in those with renal insufficiency. Renal failure has been reported in association with ACE inhibitors, mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Some patients, with no apparent pre-existing renal disease have developed increases in blood urea and creatinine concentrations when a diuretic is given concomitantly. Dosage reduction of benazepril and/or discontinuation of the diuretic may be required. It is recommended that the renal function be monitored during the first weeks of therapy.
Diuretics
Sandoz Business use only Page 8 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Patients on diuretics and especially those who are volume- and/or salt depleted, may experience an excessive reduction of blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or 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.
Dialysis Patients who are dialysed using high-flux polyacrylonitrile membranes and treated with benazepril are likely to experience anaphylactoid reactions such as facial swelling, flushing, hypotension and dyspnoea within a few minutes of commencing haemodialysis. It is recommended to use an alternative membrane or an alternative antihypertensive medicinal product.
Neutropenia/Agranulocytosis Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Benazepril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If benazepril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.
Angiooedema Angioedema may occur during the first week of treatment. In rare cases, however, angioedema may occur after long-term use. Treatment should be discontinued immediately, and antihypertensive treatment, if necessary, should be continued using a non-ACE-inhibitor drug.
Ethnic differences Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients. 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.
Cough Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Hyperkalemia ACE inhibitor treatment may lead to hyperkalaemia. If concomitant use with a potassium-sparing drug is necessary, frequent monitoring of serum potassium is advised.
Sandoz Business use only Page 9 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Surgery/Anaesthesia Benazepril may cause hypotension or even hypotensive shock in patients undergoing major surgery or during anaesthesia through the enhancement of other hypotensive potentials. If it is not possible to withhold benazepril volume management should be handled with care.
Proteinuria It may occur particularly in patients with existing renal function impairment or on relatively high doses of benazepril.
Primary hepatic disease / hepatic failure Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving benazepril who develop jaundice or marked elevations of hepatic enzymes should discontinue benazepril and receive appropriate medical follow-up.
Diabetic patients In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor.
Children and adolescents (< 18 years) Efficacy and safety has not been established.
Lactose 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.
Concomitant Therapy with ACE Inhibitor and Angiotensin-receptorblocker Combining an ACE inhibitor with an angiotensin II receptor antagonist should be limited to individually defined cases with close monitoring of renal function, potassium levels and blood pressure (see section 4.5).
Combination with aliskiren is not-recommended in patients other than diabetic patients or patients with an impaired renal function(see section 4.5) Formatiert: Niederländisch (Niederlande)
4.64.5 Interaction with Other Medicinal Products and Other Forms of Interaction
Diuretics Patients on diuretics or fluid-depleted patients 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 2-3 days before starting treatment with benazepril
Sandoz Business use only Page 10 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
(see sections 4.2 Posology and method of administration and 4.4 Special warnings and precautions for use).Antihypertensive agents, diuretics, tricyclic antidepressants, antipsychotics, anaesthetics The antihypertensive effect is usually additive and excessive symptomatic hypotension may occur. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators may further reduce blood pressure.
Drugs causing hyperkalaemia Concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium and other drugs (e.g. ciclosporin, heparin) is not recommended in patients receiving ACE inhibitors (including benazepril), since this may lead to significant increases in serum potassium. However, if comedication is considered necessary, frequent monitoring of serum potassium is advisable.Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes (e.g. spironolactone, triamterene, amiloride, eplerenone) Significant increase in serum potassium, especially in patients with impaired renal function
Sympathomimetics Reduction of the antihypertensive effect
Allopurinol, procainamide, cytostatic therapy, immunosuppressive agents, systemic corticosteroids and other medicinal products changing blood picture Increased probability of haematological reactions, especially leucocytosis, leucopenia
Non steroidal anti-inflammatory drugs (NSAIDs) Formatiert: Italienisch (Italien) It has been shown that the hypotensive effect of ACE inhibitors may be reduced when administered concomitantly with indomethacin and other non-steroidal anti- inflammatory drugs. In a controlled clinical trial, indomethacin did not interfere with the antihypertensive effect of benazepril and no pharmacokinetic interaction was found between acetylsalicylic acid and benazepril in healthy volunteers. The combination of non-steroidal anti-inflammatory drugs and ACE inhibitors (including benazepril) can increase the risk of renal impairment and hyperkalaemia. Therefore, monitoring of renal function and potassium level is recommended.
Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including benazepril) 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.Lithium Reversible increases in serum lithium concentrations with increased cardio- and neurotoxicological effects of lithium
Dipeptidyl peptidase-IV inhibitors The risk of angioedema may be increased in patients receiving co-administration of ACE inhibitors and dipeptidyl peptidase-IV inhibitors (e.g. vildagliptin).
Sandoz Business use only Page 11 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Other agents with antihypertensive properties Benazepril may increase the hypotensive effect of other antihypertensive agents. Dosages must be adjusted accordingly.
Antidiabetic agents In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral antidiabetics may develop hypoglycaemia. Such patients should therefore be advised about the possibility of hypoglycaemic reactions, and should be monitored accordingly. 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. Antidiabetics (e.g. insulins, oral hypoglycaemic agents) Increased blood glucose lowering effect with risk of hypoglycaemia
Erythropoietin Patient responsiveness to erythropoietin may decrease when used concomitantly with ACE inhibitors (including benazepril).
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.
Probenecid Probenecid pretreatment may enhance the pharmacodynamic response of ACE inhibitors. Dose adjustment may be necessary.
The pharmacokinetics of benazepril HCl are not affected by the following drugs: Hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril HCl does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied).
Non steroidal anti-inflammatory drugs (NSAIDs) Reduction of antihypertensive effect with deterioration of renal function
Heparin Increased risk of hyperkalaemia
Alcohol Increased hypertensive effect and increased effect of alcohol
Sodium chloride Decreased antihypertensive effect
Aliskiren
Sandoz Business use only Page 12 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
In patients other than diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
Concomitant therapy with ACE inhibitor and angiotensin-receptor blocker It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with ACE inhibitor and angiotensin-receptor blocker is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single renin-angiotensin- aldosterone system agent. Dual blockade (e.g, by combining an ACE-inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure. Formatiert: Niederländisch (Niederlande)
4.74.6 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).[Nationally completed name] is contraindicated during pregnancy (see section 4.3 "Contraindications").
ACE inhibitors can cause fetal and neonatal morbidity and death when given to pregnant women. Several dozen cases have been reported in the world literature.
Use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal damage, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios, presumably due to impaired fetal renal function, has also been reported; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also
Sandoz Business use only Page 13 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00 been reported, although it is not clear whether these were due to ACE inhibitor exposure. In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated with a potentially increased risk of birth defects.
When pregnancy is established, ACE inhibitors should be discontinued as soon as possible and monitoring of the fetal development should be performed on a regular basis. In women planning to become pregnant, ACE inhibitors (including [Nationally completed name]) should not be used. Women of child-bearing age should be made aware of the potential risk and ACE inhibitors (including [Nationally completed name]) should only be given after careful counseling and consideration of individual risks and benefits.
Breast-feedingLactation 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 breast-feeding 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.
4.84.7 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.
4.94.8 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.
Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.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 and <1/10 Uncommon 1/1,000 and <1/100
Sandoz Business use only Page 14 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Rare 1/10,000 and <1/1,000 Very rare <1/10,000 including isolated cases
Table 1 Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Blood and lymphatic system disorders Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Common Decreases in haemoglobin, haematokrit, leucocytes Uncommon Anaemia, aplastic anaemia, leucopenia Very rare Haemolytic anemia, thrombocytopenia (see also section 4.4 Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Special warnings and precautions for use, Agranulocytosis/neutropenia) Immune system disorders Rare Angioedema, lip oedema; face oedema (see section 4.4 Special warnings and precautions for use, Anaphylactoid and related reactions) Endocrine disorders Formatiert: Schriftart: Fett Frequency not Syndrome of inappropriate antidiuretic hormone secretion known (SIADH) Formatiert: Niederländisch (Niederlande) Psychiatric disorders Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Rare Insomnia, nervousness and paraesthesia Nervous system disorders Common Headache, dizziness Uncommon Mood alterations, mental confusion, impotence Rare Somnolence Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Very rare Dysgeusia Ear and labyrinth disorders Very rare Tinnitus Cardiac disorders Common Palpitations, orthostatic symptoms, syncope Formatiert: Schriftart: (Standard) Helvetica, 12 Pt., Englisch Rare Orthostatic hypotension, chest pain, angina pectoris, arrhythmia (USA) Very rare Myocardial infarction, tachycardia, cerebrovascular accident Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Vascular disorders Common Flushing Respiratory, thoracic and mediastinal disorders Common Cough, symptoms of upper respiratory tract infection, bronchitis Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Uncommon Dyspnoea Very rare Bronchospasm, glossitis, xerostomia Gastrointestinal disorders Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Common Gastrointestinal disorder Uncommon Anorexia Rare Diarrhoea, constipation, nausea, vomiting, abdominal pain Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Very rare Pancreatitis, ileus Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Hepatobiliary disorders Rare Hepatitis (predominantly cholestatic), cholestatic jaundice (see section 4.4 Special warnings and precautions for use, Hepatitis and hepatic failure) Skin and subcutaneous tissue disorders
Sandoz Business use only Page 15 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Common Rash, pruritus, photosensitivity reaction Rare Pemphigus, urticaria Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Very rare Stevens-Johnson syndrome, alopecia, psoriasis, Raynaud´s phenomenon Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Musculoskeletal and connective tissue disorders Rare Arthralgia, arthritis, myalgia Renal and urinary disorders Common Pollakiuria Uncommon Proteinuria Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. Rare Blood urea nitrogen increased, serum creatinine increased, Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. uraemia Very rare Renal impairment (see section 4.4 Special warnings and Formatiert: Schriftart: (Standard) Helvetica, 12 Pt. precautions for use) General disorders and administration site conditions Common Fatigue The following adverse events of unknown frequency have been reported during postmarketing use of benazepril: small bowel angioedema, anaphylactoid reactions, hyperkalaemia, agranulocytosis, neutropenia, impaired vision (see section 4.4 Special warnings and precautions for use).
Laboratory findings As with other ACE inhibitors, minor increases in blood urea nitrogen (BUN) and serum creatinine, which were reversible on discontinuation of therapy, were 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 Special warnings and precautions for use).
Cardiovascular disorders common: severe hypotension with orthostatic effects, especially in high risk groups, dizziness, syncope, impaired vision very rare: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, palpitations, tachycardia, angina pectoris, arrhythmias
Renal and urinary disorders common: renal dysfunction uncommon: proteinuria, progression of renal dysfunction rare: uraemia, acute renal failure
Respiratory, thoracic and mediastinal disorders common: cough, bronchitis uncommon: dyspnoea, sinusitis, rhinitis very rare: bronchospasm, glossitis, xerostomia
Gastrointestinal disorders common: nausea, abdominal pain, indigestion uncommon: vomiting, diarrhoea, obstipation, anorexia, intestinal oedema and cholelithiasis, especially with existing cholecystits
Sandoz Business use only Page 16 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00 very rare: pancreatitis, ileus
Metabolism and nutrition disorders common: hyperkalemia
Nervous system disorders common: headache, fatigue, balance disorders, somnolence, apathy uncommon: mood alterations, paraesthesia, vertigo, taste disturbances, sleep disturbances, mental confusion, nervousness, impotence, blurred vision
Blood and lymphatic system disorders common: decreases in haemoglobin, haematokrit, leucocytes and thrombocytes uncommon: anaemia, aplastic anaemia, thrombocytopenia, leucopenia, Formatiert: Englisch (Großbritannien) neutropenia, agranulocytosis very rare: hemolytic anaemia
Skin and subcutaneous tissue disorders uncommon: rash, pruritus rare: urticaria, pemphigus, Stevens-Johnson Syndrome, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and /or larynx very rare: alopecia, psoriasis, Raynaud’s phenomenon
4.104.9 Overdose
Signs and symptoms Although there is very limited experience of overdosage with benazepril, the main sign to be expected is marked hypotension, which can be associated with electrolytes disturbances and renal failure.
