Enarenal

The concomitant use of Enarenal 10mg tablets with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

Dual blockade of the rennin-angiotensin-aldosterone system (RASS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RASS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Symptomatic Hypotension

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving Enarenal, symptomatic 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. In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of Enarenal and/or diuretic is adjusted. 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.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Enarenal. This effect is anticipated, and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or Enarenal may be necessary.

Aortic or Mitral Valve Stenosis/Hypertrophic Cardiomyopathy

As with all vasodilators, ACE inhibitors should be given with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Renal Function Impairment

In cases of renal impairment (creatinine clearance <80 ml/min) the initial Enarenal dosage should be adjusted according to the patient's creatinine clearance and then as a function of the patient's response to treatment.).

Renovascular hypertension

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.

Kidney Transplantation

There is no experience regarding the administration of Enarenal in patients with a recent kidney transplantation. Treatment with Enarenal is therefore not recommended.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Enarenal 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 Enarenal 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.

Hypersensitivity/Angioneurotic oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Enarenal. This may occur at any time during treatment. In such cases, Enarenal should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.

Anaphylactoid Reactions during Hymenoptera Desensitisation

Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each desensitisation.

Anaphylactoid Reactions during LDL Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.

Haemodialysis Patients

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69®) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Hypoglycaemia

Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor, should be told to closely monitor for hypoglycaemia, especially during the first month of combined use.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Enarenal blocks angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Enarenal. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age (>70 years) diabetes mellitus, inter-current events in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use of Enarenal and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Lithium

The combination of lithium and Enarenal is generally not recommended.

Lactose

Enarenal contains lactose and therefore should not be used by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Enarenal contains less than 200 mg of lactose per tablet.

Paediatric Use

There is limited efficacy and safety experience in hypertensive children >6 years old, but no experience in other indications. Limited pharmacokinetic data are available in children above 2 months of age. Enarenal is not recommended in children in other indications than hypertension.

Enarenal is not recommended in neonates and in paediatric patients with glomerular filtration rate <30 ml/min/1.73 m², as no data are available.

Pregnancy and lactation

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.

Use of Enarenal is not recommended during breast feeding.

Ethnic differences

As with other angiotensin converting enzyme inhibitors, Enarenal is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetyl salicylic acid, thrombolytics and β-blockers

Enarenal can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and β-blockers

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy.

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 inhibitors therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.

ACE inhibitors therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia)..

Should exposure to ACE inhibitors 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.

Lactation

Limited pharmacokinetic data demonstrate very low concentrations in breast milk. Although these concentrations seem to be clinically irrelevant the use of Enarenal 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 case of an older infant the use of Enarenal in breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.

Undesirable effects reported for Enarenal include:

[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), not known (cannot be estimated from the available data).]

Blood and the lymphatic system disorders:

uncommon: anaemia (including aplastic and hemolytic)

rare: neutropenia, decreases in hemoglobin, decreases in hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases

Endocrine disorders:

not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders:

uncommon: hypoglycaemia (see 4.4 'Special warnings and precautions for use', Hypoglycemia)

Nervous system and psychiatric disorders:

common: headache, depression

uncommon: confusion, somnolence, insomnia, nervousness, paresthaesia, vertigo

rare: dream abnormality, sleep disorders

Eye disorders:

very common: blurred vision

Cardiac and vascular disorders:

very common: dizziness

common: hypotension (including orthostatic hypotension), syncope, chest pain, rhythm disturbances, angina pectoris, tachycardia

uncommon: orthostatic hypotension, palpitations, myocardial infarction or cerebrovascular accident^*, possibly secondary to excessive hypotension in high risk patients (see 4.4 'Special warnings and precautions for use')

rare: Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders:

very common: cough

common: dyspnea

uncommon: rhinorrhea, sore throat and hoarseness, bronchospasm/asthma

rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia

Gastrointestinal disorders:

very common: nausea,

common: diarrhoea, abdominal pain, taste alteration

uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer

rare: stomatitis/aphthous ulcerations, glossitis

very rare: intestinal angioedema

Hepatobiliary disorders:

rare: hepatic failure, hepatitis - either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice)

Skin and subcutaneous tissue disorders:

common: rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see 4.4 'Special warnings and precautions for use')

uncommon: diaphoresis, pruritus, urticaria, alopecia

rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma

A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.

