RAMIPRIL

Posology It is recommended that Ramipril is taken each day at the same time of the day. 2). Ramipril has to be swallowed with liquid. It must not be chewed or crushed. Adults Diuretic-Treated patients Hypotension may occur following initiation of therapy with Ramipril; this is more likely in patients who are being treated concurrently with diuretics.

Caution is therefore recommended since these patients may be volume and/or salt depleted. 4). 25 mg dose. Renal function and serum potassium should be monitored. The subsequent dose of Ramipril should be adjusted according to blood pressure target.

4) and blood pressure control. 1). 5 mg daily. Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. 4). Titration and maintenance dose The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of Ramipril is 10 mg daily.

Usually the dose is administered once daily. 5 mg of Ramipril once daily. Titration and maintenance dose Depending on the patient’s tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg Ramipril once daily.

See also posology on diuretic treated patients above. 25 mg of Ramipril once daily. Titration and maintenance dose Depending on the patient's tolerability to the active substance, the dose is subsequently increased. 5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

5 mg of Ramipril once daily. Titration and maintenance dose Depending on the patient’s tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg Ramipril after one or two weeks and then to 10 mg Ramipril after a further two or three weeks is recommended.

The target daily dose is 10 mg. In patients with non- diabetic nephropathy as defined by macroproteinuria ≥ 3 g/day. 25 mg of Ramipril once daily. Titration and maintenance dose Depending on the patient’s tolerability to the active substance, the dose is subsequently increased.

5 mg after two weeks and then to 5 mg after a further two weeks is recommended. 25 mg daily. Titration and maintenance dose Ramipril should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Summary of safety profile 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.

Tabulated list of adverse reactions 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. Frequency / System Organ Class Common Uncommon Rare Very rare Not known 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 Immune system disorders Anaphylactic or anaphylactoid reactions, antinuclear antibody increased Endocrine disorders Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Metabolism and nutrition disorders Blood potassium increased Anorexia, decreased appetite Blood sodium decreased Psychiatric disorders Depressed mood, anxiety, nervousness, restlessness, Confusional state Disturbance in attention sleep disorder including somnolence 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 Cardiac disorders Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral Vascular disorders Hypotension, orthostatic blood pressure decreased, syncope Flushing Vascular stenosis, hypoperfusion, vasculitis Raynaud’s phenomenon Respiratory, thoracic and mediastinal disorders Non-productive tickling cough, bronchitis, sinusitis, dyspnoea Bronchospasm including asthma aggravated, nasal congestion Gastrointesti nal 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 Hepato- biliary 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).

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 anti-hypertensive treatments which have an established safety profile for use in pregnancy.

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.

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).

- 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).

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.

6) - Ramipril must not be used in patients with hypotensive or haemodynamically unstable states. 1) - Concomitant use with sacubitril/valsartan therapy. 5).