Treatment If ingestion is recent, activated charcoal should be considered. Gastric decontamination (e.g. vomiting, gastric lavage) may be considered in individual cases, in the early period after ingestion.
Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and maintain systemic blood pressure.
In the case of marked hypotension, physiological saline solution should be administered intravenously; depending on the clinical situation the use of vasopressors (e.g. catecholamines i.v.) may be considered.
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 (see section 4.4 Special warnings and precautions for
Sandoz Business use only Page 17 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00 use).Possible symptoms include hypotension, shock, stupor, bradycardia, electrolyte
After intake of an overdose, admission into an intensive care unit is desirable. Recommended measures include induction of vomiting, administration of activated charcoal and administration of a laxative and/or gastric lavage if the tablets were taken recently. Any dehydration, disturbances in the electrolyte balance and hypotension should be treated in an appropriate manner, e .g. plasma-substituting agents or – if the result is insufficient – by catecholamines.
Haemodialysis is not effective.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic Properties
Therapeutic/pharmacological class: angiotensin converting enzyme inhibitorPharmacotherapeutic group: ACE-inhibitors, plain ATC-Code: C 09 AA 07
Benazepril (benazepril HCl) is a prodrug which, after hydrolysis to the active substance benazeprilat, inhibits the angiotensin-converting enzyme (ACE) and so blocks the conversion of angiotensin I to angiotensin II. This reduces all the effects mediated by angiotensin II - i.e. vasoconstriction and production of aldosterone, which promotes the reabsorption of sodium and water in the renal tubules - and elevates cardiac output. Benazepril diminishes the reflex-induced sympathetic increase in heart rate which occurs in response to vasodilatation.
Hypertension Like other ACE inhibitors, benazepril also inhibits degradation of the vasodilator bradykinin by kininase; this inhibition may contribute to the antihypertensive effect.
Benazepril reduces sitting, supine, and standing blood pressure in all grades of hypertension. In most patients, antihypertensive activity sets in about 1 hour after administration of a single oral dose, and maximum reduction of blood pressure is achieved within 2-4 hours. The antihypertensive effect lasts for at least 24 hours after administration. During repeated administration the maximum reduction in blood pressure with each dose is generally reached after 1 week and continues during long-term therapy. The antihypertensive effects are maintained irrespective of race, age, or baseline plasma renin activity. The maximum recommended daily dose of benazepril in hypertensive patients is 40 mg, given as a single dose or two doses. A dose of 80 mg gives an increased response, but experience with this dose is limited.
The antihypertensive effects of benazepril did not differ appreciably between patients receiving high-sodium or low-sodium diets.
Sandoz Business use only Page 18 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Abrupt withdrawal of benazepril has not been associated with a rapid increase in blood pressure. In a study in healthy subjects, single doses of benazepril produced an increase in renal blood flow and had no effect on the glomerular filtration rate.
The antihypertensive effects of benazepril and thiazide-type diuretics are synergistic. Concomitant use of benazepril with other antihypertensive drugs, including beta- blockers and calcium antagonists, has generally produced further decreases in blood pressure.
In a clinical study of 107 paediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or three benazepril dose groups (i.e. 5 or 10 mg/d, 10 or 20 mg/d, 20 or 40 mg/d, depending on the bodyweight) and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on benazepril. No dose-response was observed for the three dose groups.
