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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ramipril 1.25 mg Capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 1.25 mg ramipril.

For excipients, see 6.1

3 PHARMACEUTICAL FORM

Capsule, hard,

Light grey capsules; marked with “R” and “1.25”

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

♦    For reducing the risk of myocardial infarction, stroke, cardiovascular death or need for revascularisation procedures in patients of 55 years or more who have clinical evidence of cardiovascular disease (previous MI, unstable angina or multivessel CABG or multivessel PTCA), stroke or peripheral vascular disease.

♦    Also for reducing the risk of myocardial infarction, stroke, cardiovascular death or need for revascularisation procedures in diabetic patients of 55 years or more who have one or more of the following clinical findings: hypertension (systolic blood pressure> 160mmHg or diastolic blood pressure> 90mmHg); high total cholesterol >5.2 mmol/L); low HDL (<0.9 mmol/L); current smoker; known microalbuminuria; clinical evidence of previous vascular disease.

♦    Ramipril is indicated for the treatment of mild to moderate hypertension.

4.2 Posology and method of administration

Oral administration.

Ramipril capsules should be taken with a glass of water. The absorption of ramipril is not affected by food. It must not be chewed or crushed.

It is recommended that ramipril is taken each day at the same time of the day.

Dosage and Administration:

Reducing the risk of myocardial infarction, stroke or cardiovascular death and/or the need for revascularisation procedures: The recommended initial dose is 2.5mg Ramipril once a day. Depending on the tolerability, the dose should be gradually increased. It is therefore recommended that this dose is doubled after about one week of treatment then, after a further 3 weeks, it should be finally increased to 10mg. The usual maintenance dose is 10mg Ramipril once a day. Patients already stabilised on lower doses of Ramipril for other indications where possible should be titrated to 10mg Ramipril once daily.

Hypertension: The recommended initial dosage in patients not on diuretics and without congestive heart failure is 1.25 mg Ramipril once a day. Dosage should be increased incrementally at intervals of 1 - 2 weeks, based on patient response, up to a maximum of 10 mg once a day.

A 1.25 mg dose will only achieve a therapeutic response in a minority of patients. The usual maintenance dose is 2.5 - 5 mg as a single daily dose. If the patient response is still unsatisfactory at a dose of 10 mg Ramipril, combination treatment is recommended.

In diuretic treated patients, the diuretic should be discontinued 2 - 3 days before beginning therapy with Ramipril to reduce the likelihood of symptomatic hypotension. It may be resumed later if required (see Sections 4.3, 4.4, 4.5 and 5.1).

In hypertensive patients who also have congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients therapy should be started at a dose of 1.25 mg under close medical supervision in hospital.

Dosage adjustment in renal impairment: The usual dose of Ramipril is recommended for patients with a creatinine clearance> 30 ml/min (serum creatinine < 165 pmol/l). For patients with a creatinine clearance < 30 ml/min (serum creatinine>165 pmol/l) the initial dose is 1.25 mg Ramipril once daily and the maximum dose 5 mg Ramipril once daily.

In patients with severe renal impairment (creatinine clearance < 10 ml/min and serum creatinine of 400-650 pmol/l), the recommended initial dose is also 1.25 mg Ramipril once a day, but the maintenance dose should not exceed 2.5 mg Ramipril once a day.

Dosage in hepatic impairment: In patients with impaired liver function the metabolism of the parent compound ramipril, and therefore the formation of the bioactive metabolite ramiprilat, is delayed due to a diminished activity of esterases in the liver, resulting in elevated plasma ramipril levels. Treatment with ramipril should therefore be initiated at a dose of 1.25 mg under close medical supervision in patients with impaired liver function.

Elderly: Caution in elderly patients with concomitant use of diuretics, congestive heart failure or renal or hepatic insufficiency. The dose should be titrated according to need for the control of blood pressure.

Paediatric population: The safety and efficacy of ramipril in children has not yet been established. Currently available data for ramipril are described in sections 4.8, 5.1, 5.2 & 5.3 but no specific recommendation on posology can be made.

4.3    Contraindications

•    Hypersensitivity to Ramipril, to any ACE inhibitor or to any of the excipients.

•    History of angioneurotic oedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs, see also section 4.8 Undesirable effects).

•    Haemodynamically relevant bilateral renal artery stenosis or severe stenosis of the artery supplying a single functioning kidney.

•    Ramipril must not be used in patients with Hypotensive or haemodynamically unstable patients.

