Prexanil

Posology

The dose should be individualised according to the patient profile and blood pressure response.

Hypertension

Prexanil erbumine may be used in monotherapy or in combination with other classes of anti-hypertensive therapy.

The recommended starting dose is 4 mg given once daily in the morning.

Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation or severe hypertension) may experience an excessive drop in blood pressure following the initial dose. A starting dose of 2 mg is recommended in such patients and the initiation of treatment should take place under medical supervision. The dose may be increased to 8 mg once daily after one month of treatment.

Symptomatic hypotension may occur following initiation of therapy with Prexanil erbumine; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with Prexanil erbumine.

In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Prexanil erbumine should be initiated with a 2 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Prexanil erbumine should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.

In elderly patients treatment should be initiated at a dose of 2 mg, which may be progressively increased to 4 mg after one month, then to 8 mg if necessary, depending on renal function (see Table 1 “Dosage adjustment in renal impairment”, below).

Symptomatic heart failure

It is recommended that Prexanil erbumine, generally associated with a non-potassium-sparing diuretic and/or digoxin and/or a beta-blocker, be introduced under close medical supervision with a recommended starting dose of 2 mg taken in the morning. This dose may be increased after 2 weeks to 4 mg once daily, if tolerated.

The dose adjustment should be based on the clinical response of the individual patient.

In severe heart failure and in other patients considered to be at high risk (patients with impaired renal function and a tendency to have electrolyte disturbances, patients receiving simultaneous treatment with diuretics and/or treatment with vasodilating agents), treatment should be initiated under careful supervision.

Patients at high risk of symptomatic hypotension, e.g. patients with salt depletion, with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy, should have these conditions corrected, if possible, prior to therapy with Prexanil erbumine. Blood pressure, renal function and serum potassium should be monitored closely, both before and during treatment with Prexanil Erbumine.

Stable coronary artery disease

Prexanil erbumine should be introduced at a dose of 4 mg once daily for two weeks, then increased to 8 mg once daily, depending on renal function and provided that the 4 mg dose is well tolerated.

Elderly patients should receive 2 mg once daily for one week, then 4 mg once daily the next week, before increasing the dose up to 8 mg once daily, depending on renal function (see Table 1 “Dosage adjustment in renal impairment”, below). The dose should be increased only if the previous lower dose is well tolerated.

Special populations

Renal impairment

Dosage in patients with renal impairment should be based on creatinine clearance as outlined in table 1 below:

Table 1: dosage adjustment in renal impairment

* Dialysis clearance of Prexanilat is 70 ml/min.

For patients on haemodialysis, the dose should be taken after dialysis.

Hepatic impairment

No dosage adjustment is necessary in patients with hepatic impairment.

Paediatric population

Efficacy and safety of use in children and adolescents aged below 18 years have not been established. Therefore, use in children and adolescents is not recommended.

Method of administration

For oral use.

It is recommended that Prexanil Erbumine is taken once daily in the morning, before a meal.

Posology

The dose should be individualised according to the patient profile and blood pressure response.

Hypertension

Prexanil may be used in monotherapy or in combination with other classes of anti-hypertensive therapy.

The recommended starting dose is 4 mg given once daily in the morning.

Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation or severe hypertension) may experience an excessive drop in blood pressure following the initial dose. A starting dose of 2 mg is recommended in such patients and the initiation of treatment should take place under medical supervision. The dose may be increased to 8 mg once daily after one month of treatment.

Symptomatic hypotension may occur following initiation of therapy with Prexanil; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with Prexanil.

In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Prexanil should be initiated with a 2 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Prexanil should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.

In elderly patients treatment should be initiated at a dose of 2 mg, which may be progressively increased to 4 mg after one month, then to 8 mg if necessary, depending on renal function (see Table 1 “Dosage adjustment in renal impairment”, below).

Symptomatic heart failure

It is recommended that Prexanil, generally associated with a non-potassium-sparing diuretic and/or digoxin and/or a beta-blocker, be introduced under close medical supervision with a recommended starting dose of 2 mg taken in the morning. This dose may be increased after 2 weeks to 4 mg once daily, if tolerated.

The dose adjustment should be based on the clinical response of the individual patient.

In severe heart failure and in other patients considered to be at high risk (patients with impaired renal function and a tendency to have electrolyte disturbances, patients receiving simultaneous treatment with diuretics and/or treatment with vasodilating agents), treatment should be initiated under careful supervision.

Patients at high risk of symptomatic hypotension, e.g. patients with salt depletion, with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy, should have these conditions corrected, if possible, prior to therapy with Prexanil. Blood pressure, renal function and serum potassium should be monitored closely, both before and during treatment with Prexanil.

Stable coronary artery disease

Prexanil should be introduced at a dose of 4 mg once daily for two weeks, then increased to 8 mg once daily, depending on renal function and provided that the 4 mg dose is well tolerated.

