· High blood pressure.

· Reduced progression of renal insufficiency in patients with glomerular nephropathy with hypertension and proteinuria and with creatinine clearance between 30 and 60 ml / min. Hyperkalaemia in these patients should be taken into account, appropriate monitoring is indispensable.

Benazepril is administered as a daily intake.

Hypertension, essential

In the absence of prior or renal insufficiency (in common practice): the effective dosage is 10 mg per day in a single dose If necessary, a non-hyperkalaemic diuretic may be Associated, in order to obtain an additional decrease in arterial pressure.


O or stop the diuretic 3 days before to reintroduce thereafter if necessary

O or administer initial doses of 2.5 mg and adjust them according to the blood pressure response obtained

It is recommended to dose plasma creatinine and serum potassium before treatment and within 15 days of initiation of treatment.

· In subjects older than 70 years of age (see section 4.4), treatment should be initiated with a lower dose (5 mg / day), if necessary up to 10 mg / day after one month of treatment.

In retrovascular hypertension, it is recommended to start treatment at 2.5 mg / day, to be adjusted thereafter to the patient's blood pressure response: Serum creatinine and serum potassium will be controlled In order to detect the occurrence of any functional renal insufficiency (see section Caveats and precautions for use).

In the case of renal insufficiency, the dosage of benazepril is adjusted to the degree of this deficiency

O if the creatinine clearance is greater than or equal to 30 ml / min, there is no need to change the dosage

O If the creatinine clearance is less than 30 ml / min, a daily dose of 5 mg per day is recommended.
In these patients, normal medical practice includes periodic control of potassium and creatinine, for example every two months in a period of stability, therapeutic.

The diuretics to be combined, in this case are the so-called diuretics of the loop.

Benazeprilate is weakly dialyzable (see Warnings and Precautions for Use).

In the slowing progression of renal insufficiency, in patients with glomerular nephropathy with hypertension and proteinuria and with creatinine clearance between 30 and 60 ml / min

The recommended dose is 10 mg per day. Monitoring of serum potassium is essential. Other therapies, antihypertensives may be combined with BENAZEPRIL, MYLAN if necessary (see sections, Contraindications, Warnings and Precautions, Interactions with other medicinal products and other forms of interaction and pharmacodynamic properties ).

INHIBITORS OF THE CONVERSION ENZYME (IEC) NOT ASSOCIATED, ATC Code: C09AA07

Mechanism of action, pharmacological

Benazepril is an angiotensin converting enzyme (ACE) inhibitor of angiotensin II, a vasoconstrictor substance but also a stimulant of aldosterone secretion by the adrenal cortex. Br>

The result is

· Decreased secretion of aldosterone

· Elevated renin activity, plasma, aldosterone no longer having negative feedback

A decrease in total peripheral resistance with a preferential action on the muscular and renal territories, without this drop being accompanied by hydrosodic retention or reflex tachycardia in chronic treatment
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The antihypertensive action of benazepril also occurs in subjects with low or normal renin concentrations

Benazepril acts through its active metabolite, benazeprilate, the other metabolites, being inactive.


Benazepril is active in all stages of arterial hypertension: mild, moderate or severe, decreased pressure, systolic and diastolic arterial pressure, decubitus, and orthostatism with no change in cardiac rhythm.

The antihypertensive activity, after a single dose, takes place from the first hour, is maximum between 2 and 4 hours, and is maintained for 24 hours. >
The residual blockade of the 24-hour conversion enzyme is very high, ranging from about 90% to 95%.


The discontinuation of treatment is not accompanied by a rebound in hypertension:

If necessary, the addition of a thiazide diuretic results in additive synergy. The combination of an enzyme-conversion inhibitor and a thiazide also reduces the risk of hypokalemia induced by the diuretic alone.
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The use of the combination of an ACE inhibitor with an angiotensin II receptor antagonist (ARA II) was analyzed in two large randomized controlled trials (ONTARGET ONLY Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes). The ONTARGET study was performed in patients with a history of disease, cardiovascular disease or cerebrovascular disease, or with type 2 diabetes with target organs. The VA NEPHRON-D study was performed in type 2 diabetic patients with diabetic nephropathy

Compared to monotherapy, these studies did not demonstrate any significant beneficial effect on the progression of renal and / or cardiovascular disease and mortality, while there was an increase Of the risk of hyperkalemia, acute renal failure and / or hypotension

These results are also applicable to other IEC and ARA II, taking into account the similarity of their pharmacodynamic properties.