Congestive heart failure (CHF) In patients pretreated with digitalis and a diuretic, benazepril brought about an increase in cardiac output and exercise tolerance, and a reduction in pulmonary wedge pressure, systemic vascular resistance, and blood pressure. Heart rate was slightly reduced. Treatment with benazepril in CHF patients also lessened fatigue, rales, oedema, and improved NYHA class. Clinical trials have shown that the improvement in haemodynamic variables lasts for 24 hours with once-daily dosing.Benazepril is a potent inhibitor of angiotensin converting enzyme. In patients with hypertension administration of [Nationally completed name] results in a reduction of supine and standing blood pressure to about the same extent with no compensatory increase of 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 glomerular filtration rate is usually unchanged. Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term therapy. Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure. ACE inhibitors are effective even in patients with low-renin hypertension. Although antihypertensive effects have been found in the races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non- black patients. This difference disappears when a diuretic as added.
The antihypertensive effect starts 1 hour after oral intake and lasts for about 24 hours.
Benazepril treatment gives relief of symptoms to patients with congestive heart failure. In contrast to other ACE-inhibitors, possible effects of benazepril on mortality have not been examined in placebo-controlled studies.
Sandoz Business use only Page 19 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
5.2 Pharmacokinetic Properties
Absorption and plasma concentrations At least 37% of an oral dose of benazepril HCl is absorbed. The prodrug is then rapidly converted to the pharmacologically active metabolite, benazeprilat. After administration of benazepril HCl on an empty stomach, peak plasma concentrations of benazepril and benazeprilat are reached after 30 and 60-90 minutes, respectively.
The absolute bioavailability of benazeprilat after oral administration of benazepril HCl is about 28% of the bioavailability after i.v. administration of the metabolite itself. Taking the tablets after food delays absorption, but does not affect the amount absorbed and converted to benazeprilat. Benazepril HCl can therefore be taken with or without food.
In the dose range 5-20 mg, the AUC and peak plasma concentrations of benazepril and benazeprilat are approximately proportional to the size of the dose. Small but statistically significant deviations from dose-proportionality are observed in the wider dose range of 2-80 mg. This may be due to the saturable binding of benazeprilat to ACE.
The kinetics do not change during multiple dosing (5-20 mg once daily). Benazepril does not accumulate. Benazeprilat accumulates only slightly; the steady-state AUC is about 20% higher than that observed during the first 24-hour dosage interval. The effective accumulation half-life of benazeprilat is 10-11 hours. Steady-state levels are reached after 2-3 days.
Distribution About 95% benazepril and benazeprilat binds to human serum proteins (mainly albumin). Binding is not affected by age. The steady-state distribution volume of benazeprilat is about 9 litres.
Biotransformation Benazepril is extensively metabolised, the main metabolite being benazeprilat. This conversion is thought to occur by enzymatic hydrolysis, mainly in the liver. Two further metabolites are the acyl glucuronide conjugates of benazepril and benazeprilat.
Elimination Benazepril is eliminated mainly by metabolic clearance. Benazeprilat is eliminated via the kidneys and the bile; renal excretion is the main route in patients with normal renal function. Metabolic clearance of systemically available benazeprilat is of secondary importance. In the urine, benazepril accounts for less than 1% and benazeprilat for about 20% of an oral dose. Elimination of benazepril from plasma is complete after 4 hours. Elimination of benazeprilat is biphasic with an initial half-life of about 3 hours and a terminal half-life of about 22 hours. The terminal elimination phase (from 24 hours onwards) suggests strong binding of benazeprilat to ACE.
Special patient populations Paediatric
Sandoz Business use only Page 20 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
In paediatric patients, (N = 45) hypertensive, aged 6 to 16 years, given multiple daily doses of benazepril hydrochloride (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents (aged 13 to 16 years), it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of benazeprilat in paediatric patients was around 5 hours, one third that observed in adults.
Hypertensive patients Steady-state trough plasma concentrations of benazeprilat correlate with the size of the daily dose.
Patients with congestive heart failure Absorption of benazepril and its conversion to benazeprilat are not affected. Because elimination is slightly slower, steady-state trough concentrations of benazeprilat tend to be higher in this group than in healthy subjects or hypertensive patients.