•    Second and third trimester of pregnancy (See sections 4.4 and 4.6 Pregnancy and lactation)

•    Dialysis using polyacrylonitrilemembranes (see section 4.4 Special warnings and precautions for use)

•    Low-density lipoprotein apheresis with dextran sulphate (see section

4.4 Special warnings and precautions for use)

•    Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

•    The concomitant use of Ramipril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see Sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Special populations

-Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/AIIRAs 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/AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

-Patients at particular risk of hypotension

-Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

-    patients with severe hypertension

-    patients with decompensated congestive heart failure

-    patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

-    patients with unilateral renal artery stenosis with a second functional kidney

-    patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

-    patients with liver cirrhosis and/or ascites

-    patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

-Transient or persistent heart failure post MI

-Patients at risk of cardiac or cerebral ischemia in case of acute hypotension The initial phase of treatment requires special medical supervision.

-Elderly patients See section 4.2.

- Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

-Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

-Angioedema:

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, ramipril must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

-Anaphylactic reactions during desensitization:

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of ramipril should be considered prior to desensitization.

-Hyperkalaemia:

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including ramipril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis:

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in afro-caribbean patients than in non afro-caribbean patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in afro-caribbean people than in non afro-caribbean patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

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

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 (see Section 4.5 and 5.1).

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.

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, adrenalin) that may reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of ramipril is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia. Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

4.6 Pregnancy and lactation

Pregnancy:

The use of Ace inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of Ace inhibitors is contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4)._

Epidemiological evidence regarding the risk of teratogenicity following exposure of 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 trimester is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). See section 5.3).

Should exposure to ACE 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 (see section 4.3 and 4.4).

Lactation:

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on ability to drive and use machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery). This occurs especially at the start of treatment, when changing over from other preparations and during concomitant use of alcohol. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Cardiac disorders		Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral
Blood and lymphatic system disorders		Eosinophilia	White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased		Bone marrow failure, pancytopenia, haemolytic anaemia
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, ageusia, dysgeusia,	Tremor, balance disorder		Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia
Eye disorders		Visual disturbance including blurred vision	Conjunctivitis
Ear and labyrinth disorders			Hearing impaired, tinnitus
Respiratory, thoracic and mediastinal disorders	Non-productive tickling cough, bronchitis, sinusitis, dyspnoea	Bronchospasm including asthma aggravated, nasal congestion

Gastrointestinal disorders	Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting	Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth	Glossitis		Aphtous stomatitis
Renal and urinary disorders		Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased
Skin and subcutaneous tissue disorders	Rash in particular maculo-papular	Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis	Exfoliative dermatitis, urticaria, onycholysis,	Photosensitivity reaction	Toxic epidermal necrolysis, Stevens- Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid

					exanthema or enanthema, alopecia
Musculoskeletal and connective tissue disorders	Muscle spasms, myalgia	Arthralgia
Metabolism and nutrition disorders	Blood potassium increased	Anorexia, decreased appetite,			Blood sodium decreased
Vascular disorders	Hypotension, orthostatic blood pressure decreased, syncope	Flushing	Vascular stenosis, hypoperfusion, vasculitis		Raynaud’s phenomenon
General disorders and administration site conditions	Chest pain, fatigue	Pyrexia	Asthenia
Immune system disorders					Anaphylactic or anaphylactoid reactions, antinuclear antibody increased
Hepatobiliary disorders		Hepatic enzymes and/or bilirubin conjugated increased,	Jaundice cholestatic, hepatocellular damage		Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).
Reproductive system and breast disorders		Transient erectile impotence, libido decreased			Gynaecomastia

Psychiatric		Depressed	Confusional		Disturbance in
disorders		mood, anxiety,	state		attention
		nervousness,
		restlessness, sleep disorder including somnolence

Deleted: I)

Paediatric Population

The safety of ramipril was monitored in 325 children and adolescents, aged 2-16 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

•    Tachycardia, nasal congestion and rhinitis ‘common’ (i.e. >1/100 to <1/10) in paediatric, and ‘uncommon’ (i.e. > 1/1,000 to < 1/100) in adult population

•    Conjunctivitis ‘common’ (i.e. >1/100 to <1/10) in paediatric while ‘rare’ (i.e. >1/10,000 to < 1/1,000) in adult population

•    Tremor and urticaria ‘uncommon’ (i.e. > 1/1,000 to < 1/100) in paediatric population while ‘rare’ (i.e. > 1/10,000 to < 1/1,000) in adult population.

