Fibrosan

- Hypersensitivity to enalapril, to any of the excipients or any other ACE inhibitor

- History of angioedema associated with previous ACE-inhibitor therapy

- Hereditary or idiopathic angioedema

- Second and third trimesters of pregnancy

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

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

Pretreatment assessment of renal function:

Evaluation of the patient should include assessment of renal function prior to initiation of therapy, and during treatment where appropriate.

Symptomatic hypotension:

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Enalapril tablets, 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 (see “Posology and method of administration” for management of these patients). In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of 'Enalapril' and/or diuretic is adjusted.

Similar considerations may apply to patients with ischaemic 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 a supine position. Volume repletion with oral fluids or intravenous normal saline may be required. Intravenous atropine may be necessary if there is associated bradycardia. A transient hypotensive response is not a contra-indication to further doses, which can usually be given 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 Enalapril tablets. This effect is anticipated, and usually is not a reason to discontinue treatment. If such hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or Enalapril tablets may become 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 enalapril dosage should be adjusted according to the patient's creatinine clearance and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients.

Renal failure has been reported in association with enalapril tablets and has been occurring mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure when associated with therapy with enalapril tablets is usually reversible.

Some hypertensive patients, with no apparent pre-existing renal disease, have developed increases in blood urea and creatinine when enalapril tablets have been given concurrently with a diuretic.).

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 'Enalapril' in patients with a recent kidney transplantation. Treatment with 'Enalapril' 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. Enalapril 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 enalapril 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 with angiotensin-converting enzyme inhibitors, including Enalapril tablets. This may occur at any time during treatment. In such cases, Enalapril tablets should be discontinued immediately 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 (see also4.3).

Patients receiving co-administration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Anaphylactic reactions during hymenoptera desensitisation:

Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom (e.g. Bee or Wasp 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 sulphate 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 hypoglycemia, especially during the first month of combined use. (See 4.5

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.

Surgery / Anaesthesia:

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Enalapril 5 mg, tablets block 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 Enalapril. 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 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 Enalapril 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 Enalapril is generally not recommended.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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

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.”

Lactose

Enalapril tablets 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. Enalapril Tablets contains less than 200 mg of lactose per tablet.

Paediatric population

'Enalapril' 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

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.

Ethnic differences

As with other angiotensin-converting enzyme inhibitors, Enalapril 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.

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 Fibrosan, 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 Fibrosan 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 Fibrosan. 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 Fibrosan 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 Fibrosan 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 Fibrosan in patients with a recent kidney transplantation. Treatment with Fibrosan 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. Fibrosan 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 Fibrosan 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 Fibrosan. This may occur at any time during treatment. In such cases, Fibrosan 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, Fibrosan 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 Fibrosan. 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 Fibrosan 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 Fibrosan is generally not recommended.

Lactose

Fibrosan 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. Fibrosan 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. Fibrosan is not recommended in children in other indications than hypertension.

Fibrosan 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 Fibrosan is not recommended during breast feeding.

Ethnic differences

As with other angiotensin converting enzyme inhibitors, Fibrosan 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 in to account occasionally dizziness or weariness may occur.

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

Undesirable effects reported for enalapril 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 haemolytic).

Rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, 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).

Nervous system and psychiatric disorders

Common: headache, depression, syncope, taste alteration

Uncommon: confusion, somnolence, insomnia, nervousness, paresthesia, vertigo

Rare: dream abnormality, sleep disorders

Very common: dizziness

Eye disorders:

Very common: blurred vision.

Ear and Labyrinth disorders:

Uncommon: Tinnitus

Cardiac and vascular disorders:

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)

Rare: Raynaud's phenomenon

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

Respiratory disorders:

Very common: cough.

Common: dyspnoea.

Uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma.

Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastro-intestinal disorders:

Very common: nausea.

Common: diarrhoea, abdominal pain

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

Uncommon: diaphoresis, pruritus, urticaria, alopecia.

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

Not known: 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.

Musculoskeletal, connective tissue, and bone disorders

Uncommon: Muscle cramps

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:, malaise, fever.

Investigations:

Common: hyperkalaemia, increases in serum creatinine.

Uncommon: increases in blood urea, hyponatraemia.