Age, mild to moderate renal failure, nephrotic syndrome and hepatic dysfunction The kinetics of benazepril and benazeprilat are not greatly affected by old age, mild or moderate renal impairment (creatinine clearance 30-80 mL/min), or nephrotic syndrome. The kinetics and bioavailability of benazeprilat are not affected in patients with hepatic dysfunction due to cirrhosis, and dose adjustment is not necessary in such patients.
Severe renal failure and end-stage renal disease The kinetics of benazeprilat are substantially affected by severe renal impairment (creatinine clearance < 30 mL/min), which necessitates dose reduction as a result of slower elimination and higher accumulation. Benazepril and benazeprilat are eliminated from the plasma even in patients with end-stage renal disease, the kinetics being similar to those in patients with severe renal impairment. Non-renal (i.e. biliary or metabolic) clearance partly compensates for deficient renal clearance.
Haemodialysis Regular haemodialysis starting at least 2 hours after administration of benazepril HCl does not significantly affect plasma concentrations of benazepril and benazeprilat, which means that no additional dose needs to be given after dialysis. Only a small amount of benazeprilat is removed from the body by dialysis. Benazepril hydrochloride: The prodrug benazepril hydrochloride metabolised (hydrolysis, which takes place mainly in the liver) into benazeprilat, the only active metabolite. After oral administration at least 37% of the dose is absorbed. The bioavailability is approximately 28 % of orally administered benazepril hydrochloride in comparison 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 and benazeprilat is about 95 %.
In patients with severe impaired renal function (creatinine clearance < 30 ml/min) reduced elimination and thus increased accumulation of benazeprilat occurs. In patients with moderate renal impairment (creatinine clearance > 30 ml/min) only
Sandoz Business use only Page 21 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00 slight changes of pharmacokinetics has been observed requiring no dose adjustment.
Lactation Formatiert: Schriftart: Nicht Fett 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
Reproduction toxicity studies No adverse effects on reproductive performance were observed in male and female rats treated with up to 500 mg/kg/day of benazepril HCl.
No direct embryotoxic, fetotoxic, or teratogenic effects were seen in mice treated with up to 150 mg/kg/day, rats treated with up to 500 mg/kg/day, and rabbits treated with up to 5 mg/kg/day.
Mutagenicity In a series of in vitro and in vivo tests no mutagenic potential was detected.
Carcinogenicity No evidence of a tumorigenic effect was seen when benazepril HCl was administered to rats in doses of up to 150 mg/kg/day (250 times the maximum recommended total human dose). No evidence of carcinogenicity was seen when benazepril HCl was administered for 104 weeks to mice in the same doses.
Juvenile toxicity No non-clinical studies have been conducted with the purpose of investigating potential juvenile toxicity of benazepril HCl.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 produced 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/nutrients delivery to the fetus.
Sandoz Business use only Page 22 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
6 PHARMACEUTICAL PARTICULARS
6.1 List of Excipients tablet core: cellulose, microcrystalline crospovidone hydrogenated castor oil lactose monohydrate silica colloidal, anhydrous starch, pregelatinised film-coating material: lactose monohydrate hypromellose macrogol 4000 titandioxide (E 171) 5 and 10 mg: iron oxide, yellow (E 172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special Precautions for Storage
Do not store above 30°C.
6.5 Nature and Contents of Container
The tablets are packed in Aclar-PVC/aluminium blisters and inserted in a carton. Original packages containing 14, 20, 28, 30, 42, 50, 98, 100, 280 (20x14), 280 tablets Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORIZATION HOLDER HEXAL AG
Sandoz Business use only Page 23 of 23 1.3.1 spc-label-pl - common-spc-ii006-003response - 1 Jun-18-2013 (DE/H/1485-1486/001-002-003/II/006-003 Response to PVAR) BENAZEPRIL HYDROCHLORIDE 10 MG; 20 MG; 5 MG FILM- 800-0328.00 800-0324.00 COATED TABLET 800-0326.00
Industriestraße 25 D-83607 Holzkirchen Germany
8 MARKETING AUTHORIZATION NUMBER
9 DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION
10 DATE OF REVISION OF THE TEXT August 2012