The overall safety profile for ramipril in paediatric patients does not differ significantly from the safety profile in adults.

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5.1 Pharmacodynamic properties

ATC Code: C09A A05 Mechanism of action:

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase

II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart Failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/N ephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented

microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

	Ramipril	Placebo	relative risk (95% confidence interval)	p-value
	%	%
All patients	n=4,645	N=4,652
Primary combined events	14.0	17.8	0.78 (0.700.86)	<0.001
Myocardial infarction	9.9	12.3	0.80 (0.700.90)	<0.001
Death from cardiovascular causes	6.1	8.1	0.74 (0.640.87)	<0.001
Stroke	3.4	4.9	0.68 (0.560.84)	<0.001
Secondary endpoints
Death from any cause	10.4	12.2	0.84 (0.750.95)	0.005
Need for Revascularisation	16.0	18.3	0.85 (0.770.94)	0.002
Hospitalisation for unstable angina	12.1	12.3	0.98 (0.871.10)	NS
Hospitalisation for heart failure	3.2	3.5	0.88 (0.701.10)	0.25
Complications related to	6.4	7.6	0.84 (0.720.98)	0.03

The MICRO-HOPE study, a predefined substudy from HOPE, investigated the effect of the addition of ramipril 10 mg to the current medical regimen versus placebo in 3,577 patients at least 2 55 years old (with no upper limit of age), with a majority of type 2 diabetes (and at least another CV risk factor), normotensive or hypertensive.

The primary analysis showed that 117 (6.5 %) participants on ramipril and 149 (8.4 %) on placebo developed overt nephropathy, which corresponds to a RRR 24 %; 95 % CI [3-40], p = 0.027.

The REIN study, a multicenter randomized, double-blind parallel group, placebo-controlled study aimed at assessing the effect of treatment with ramipril on the rate of decline of glomerular function rate (GFR) in 352 normotensive or hypertensive patients (18-70 years old) suffering from mild (i.e. mean urinary protein excretion > 1 and < 3 g/24 h) or severe proteinuria (23 g/24 h) due to chronic non-diabetic nephropathy. Both subpopulations were prospectively stratified.

The main analysis of patients with the most severe proteinuria (stratum prematurely disrupted due to benefit in ramipril group) showed that the mean rate of GFR decline per month was lower with ramipril than with placebo; -0.54 (0.66) vs. -0.88 (1.03) ml/min/month, p = 0.038. The intergroup difference was thus 0.34 [0.03-0.65] per month, and around 4 ml/min/year; 23.1 % of the patients in the ramipril group reached the combined secondary endpoint of doubling of baseline serum creatinine concentration and/or end- stage renal disease (ESRD) (need for dialysis or renal transplantation) vs. 45.5% in the placebo group (p = 0.02).

Secondary prevention after acute myocardial infarction

The AIRE study included more than 2,000 patients with transient/persistent clinical signs of heart failure after documented myocardial infarction. The ramipril treatment was started 3 to 10 days after the acute myocardial infarction. The study showed that after an average follow-up time of 15 months the mortality in ramipril-treated patients was 16.9 % and in the placebo treated patients was 22.6 %. This means an absolute mortality reduction of 5.7 % and a relative risk reduction of 27 % (95 % CI [1140%]).

Paediatric population:

In a randomized, double- blind clinical study involving 244 paediatric patients with hypertension (73% primary hypertension), aged 6-16 years, patients received either low dose, medium dose or high dose of ramipril to achieve plasma concentrations of ramiprilat corresponding to the adult dose range of 1.25mg, 5mg and 20mg on the basis of body weight. At the end of 4 weeks, ramipril was ineffective in the endpoint of lowering systolic blood pressure but lowered diastolic blood pressure at the highest dose. Both medium and high doses of ramipril showed significant reduction of both systolic and diastolic BP in children with confirmed hypertension.

This effect was not seen in a 4 weeks dose-escalation, randomized, double-blind withdrawal study 218 paediatric patients aged 6-16 (75% primary hypertension),

where both diastolic and systolic blood pressures demonstrated a modest rebound but not a statistically significant return to baseline, in all three dose levels tested low dose (0.625mg - 2.5mg), medium dose (2.5mg-10mg) or high dose (5mg-20mg) ramipril based on weight. Ramipril did not have a linear dose response in the paediatric population studied.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of 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. CV 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.