Rare: elevations of liver enzymes, elevations of serum bilirubin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow card in the Google play or Apple App store.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetyl salicylic acid, thrombolytics and β-blockers

Fibrosan 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 Fibrosan 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 Fibrosan 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 Fibrosan 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 features of overdosage reported to date are marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin-aldosterone 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 enalaprilat 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 Enalapril, respectively.

The recommended treatment of overdosage is intravenous infusion of normal saline solution.) 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. 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 Fibrosanat 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 Fibrosan, 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 Fibrosan maleate (e.g., emesis, gastric lavage, administration of absorbents, and sodium sulphate). Fibrosan 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.

Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors, ATC Code: C09A A02

Enalapril tablets contain the maleate salt of enalapril, 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 into the pressor substance angiotensin II. After absorption, Enalapril tablets are hydrolysed to Enalaprilat which inhibits ACE. Inhibition of ACE results in decreased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion.

ACE is identical to kinase II, the use of ACE inhibitors may therefore block the degradation of bradykinina potent vasodepressor peptide. The possible role of this mechanism in the therapeutic effects of enalapril has not yet been elucidated.

Mechanism of action

While the mechanism through which Enalapril 10 mg, tablets lower blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, which plays a major role in the regulation of blood pressure, Enalapril 10 mg, tablets are antihypertensive even in patients with low-renin hypertension.

Pharmacodynamic effects

Administration of Enalapril 10 mg, tablets 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 Enalapril 10 mg, tablets 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 enalapril.

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 Enalapril 10 mg, tablets 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 enalapril. When given together with thiazidetype diuretics, the blood pressure lowering effects of Enalapril 10 mg, tablets are at least additive.

Enalapril 10 mg, tablets may reduce or prevent the development of thiazide induced hypokalaemia.

In patients with heart failure on therapy with digitalis and diuretics, treatment with oral or injection Enalapril, 10mg tablets 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, enalapril retarded progressive cardiac dilatation/enlargement and failure,as evidenced by reduced left ventricular end diastolic and systolic volumes and improved ejection fraction.

Dual Blockade of the renin angiotensin aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHROND (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACEinhibitor 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 endorgan damage. VA NEPHROND 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 ACEinhibitors 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.

Clinical efficacy and safety

A multicentre, randomised, doubleblind, placebocontrolled trial (SOLVD Prevention trial) examined a population with asymptomatic left ventricular dysfunction (LVEF<35%). 4,228 patients were randomised to receive either placebo (n=2,117) or enalapril (n=2,111). In the placebo group, 818 patients had heart failure or died (38.6%) as compared with 630 in the enalapril group (29.8%) (risk reduction: 29%; 95% CI; 2136%; p<0.001). 518 patients in the placebo group (24.5%) and 434 in the enalapril group (20.6%) died or were hospitalised for new or worsening heart failure (risk reduction 20%; 95% CI; 930%; 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%). 2,569 patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n=1,284) or enalapril (n=1,285). There were 510 deaths in the placebo group (39.7%) as compared with 452 in the enalapril group (35.2%) (reduction in risk, 16%; 95% CI, 526% ; p=0.0036). There were 461 cardiovascular deaths in the placebo group as compared with 399 in the enalapril group (risk reduction 18%, 95% CI, 628%, p<0.002), mainly due to a decrease of deaths due to progressive heart failure (251 in the placebo group vs 209 in the enalapril group, risk reduction 22%, 95% CI, 635%). Fewer patients died or were hospitalised for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26%; 95% CI, 1834%; p<0.0001). Overall in SOLVD study, in patients with left ventricular dysfunction, Enalapril, 10mg tablets reduced the risk of myocardial infarction by 23% (95% CI, 1134%; p<0.001) and reduced the risk of hospitalisation for unstable angina pectoris by 20% (95% CI, 929% ; p<0.001).

Paediatric population

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 enalapril daily and patients who weighed >50 kg received either 1.25, 5 or 40 mg of enalapril daily. Enalapril administration once daily lowered trough blood pressure in a dose dependent manner. The dose dependent antihypertensive efficacy of enalapril 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.

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

Fibrosan 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, Fibrosan is hydrolysed to Fibrosanat 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 'Fibrosan' may therefore also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of 'Fibrosan' remains to be elucidated.