Renal and urinary disorders:

uncommon: renal dysfunction, renal failure, proteinuria

rare: oliguria

Reproductive system and breast disorders:

uncommon: impotence

rare: gynecomastia

General disorders and administration site conditions:

very common: asthenia

common: fatigue

uncommon: muscle cramps, flushing, tinnitus, malaise, fever

Investigations:

common: hyperkalemia, increases in serum creatinine

uncommon: increases in blood urea, hyponatremia

rare: elevations of liver enzymes, elevations of serum bilirubin

^* Incidence rates were comparable to those in the placebo and active control groups in the clinical trials

Limited data are available for overdosage in humans. The most prominent the features of overdosage that have been reported to date are marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system and stupor. Symptoms associated with overdosage of ACE inhibitors may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Serum Enarenalat levels 100 times and 200 times higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of Enarenal, respectively.

The recommended treatment of overdosage is intravenous infusion of normal saline 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. If ingestion is recent, take measures aimed at eliminating Enarenal maleate (e.g., emesis, gastric lavage, administration of absorbents, and sodium sulphate). Enarenal can be removed from the general circulation by haemodialysis (See 4.4 'special warnings and precautions for use',haemodialysis patients). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Two large randomised, comtrolled 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 patient 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 hypotention 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 blocers should therefore not be used concomitantly in patient with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study design to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patient 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, hypotention and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Pharmacotherapeutic Group- Angiotension Converting Enzyme (ACE) inhibitor-

ATC Code: C09AA02

Enarenal maleate is a derivative of two amino acids; L-alanine and L-proline. Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, Enarenal is hydrolysed to Enarenalat which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion.

ACE is identical to kinase II. Thus 'Enarenal' may therefore also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of 'Enarenal' remains to be elucidated.

While the mechanism through which 'Enarenal' lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, 'Enarenal' is antihypertensive even in patients with low-renin hypertension.

Administration of 'Enarenal' to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.

Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of 'Enarenal' has not been associated with rapid increase in blood pressure.

Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of Enarenal. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration. The duration of effect is dose-related. However, at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours.

In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of 'Enarenal' there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.

In short term clinical studies in diabetic and nondiabetic patients with renal disease, decreases in albuminuria and urinary excretion of IgG and total urinary protein were seen after the administration of Enarenal.

When given together with thiazide-type diuretics, the blood pressure-lowering effects of 'Enarenal' are at least additive. 'Enarenal' may reduce or prevent the development of thiazide-induced hypokalemia.

In patients with heart failure on therapy with digitalis and diuretics, treatment with oral or Injection 'Enarenal' was associated with decreases in peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure was also reduced. Exercise tolerance and severity of heart failure, as measured by New York Heart Association criteria, improved. These actions continued during chronic therapy.

In patients with mild to moderate heart failure, Enarenal retarded progressive cardiac dilatation/enlargement and failure, as evidenced by reduced left ventricular end diastolic and systolic volumes and improved ejection fraction.

A multicentre, randomised, double-blind, placebo-controlled trial (SOLVD Prevention trial) examined a population with asymptomatic left ventricular dysfunction (LVEF<35%). 4228 patients were randomised to receive either placebo (n=2117) or Enarenal (n=2111). In the placebo group, 818 patients had heart failure or died (38.6%) as compared with 630 in the Enarenal group (29.8%) (risk reduction: 29%; 95% CI; 21 - 36%; p<0.001). 518 patients in the placebo group (24.5%) and 434 in the Enarenal group (20.6%) died or were hospitalised for new or worsening heart failure (risk reduction 20%; 95% CI; 9 - 30%; p<0.001).

A multicentre, randomised, double-blind, placebo-controlled trial (SOLVD Treatment trial) examined a population with symptomatic congestive heart failure due to systolic dysfunction (ejection fraction <35%). 2569 patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n=1284) or Enarenal (n=1285). There were 510 deaths in the placebo group (39.7%) as compared with 452 in the Enarenal group (35.2%) (reduction in risk, 16%; 95% CI, 5 - 26%; p=0.0036). There were 461 cardiovascular deaths in the placebo group as compared with 399 in the Enarenal group (risk reduction 18%, 95% CI, 6 - 28%, p<0.002), mainly due to a decrease of deaths due to progressive heart failure (251 in the placebo group vs 209 in the Enarenal group, risk reduction 22%, 95% CI, 6 - 35%). Fewer patients died or were hospitalised for worsening heart failure (736 in the placebo group and 613 in the Enarenal group; risk reduction, 26%; 95% CI, 18 - 34%; p<0.0001). Overall in SOLVD study, in patients with left ventricular dysfunction, 'Enarenal' reduced the risk of myocardial infarction by 23% (95% CI, 11 - 34%; p<0.001) and reduced the risk of hospitalisation for unstable angina pectoris by 20% (95% CI, 9 - 29%; p<0.001).