The concomitant use of aliskiren with an ACE-inhibitor or an angiotensin II receptor blocker is contraindicated in patients with type 2 diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

5.2 Pharmacokinetic properties

Pharmacokinetics and Metabolism

Absorption:

Following oral administration ramipril is rapidly absorbed from the gastrointestinal tract; peak plasma concentrations of ramipril are reached within one hour. Based on urinary recovery, the extent of absorption is at least 56 % and is not significantly influenced by the presence of food in the gastrointestinal tract. The bioavailability of

the active metabolite ramipril at after oral administration of 2.5 mg and 5 mg ramipril is 45 %.

Peak plasma concentrations of the active metabolite, ramiprilat, are reached within 2 -4 hours. Steady state plasma concentrations of ramiprilat after once daily dosing with the usual doses of ramipril are reached by about the fourth day of treatment.

Distribution:

The serum protein binding of ramipril is about 73 % and that of ramiprilat about 56 %.

Metabolism:

Ramipril is almost completely metabolised to ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.

Elimination:

Excretion of the metabolites is primarily renal.

Plasma concentrations of ramiprilat decline in a polyphasic manner. Because of its potent, saturable binding to ACE and slow dissociation from the enzyme, ramiprilat shows a prolonged terminal elimination phase at very low plasma concentrations.. The effective half-life of ramiprilat after multiple once daily administration of ramipril is 13 - 17 hours for 5 - 10 mg ramipril and markedly longer for lower doses, 1.25 - 2.5 mg ramipril. This difference is related to the long terminal phase of the ramiprilat concentration time curve observed at very low plasma concentrations. This terminal phase is independent of the dose, indicating a saturable capacity of the enzyme to bind ramiprilat.

Lactation:

One single oral dose of ramipril produced an undetectable level in breast milk. However the effect of multiple doses is not known.

Patients with renal impairment (see section 4.2)

Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.

Patients with hepatic impairment (see section 4.2)

In patients with impaired liver function, the metabolism of ramipril to ramiprilat was delayed, due to diminished activity of hepatic esterases, and plasma ramipril levels in these patients were increased. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function.

Paediatric population:

The pharmacokinetic profile of ramipril was studied in 30 paediatric patients, aged 216 years, weighing >10kg. After doses of 0.05 to 0.2mg/kg, ramipril was rapidly and extensively metabolized to ramipirlat. Peak plasma concentrations of ramiprilat occurred within 2-3 hours. Ramiprilat clearance highly correlated with the log of body weight (p<0.01) as well as dose (p<0.001). Clearance and volume of distribution increased with increasing age for each dose group.

The dose of 0.05mg/kg in children achieved exposure levels comparable to those in adults treated with ramipril 5mg. The dose of 0.2mg/kg in children resulted in exposure levels higher than the maximum recommended dose of 10mg per day in adults.

5.3 Preclinical safety data

Oral administration of ramipril has been found to be devoid of acute toxicity in rodents and dogs. Studies involving chronic oral administration have been conducted in rats, dogs and monkeys. Indications of plasma electrolyte shifts and changes in blood picture have been found in the 3 species.

As an expression of the pharmacodynamic activity of ramipril, pronounced enlargement of the juxtaglomerular apparatus has been noted in the dog and monkey from daily doses of 250 mg/kg/d.

Rats, dogs and monkeys tolerated daily doses of 2, 2.5 and 8 mg/kg/d respectively without harmful effects.

Reproduction toxicology studies in the rat, rabbit and monkey did not disclose any teratogenic properties.

Fertility was not impaired either in male or in female rats. The administration of ramipril to female rats during the fetal period and lactation produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at daily doses of 50 mg/kg body weight and higher.

Extensive mutagenicity testing using several test systems has yielded no indication that ramipril possesses mutagenic or genotoxic properties.

Irreversible kidney damage has been observed in very youg rats given a single dose of ramipril.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Excipients:

Starch pregelatinised Gelatin

Titanium Dioxide (E171)

Black Iron Oxide (E172)

Printing Ink Shellac (E904)

Dehydrated Alcohol (E1510) Isopropyl Alcohol Butyl Alcohol Propylene Glycol (E1520)

Strong Ammonia Solution (E527) Black Iron Oxide (E172) Potassium Hydroxide (E525) Purified Water

6.2    Incompatibilities

Not applicable

6.3    Shelf Life

30 months

6.4    Special precautions for storage

Do not store above 25 °C.

Store in the original package

6.5 Nature and contents of container

Al/Al blister

Pack sizes: 7, 21, 28, 30, 50, 100 capsules.

Not all pack sizes may be marketed.