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

Administration of 'Fibrosan' 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 'Fibrosan' 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 Fibrosan. 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 'Fibrosan' 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 Fibrosan.

When given together with thiazide-type diuretics, the blood pressure-lowering effects of 'Fibrosan' are at least additive. 'Fibrosan' 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 'Fibrosan' 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, Fibrosan 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 Fibrosan (n=2111). In the placebo group, 818 patients had heart failure or died (38.6%) as compared with 630 in the Fibrosan 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 Fibrosan 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 Fibrosan (n=1285). There were 510 deaths in the placebo group (39.7%) as compared with 452 in the Fibrosan 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 Fibrosan 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 Fibrosan 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 Fibrosan group; risk reduction, 26%; 95% CI, 18 - 34%; p<0.0001). Overall in SOLVD study, in patients with left ventricular dysfunction, 'Fibrosan' 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 Fibrosan daily and patients who weighed >50 kg received either 1.25, 5 or 40 mg of Fibrosan daily. Fibrosan administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of Fibrosan 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

Enalapril tablets are rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from Enalapril tablets is approximately 60%.

Following absorption, Enalapril tablets are rapidly and extensively hydrolysed to enalaprilat. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of Enalapril tablets. Excretion of Enalapril tablets is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose and intact enalapril. In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration. The effective half-life for accumulation of enalaprilat following multiple doses of Enalapril tablets is 11 hours. Accumulation may occur, however in patients with severely impaired renal function, and the dosage of enalapril should be adjusted accordingly. The absorption of Enalapril tablets is not influenced by the presence of food in the gastro-intestinal tract. The extent of absorption and hydrolysis of enalapril is similar for the various doses in the recommended therapeutic range.

Distribution

Over the range of concentrations which are therapeutically relevant, enalapril binding to human plasma protein does not exceed 60%

Biotransformation

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

Elimination

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

Renal impairment

The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60ml/min) steady state AUC of enalapril 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 enalapril following multiple doses of Fibrosan is prolonged at this level of renal insufficiency and time to steady state is delayed. Enalapril may be removed from the general circulation by haemodialysis. The dialysis clearance is 62ml/min.

Children and adolescents

A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female paediatric patients aged 2 months to ≤ 16 years following daily oral administration of 0.07 to 0.14 mg/kg Fibrosan. There were no major differences in the pharmacokinetics of enalapril 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 enalapril was 14 hours

Lactation:

After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7 µg/L (range 0.54 to 5.9 µg/L) at 4 to 6 hours after the dose. The average peak enalaprilat 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 enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 µg/L 4 hours after a dose and peak enalaprilat levels of 0.75 µg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44 µg/L and 0.63 µg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2 µg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10 mg in two mothers; enalapril levels were not determined.

Absorption

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

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

Distribution

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

Biotransformation

Except for conversion to Fibrosanat, there is no evidence for significant metabolism of Fibrosan.

Elimination

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

Renal impairment

The exposure of Fibrosan and Fibrosanat 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 Fibrosanat 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 Fibrosanat following multiple doses of Fibrosan maleate is prolonged at this level of renal insufficiency and time to steady state is delayed. (See 4.2 'Posology and method of administration'.) Fibrosanat 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 Fibrosan maleate. There were no major differences in the pharmacokinetics of Fibrosanat 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 Fibrosanat was 14 hours

Lactation: After a single 20 mg oral dose in five postpartum women, the average peak Fibrosan 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 Fibrosanat 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 Fibrosan 10 mg daily for 11 months had peak Fibrosan milk levels of 2 μg/L 4 hours after a dose and peak Fibrosan at levels of 0.75 μg/L about 9 hours after the dose. The total amount of Fibrosan and Fibrosanat measured in milk during the 24 hour period was 1.44μg/L and 0.63 μg/L of milk respectively. Fibrosanat milk levels were undetectable (<0.2 μg/L) 4 hours after a single dose of Fibrosan 5 mg in one mother and 10mg in two mothers; Fibrosan levels were not determined.

Preclinical 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 enalapril has no effects on fertility and reproductive performance in rats, and is not teratogenic. In a study in which female rats were dose 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 foetotoxic (causing injury and/or death to the foetus) when given in the second or third trimester.

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 Fibrosan 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.

None.

Not applicable

Not applicable.

None