IEC and ARA II should therefore not be combined in patients with diabetic nephropathy.

The ALTITUDE study (Aliskiren Trial, in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was carried out with the aim of evaluating the benefit of the addition of aliskiren to standard treatment with IEC or ARA II In patients with type 2 diabetes and chronic renal insufficiency, with or without cardiovascular disorders. This study was terminated prematurely due to an increased risk of adverse events. Cardiovascular, vascular and cerebral deaths were more frequent in the aliskiren group than in the placebo group, even in adverse events and in some serious adverse events such as hyperkalemia, hypotension And renal insufficiency were reported more frequently in the aliskiren group than in the placebo group.


The primary efficacy endpoint was progression of renal insufficiency: number of patients with either doubling of serum creatinine or indication with renal replacement therapy

During the study period, 88 patients met this criterion: 57 patients treated with placebo, 31 patients with benazepril (p

This medication contains oil, castor oil and may cause digestive problems (laxative effect, mild, diarrhea)

Double blockade of the system, renin-angiotensin-aldosterone (RAAS)

It is established that the combination of ACE inhibitors, angiotensin II receptor antagonists (ARA II) or aliskiren increases the risk of hypotension, Hyperkalaemia and impairment of renal function (including the risk of acute renal failure)

Therefore, the double blockade of RAAS by the combination of IEC, ARA II or aliskiren is not recommended (see sections Interactions with other medicines and other forms of interactions and properties Pharmacodynamics).

Nevertheless, if such an association is considered absolutely necessary, it can only be done under the supervision of a specialist and with close and frequent control of renal function, ionogram, blood pressure Arterial pressure. ACE inhibitors and ARBs II should not be combined in patients with diabetic nephropathy

Risk of neutropenia / agranulocytosis in the field, immunosuppressed

ACE inhibitors have unusually resulted in agranulocytosis and / or bone marrow depression when administered
· At high doses

· In patients with renal insufficiency associated with systemic diseases (collagenases such as lupus, disseminated erythematosus or scleroderma) with immunosuppressive and / or potentially leucopenic treatment
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The strict observance of the recommended dosages seems to constitute the best prevention of the occurrence of these events. However, if a conversion enzyme inhibitor is to be administered to this type of patient, the benefit / risk ratio will be carefully measured.


Angioedema of the face, extremities, lips, tongue, glottis and / or larynx has been rarely reported in patients treated with an ACE inhibitor, including benazepril . In such cases, benazepril should be discontinued immediately and the patient should be monitored until the edema has disappeared.


Angioedema associated with laryngeal edema may be fatal When tongue, glottis, or larynx is involved, which can lead to airway obstruction, a subcutaneous adrenaline , 1/1000 (0.3 ml to 0.5 ml) should be administered promptly and the other appropriate treatments should be applied.
The prescription of an ACE inhibitor should no longer be considered in these patients (see section Contraindications).



The incidence of angioedema when converting enzyme therapy is higher in black patients than in other patients.
Patients with a history of angioedema not related to the use of a conversion enzyme inhibitor have an increased risk of angioedema under the enzyme-converting enzyme inhibitor

Hemodialysis

Anaphylactoid reactions (edema of the tongue and lips with dyspnea and decreased blood pressure) have also been observed during hemodialysis using high permeability membranes (polyacrylonitrile) in patients treated with anti - Conversion enzyme. It is recommended to avoid this association

Pregnancy

ACE inhibitors should not be started during pregnancy. Unless IEC treatment is considered essential, it is recommended that patients considering pregnancy modify their antihypertensive therapy for a drug with a well established safety profile during pregnancy. In case of diagnosis of pregnancy, treatment with IEC should be stopped immediately and if necessary an alternative treatment will be started (see sections Contraindications and Pregnancy and lactation)

Breastfeeding

The use of benazepril is not recommended in women who are breast-feeding (see section Pregnancy and breast-feeding).
Precautions for use

Cough

A dry cough has been reported with the use of the enzyme inhibitors of conversion. It is characterized by its persistence, as well as by its disappearance at the end of the treatment.

The iatrogenic etiology should be considered in the presence of this symptom.
In cases where the prescription of an ACE inhibitor is essential, further processing may be considered.

Child

The efficacy and tolerability of benazepril in children have not been established

Risk of hypotension, arterial and / or renal insufficiency (in case of heart failure, hydro depletion, sodium, etc.)
A significant stimulation of the renin-angiotensin-aldosterone system is observed, particularly in patients with severe hydro-sodium depletion (deodorized, strict or prolonged diuretic treatment), in patients with initially low blood pressure Renal artery stenosis, congestive heart failure or cirrhosis, edema-ascitic.

