1.25 mg ramipril.

Yellow opaque/white opaque hard gelatin capsules

- Treatment of hypertension.
- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:  

• manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or 
• diabetes with at least one cardiovascular risk factor.

- Treatment of renal disease:

• Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,
• Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor
• Manifest glomerular non diabetic nephropathy as defined by macroproteinuria  3 g/day. 

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

Oral use.

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

Ramipril capsules can be taken before, with or after meals, because food intake does not modify its bioavailability.

Ramipril capsules should be swallowed with liquid. They 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.

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

In hypertensive patients in whom the diuretic is not discontinued, therapy with ramipril should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of ramipril should be adjusted according to blood pressure target.

Hypertension

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

Ramipril may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

Ramipril should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision.

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.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 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.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 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.

Starting dose:

The recommended initial dose is 1.25 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 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.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance:

- if creatinine clearance is  60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 10 mg;

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered a few hours after haemodialysis is performed.

Patients with hepatic impairment

In patients with hepatic impairment, treatment with ramipril must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg ramipril.

Paediatric population

Ramipril is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

Initial doses should be lower and subsequent dose titration should be more gradual because of a greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

- Hypersensitivity to the active substance, any of the excipients or any other ACE(Angiotensin Converting Enzyme) inhibitors.

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs).

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- 2nd and 3rd trimester of pregnancy

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states

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. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

• 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 failur
• patients with haemodynamically relevant leftventricular 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 up 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.

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. 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.

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. 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 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.

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.

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black 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.

Contra-indicated 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. 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.

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) 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.

Lithium Salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased.. Lithium levels 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.

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.

Winthrop Pharmaceuticals UK Ltd

POM

17 November 2009