There is limited experience of the use in hypertensive paediatric patients>6 years. In a clinical study involving 110 hypertensive paediatric patients 6 to 16 years of age with a body weight >20 kg and a glomerular filtration rate>30 ml/min/1.73 m², patients who weighed <50 kg received either 0.625, 2.5 or 20 mg of Enarenal daily and patients who weighed >50 kg received either 1.25, 5 or 40 mg of Enarenal daily. Enarenal administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of Enarenal was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. The maximum dose studied was 0.58 mg/kg (up to 40 mg) once daily. The adverse experience profile for paediatric patients is not different from that seen in adult patients.

Absorption

Oral Enarenal maleate is rapidly absorbed, with peak serum concentrations of Enarenal occurring within one hour.Based on urinary recovery, the extent of absorption of oral Enarenal is approximately 60%. Absorption is not affected by food in the gastrointestinal tract.

Following absorption, Enarenal is rapidly and extensively hydrolysed to Enarenalat.,a potent angiotensin converting enzyme inhibitor. Peak serum concentrations of Enarenalat occur 3 to 4 hours after an oral dose of Enarenal. The effective half-life for accumulation of Enarenalat following multiple doses of Enarenal is 11 hours. In subjects with normal renal function, steady-state serum concentrations of Enarenalat were reached after 4 days of treatment.

Distribution

Over the range of concentrations which are therapeutically relevant, Enarenalat binding to human plasma proteins does not exceed 60%.

Biotransformation

Except for conversion to Enarenalat, there is no evidence for significant metabolism of Enarenal.

Elimination

Excretion of Enarenalat is primarily renal. The principal components in urine are Enarenalat, accounting for about 40% of the dose, and intact Enarenal (about 20%).

Renal impairment

The exposure of Enarenal and Enarenalat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min) steady state AUC of Enarenalat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤30 ml/min), AUC was increased approximately 8-fold. The effective half-life of Enarenalat following multiple doses of Enarenal maleate is prolonged at this level of renal insufficiency and time to steady state is delayed. (See 4.2 'Posology and method of administration'.) Enarenalat may be removed from the general circulation by hemodialysis. The dialysis clearance is 62 ml/min.

Children and adolescents

A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg Enarenal maleate. There were no major differences in the pharmacokinetics of Enarenalat in children compared with historic data in adults. The data indicate an increase in AUC (normalised to dose per body weight) with increased age; however, an increase in AUC is not observed when data are normalised by body surface area. At steady state, the mean effective half-life for accumulation of Enarenalat was 14 hours

Lactation: After a single 20 mg oral dose in five postpartum women, the average peak Enarenal milk level was 1.7μg/L (range 0.54 to 5.9 μg/L) at 4 to 6 hours after the dose. The average peak Enarenalat level was 1. 7 μg/L (range 1.2 to 2.3 μg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage. A woman who had been taking oral Enarenal 10 mg daily for 11 months had peak Enarenal milk levels of 2 μg/L 4 hours after a dose and peak Enarenal at levels of 0.75 μg/L about 9 hours after the dose. The total amount of Enarenal and Enarenalat measured in milk during the 24 hour period was 1.44μg/L and 0.63 μg/L of milk respectively. Enarenalat milk levels were undetectable (<0.2 μg/L) 4 hours after a single dose of Enarenal 5 mg in one mother and 10mg in two mothers; Enarenal levels were not determined.

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that Enarenal does not have serious adverse effects on fertility and reproductive performance in rats, and is not teratogenic. In a study in which female rats were dosed prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The compound has been shown to cross the placenta and is secreted in milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to be fetotoxic (causing injury and/or death to the fetus) when given in the second or third trimester.

Not applicable

None