The blocking of this system by an inhibitor of the conversion enzyme can then cause a sudden drop in blood pressure and / or, rarely and in the first two weeks of treatment, A more variable delay, elevation of plasma creatinine indicative of acute functional renal failure,

In all these cases, the initiation of the treatment must be progressive (see section Posology and mode of administration).

Subject: aged

Renal function and serum potassium are appreciated prior to initiation of treatment (see Dosage and Administration). The starting dose is adjusted as a function of the blood pressure response, a fortiori in the case of hydrolysed depletion, in order to avoid any sudden onset hypotension. Br>
Renal insufficiency

In patients with renal insufficiency (creatinine clearance less than 30 ml / min), the dosage is reduced (see section 4.2).

In these patients, and in patients with glomerular nephropathy, normal medical practice includes periodic control of potassium and creatinine (see section Dosage and Mode of Administration).

Subject with known atherosclerosis

Since the risk of hypotension exists, especially in all patients with ischemic heart disease or cerebral circulatory insufficiency, starting with low-dose therapy.

Hypertension, renovascular

Treatment of renal arterial hypertension is revascularization Nevertheless, ACE inhibitors may be useful for patients with hypertension, renovascular awaiting corrective intervention, or Is not possible.

Treatment should then be instituted with a low dose and monitoring of renal function and serum potassium should be performed, some patients having developed functional renal insufficiency, reversible, discontinuation of treatment.

Anemia

Anemia with decreased hemoglobin has been demonstrated, and in renal transplant patients or hemodialysis patients, the decrease is even more pronounced when the baseline values ​​are high. This effect does not appear to be dose-dependent but would be related to the mechanism of action of the enzyme inhibitors of
This decrease is moderate, occurs within 1 to 6 months and then remains stable. It is reversible upon cessation of treatment. This can be prosecuted in this type of patient, by performing a regular hematological control.

Other populations at risk

In patients with severe cardiac insufficiency (Stage IV) or in patients with insulin-dependent diabetes (tendency, spontaneous hyperkalaemia), treatment will be initiated under medical supervision with a reduced initial dosage.

Do not interrupt beta-blocker therapy in hypertensive patients with coronary artery disease: IEC will be added to the beta-blocker.

Surgical intervention

In the case of anesthesia, and more, when anesthesia is performed with hypotensive agents, inhibitors of the enzyme of conversion are at the origin of hypotension. It is possible, therefore, is recommended the day before the intervention for long-acting conversion enzyme inhibitors, such as benazepril.
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Data from clinical trials have shown that double blockade of the renin-angiotensin-aldosterone system (RAAS) by the concomitant use of conversion enzyme inhibitors, angiotensin receptor antagonists Or aliskiren is associated with a higher frequency of undesirable events such as hypotension, hyperkalaemia, and impaired renal function (including acute renal failure) in comparison to; The use of a single medicinal product acting on the RAAS (see section 4.3).
Some drugs or classes of therapeutics are likely to promote the occurrence of hyperkalaemia: potassium salts, potassium-sparing diuretics, inhibitors, angiotensin II inhibitors, anti-angiotensin II Non-steroidal inflammatory drugs, heparins (low molecular weight or non-fractionated), ciclosporin and tacrolimus, trimethoprim.

In hypertension: when a previous diuretic treatment may have resulted in water depletion,
· Either stop the diuretic before beginning treatment with ACE inhibitors and reintroduce a diuretic, hypokalemia if necessary, later
· Or administer reduced initial doses of IEC and gradually increase the dosage.

In congestive heart failure: treated with diuretics, start with a very low dose of IEC, possibly after reducing the dose of the associated hypokalemic diuretic.
In all cases: monitor renal function (creatinine) in the first few weeks of treatment with IEC.

(Aspirin) ≥ 3 g / d , NSAIDs, including inhibitors, selective COX-2 and acetylsalicylic acid
Acute renal failure in the patient at risk (elderly and / or dehydrated) by decreased filtration, glomerular (inhibition of prostaglandins, vasodilators due to NSAIDs or aspirin).

In addition, antihypertensive effect reduction.

Hydrate the patient, monitor the function, renal at the beginning of treatment.
+; Baclofen

Increased effect, antihypertensive.