Elderly patients should receive 2 mg once daily for one week, then 4 mg once daily the next week, before increasing the dose up to 8 mg once daily, depending on renal function (see Table 1 “Dosage adjustment in renal impairment”, below). The dose should be increased only if the previous lower dose is well tolerated.

Special populations

Renal impairment

Dosage in patients with renal impairment should be based on creatinine clearance as outlined in table 1 below:

Table 1: dosage adjustment in renal impairment

* Dialysis clearance of perindoprilat is 70 ml/min.

For patients on haemodialysis, the dose should be taken after dialysis.

Hepatic impairment

No dosage adjustment is necessary in patients with hepatic impairment.

Paediatric population

Efficacy and safety of use in children and adolescents aged below 18 years have not been established. Therefore, use in children and adolescents is not recommended.

Method of administration

For oral use.

It is recommended that Prexanil is taken once daily in the morning, before a meal.

Limited data are available for overdosage in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

The recommended treatment of overdosage is intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Prexanil may be removed from the general circulation by haemodialysis. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Limited data are available for overdosage in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

The recommended treatment of overdosage is intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Perindopril may be removed from the general circulation by haemodialysis. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Pharmacotherapeutic group: ACE inhibitor, plain, ATC code: C09A A04

Mechanism of action

Prexanil is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme, ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release), and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g. cough).

Prexanil acts through its active metabolite, Prexanilat. The other metabolites show no inhibition of ACE activity in vitro.

Clinical efficacy and safety

Dual blockade of the reninangiotensinaldosterone system (RAAS) clinical trial data

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 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.

Hypertension

Prexanil is active in all grades of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions is observed.

Prexanil reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral blood flow increases, with no effect on heart rate.

Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually unchanged.

The anti-hypertensive activity is maximal between 4 and 6 hours after a single dose and is sustained for at least 24 hours: trough effects are about 87-100 % of peak effects.

The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and persists without the occurrence of tachyphylaxis.

Discontinuation of treatment does not lead to a rebound effect.

Prexanil reduces left ventricular hypertrophy.

In man, Prexanil has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and decreases the media: lumen ratio of small arteries.

An adjunctive therapy with a thiazide diuretic produces an additive type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.

Heart failure

Prexanil Erbumine reduces cardiac work by a decrease in pre-load and after-load.

Studies in patients with heart failure have demonstrated:

- Decreased left and right ventricular filling pressures,

- Reduced total peripheral vascular resistance,

- Increased cardiac output and improved cardiac index.

In comparative studies, the first administration of 2 mg of Prexanil to patients with mild to moderate heart failure was not associated with any significant reduction of blood pressure as compared to placebo.

Patients with stable coronary artery disease

The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting 4 years.

Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised to 8 mg Prexanil (n=6110) or placebo (n=6108).

The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or a previous coronary revascularisation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid lowering agents and beta-blockers.

The main efficacy criterion was the composite of cardiovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with 8 mg Prexanil once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of 20%, 95%CI [9.4; 28.6] - p<0.001).

In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] - p<0.001) in the primary endpoint was observed by comparison to placebo.

Paediatric population

The safety and efficacy of Prexanil in children and adolescents aged below 18 years have not been established.

In an open, non-comparative clinical study in 62 hypertensive children aged from 2 to 15 years with a glomerular filtration rate > 30 ml/min/1.73 m², patients received Prexanil with an average dose of 0.07 mg/kg. The dose was individualised according to the patient profile and blood pressure response up to a maximum dose of 0.135 mg/kg/day.

Fifty-nine patients completed the period of three months, and 36 patients completed the extension period of the study, i.e. were followed at least 24 months (mean study duration: 44 months).

Systolic and diastolic blood pressure remained stable from the inclusion to the last assessment in patients previously treated by other antihypertensive treatments, and decreased in naïve patients.

More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last assessment.

The safety was consistent with the known safety profile of Prexanil.

Pharmacotherapeutic group: ACE inhibitor, plain, ATC code: C09A A04

Mechanism of action

Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme, ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release), and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g. cough).

Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.

Clinical efficacy and safety

Dual blockade of the reninangiotensinaldosterone system (RAAS) clinical trial data

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 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.

Hypertension

Perindopril is active in all grades of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions is observed.

Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral blood flow increases, with no effect on heart rate.

Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually unchanged.

The anti-hypertensive activity is maximal between 4 and 6 hours after a single dose and is sustained for at least 24 hours: trough effects are about 87-100 % of peak effects.

The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and persists without the occurrence of tachyphylaxis.

Discontinuation of treatment does not lead to a rebound effect.

Perindopril reduces left ventricular hypertrophy.

In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and decreases the media: lumen ratio of small arteries.

An adjunctive therapy with a thiazide diuretic produces an additive type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.

Heart failure

Prexanil reduces cardiac work by a decrease in pre-load and after-load.

Studies in patients with heart failure have demonstrated:

- Decreased left and right ventricular filling pressures,

- Reduced total peripheral vascular resistance,

- Increased cardiac output and improved cardiac index.

In comparative studies, the first administration of 2 mg of perindopril to patients with mild to moderate heart failure was not associated with any significant reduction of blood pressure as compared to placebo.

Patients with stable coronary artery disease

The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting 4 years.

Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised to 8 mg perindopril (n=6110) or placebo (n=6108).

The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or a previous coronary revascularisation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid lowering agents and beta-blockers.

The main efficacy criterion was the composite of cardiovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with 8 mg perindopril once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of 20%, 95%CI [9.4; 28.6] - p<0.001).

In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] - p<0.001) in the primary endpoint was observed by comparison to placebo.

Paediatric population

The safety and efficacy of perindopril in children and adolescents aged below 18 years have not been established.

In an open, non-comparative clinical study in 62 hypertensive children aged from 2 to 15 years with a glomerular filtration rate > 30 ml/min/1.73 m², patients received perindopril with an average dose of 0.07 mg/kg. The dose was individualised according to the patient profile and blood pressure response up to a maximum dose of 0.135 mg/kg/day.

Fifty-nine patients completed the period of three months, and 36 patients completed the extension period of the study, i.e. were followed at least 24 months (mean study duration: 44 months).

Systolic and diastolic blood pressure remained stable from the inclusion to the last assessment in patients previously treated by other antihypertensive treatments, and decreased in naïve patients.

More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last assessment.

The safety was consistent with the known safety profile of perindopril.

Absorção

Após administração oral, a absorção de Prexanil é rápida e a concentração máxima é atingida dentro de 1 hora. A meia-vida plasmática do Prexanil é igual a 1 hora.

Prexanil é um pró-droga. Vinte e sete por cento da dose administrada de Prexanil atinge a corrente sanguínea como metabolito ativo Prexanilat. Além do Prexanilat ativo, o Prexanil produz cinco metabólitos, todos inativos. O pico da concentração plasmática de Prexanilat é alcançado em 3 a 4 horas.

Como a ingestão de alimentos diminui a conversão para Prexanilat, daí a biodisponibilidade, a Prexanil erbumina deve ser administrada por via oral em uma dose diária única na manhã anterior a uma refeição.

Foi demonstrada uma relação linear entre a dose de Prexanil e sua exposição plasmática.

Distribuição

O volume de distribuição é de aproximadamente 0,2 l / kg para Prexanilat não ligado. A ligação do Prexanilat às proteínas plasmáticas é de 20%, principalmente à enzima de conversão da angiotensina, mas depende da concentração.

Eliminação

O pré-xanilat é eliminado na urina e a meia-vida terminal da fração não ligada é de aproximadamente 17 horas, resultando em estado estacionário em 4 dias.

Populações especiais

A eliminação do Prexanilat é diminuída em idosos e também em pacientes com insuficiência cardíaca ou renal. O ajuste da dose na insuficiência renal é desejável, dependendo do grau de comprometimento (depuração da creatinina).

A depuração dialis de Prexanilat é igual a 70 ml / min.

A cinética do prexanil é modificada em pacientes com cirrose: a depuração hepática da molécula parental é reduzida pela metade. No entanto, a quantidade de Prexanilat formada não é reduzida e, portanto, não é necessário ajuste posológico.

Absorção

Após administração oral, a absorção do perindopril é rápida e a concentração máxima é atingida dentro de 1 hora. A meia-vida plasmática do perindopril é igual a 1 hora.

O perindopril é um pró-droga. Vinte e sete por cento da dose administrada de perindopril atinge a corrente sanguínea como metabolito ativo perindoprilato. Além do perindoprilato ativo, o perindopril produz cinco metabólitos, todos inativos. O pico da concentração plasmática de perindoprilato é alcançado em 3 a 4 horas.

Como a ingestão de alimentos diminui a conversão em perindoprilato, daí a biodisponibilidade, o Prexanil deve ser administrado por via oral em uma única dose diária pela manhã antes de uma refeição.

Foi demonstrada uma relação linear entre a dose de perindopril e sua exposição plasmática.

Distribuição

O volume de distribuição é de aproximadamente 0,2 l / kg para o perindoprilato não ligado. A ligação do perindoprilato às proteínas plasmáticas é de 20%, principalmente à enzima de conversão da angiotensina, mas depende da concentração.

Eliminação

O perindoprilato é eliminado na urina e a meia-vida terminal da fração não ligada é de aproximadamente 17 horas, resultando em estado estacionário em 4 dias.

Populações especiais

A eliminação do perindoprilato diminui em idosos e também em pacientes com insuficiência cardíaca ou renal. O ajuste da dose na insuficiência renal é desejável, dependendo do grau de comprometimento (depuração da creatinina).

A depuração dialis do perindoprilato é igual a 70 ml / min.

A cinética do perindopril é modificada em pacientes com cirrose: a depuração hepática da molécula parental é reduzida pela metade. No entanto, a quantidade de perindoprilato formada não é reduzida e, portanto, não é necessário ajuste posológico.