Blood Pressure Monitoring and Dosage Adjustment of the Antihypertensive Medication If Needed

Associations to be taken into account

+ Alphabloquants for urological purposes: alfuzosin, doxazosin, prazosin tamsulosin, terazosin

Increase in hypotensive effect. Risk of increased orthostatic hypotension.

+ Amifostine

Increased effect, antihypertensive.

+ Antidepressants imipraminic, neuroleptic

Effect, antihypertensive and risk of orthostatic hypotension, increased (additive effect)

Corticosteroids, tetracosactide (pathway, general) (except hydrocortisone used as a replacement therapy in Addison's disease)

Decreased antihypertensive effect (hydrosodic retention of corticosteroids).

Not applicable.

The most probable event, in case of overdose, is hypotension.

If severe hypotension occurs, it can be controlled by placing the patient in the decubitus, lower head, and if necessary by perfusion IV of isotonic sodium chloride solution or by any other means of volume expansion. Code>
Benazeprilate, the active form of benazepril, is weakly dialyzable (see section Properties, Pharmacokinetics).
Pregnancy

Linked to: BENAZEPRIL

Use of ACE inhibitors is not recommended during the first trimester of pregnancy (see Warnings and Precautions for Use). The use of ACE inhibitors is contraindicated in the 2 nd and 3 rd trimesters of pregnancy (see sections Contraindications and Warnings and Precautions for Use)

The available epidemiological data concerning the risk of malformation after exposure to IEC in the first trimester of pregnancy are not conclusive. However, a small increase in the risk of congenital malformations can not be ruled out. A, unless treatment with ACE inhibitors is considered essential, it is recommended that patients considering pregnancy modify their antihypertensive treatment for a drug with a well-established safety profile during pregnancy. In case of pregnancy diagnosis, treatment with IEC should be discontinued immediately and, if necessary, an alternative treatment will be started.

Exposure to ACE inhibitors during the 2 nd and 3 rd trimesters of pregnancy is known to cause fetotoxicity (decreased renal function, oligo-hydramnios, delayed ossification of skull bones) and toxicity In newborns (renal insufficiency, hypotension, hyperkalaemia) (see section on safety data, preclinical). In case of exposure to an ACE from the 2nd trimester of pregnancy, it is recommended to perform a fetal ultrasound in order to verify the renal function and the bones of the vault of the skull. IEC-treated mothers should be monitored for blood pressure (see sections 4.3 and 4.4).

Breastfeeding

Linked to bénazépril

Limited pharmacokinetic data have shown low concentrations in breast milk (see section 5.2 Pharmacokinetic Properties). Although these concentrations do not appear to be clinically relevant, the use of BENAZEPRIL MYLAN 10 mg tablets is not recommended for use in breastfeeding premature infants and during the first few weeks after breast- Childbirth, because of the possible risk of adverse effects, cardiovascular and renal and because the clinical experience is limited.
In the case of an older infant, the use of BENAZEPRIL MYLAN 10 mg, film-coated tablet, breakable during breast-feeding may be considered if this treatment is necessary, and for the mother and follow-up Of the occurrence of the minor undesirable effect in the child is performed.
At the clinical level

Have been found

· Headache, asthenia, reactions, vasomotor, dizziness, palpitations

· Hypotension, orthostatic or not (see Warnings and precautions for use)

· Rash, pemphigus, Stevens syndrome, Johnson

· Digestive problems due to the presence of castor oil (nausea, vomiting, pain, abdominal pain), dysgeusia

· Isolated cases of liver disease

· A dry cough has been reported with the use of ACE inhibitors. It is characterized by its persistence as well as by its disappearance at the end of the treatment The iatrogenic etiology should be considered in the presence of this symptom.
Exceptionally

Angioedema (angioedema) (see Warnings and Precautions for Use)

Biologically speaking

Moderate increase in urea and plasma creatinine, reversible at cessation of treatment. This increase is most frequently encountered in cases of renal artery stenosis, arterial hypertension, treated with diuretics, renal insufficiency,

In the case of glomerular nephropathy, administration of an ACE inhibitor may cause proteinuria.


Anemia (see Warnings and Precautions) has been reported with conversion enzyme inhibitors on particular sites (renal transplant, hemodialysis). Hemolytic anemia has been observed.

· Hypertension · Slower progression of renal insufficiency in patients with glomerular nephropathy with hypertension and proteinuria and with creatinine clearance between 30 and 60 ml / min .; The risk of occurrence of hyperkalaemia in these patients should be taken into account, appropriate monitoring is essential.