Liracen 1,25 mg, 2,5 mg, 5 mg and 10 mg Capsule

LIRACEN are indicated for:

• Mild to moderate hypertension.
• Cardiac failure following myocardial infarction.
• To reduce proteinuria and the decline in glomerular filtration rate in patients with diabetic nephropathy and hypertension.
• To reduce the risk of myocardial infarction, stroke or cardiovascular death and to reduce the need for revascularisation procedures in patients with an increased cardiovascular risk [such as manifest coronary heart disease (with or without a history of myocardial infarction), a history of stroke or a history of peripheral vascular disease.]
• To reduce the risk of myocardial infarction, stroke or cardiovascular death in diabetic patients.

LIRACEN should be taken during or after meals with half a glass of liquid. In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of LIRACEN. The diuretic should, if possible, be discontinued for two to three days before starting therapy with LIRACEN to reduce the likelihood of hypotension. If the diuretic therapy cannot be discontinued, the initial dose of LIRACEN should be 1,25 mg.

Hypertension: Administration of LIRACEN to hypertensive patients results in a reduction of both supine and erect blood pressure. The antihypertensive effect is evident within one to two hours after intake of LIRACEN, peak effect occurs three to six hours after intake, and has been shown to be maintained for at least 24 hours at recommended doses. The dose range is 2,5 mg to 10 mg LIRACEN in a single daily dose. The recommended initial dosage in patients not on diuretics is 2,5 mg LIRACEN once a day. Dosage should be increased to 5 mg LIRACEN and up to a maximum of 10 mg LIRACEN once a day, at intervals of one to two weeks, based on patient response. A maximum dose of 10 mg should not be exceeded.

Post-myocardial infarction: The treatment with LIRACEN should be initiated in hospital 3 to 10 days after an acute myocardial infarction if the patient manifests with evidence of heart failure and is haemodynamically stable. The recommended dosage is 2,5 mg LIRACEN twice daily for two days. If well tolerated increase the dose to 5 mg LIRACEN twice daily. If patients are unable to tolerate LIRACEN 2,5 mg initially, 1,25 mg LIRACEN twice daily may be given initially and later increased to 2,5 mg twice daily.

Non-diabetic and diabetic nephropathy: The recommended initial dose is 1,25 mg LIRACEN once daily. Depending on how the patient tolerates LIRACEN, the dose should be increased. It is recommended that the dose, if increased, be doubled at intervals of 2 to 3 weeks. The maximum permitted daily dose is 10 mg LIRACEN. In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic for at least 2 to 3 days or depending on the duration of action of the diuretic, longer, before starting treatment with LIRACEN, or at least, to reducing the diuretic dose.

Dosage adjustment in renal impairment: The use of LIRACEN in dialysis patients is not recommended. To reduce the risk of myocardial infarction, stroke or cardiovascular death: The recommended initial dose is 2,5 mg LIRACEN once daily. Depending on the tolerability, the dose is gradually increased. The increase should be implemented by doubling the dose after one week of treatment. Three weeks later, it should be doubled again to the usual maintenance dose of 10 mg LIRACEN once daily.

u2022 Sensitivity to ramipril or any of the components of LIRACEN.

u2022 A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.

u2022 Hereditary or idiopathic angioedema.

u2022 Hypertrophic obstructive cardiomyopathy (HOCM).

u2022 Severe renal function impairment (creatinine clearance less than 30 ml/min).

u2022 Bilateral renal artery stenosis.

u2022 Renal artery stenosis in patients with a single kidney.

u2022 Aortic stenosis.

u2022 Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride.

u2022 Porphyria.

u2022 Lithium therapy: Concomitant administration with LIRACEN may lead to toxic blood concentrations of lithium.

u2022 Pregnancy and lactation (see u201cPREGNANCY AND LACTATIONu201d).

u2022 LIRACEN is not recommended for use in children.

Should a woman become pregnant while receiving LIRACEN, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine (See u201cPREGNANCY AND LACTATIONu201d). Should a woman contemplate pregnancy, the doctor should consider alternate medication. (See u201cCONTRA-INDICATIONSu201d and u201cPREGNANCY AND LACTATIONu201d).

LIRACEN should be given with caution in the following conditions:

• Cerebrovascular disease or ischaemic heart disease u2013 Reduction in blood pressure could aggravate these conditions and may result in cerebrovascular accidents and myocardial infarction.
• Volume depleted patients (e.g. by dietary salt restriction, by diuretic therapy, diarrhoea, vomiting or dialysis) u2013 Although it may occur in normo volumic patients, hypotension is more likely to occur in volume depleted patients. A sudden reduction in angiotensin II may result in severe and sudden hypotension. Treatment with LIRACEN for these products should be initiated under close medical supervision, starting with a low dose. The patient should be in a recumbent position to minimize this effect. If necessary, an intravenous infusion of 0,9 % sodium chloride (NaCl) may be administered. There is also an increased risk of LIRACEN induced renal failure, especially in those with congestive heart failure.
• Patients at a high risk of symptomatic hypotension e.g. patients with volume or salt depletion with or without hyponatremia should have these conditions corrected before therapy with LIRACEN. Monitoring is required after initiating therapy.
• Autoimmune disease, especially systemic lupus erythematosus, other collagen vascular disease or scleroderma or in patients also given immunosuppressive therapy increases the risk for development of agranulocytosis or neutropenia. Regular white blood cell counts may be necessary.
• In acute myocardial infarction, patients may develop persistent hypotension and/or impaired renal function.
• In acute myocardial infarction, treatment with LIRACEN should not be initiated in patients with evidence of renal dysfunction (serum creatinine concentrations exceeding 177 u03bcmol/l or proteinuria exceeding 500 mg/24 hours). If renal dysfunction develops during treatment (serum creatinine concentrations exceeding 177 u03bcmol/l or doubling of the pre-treatment value) then LIRACEN may need to be withdrawn (see u201cCONTRA-INDICATIONSu201d).
• Hypotension in acute myocardial infarction u2013 Treatment with LIRACEN must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These include patients with a systolic blood pressure of 99,98 mmHg or lower or cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 119,93 mmHg or lower. Maintenance doses should be reduced if systolic blood pressure is 99,98 mmHg or lower. LIRACEN should be withdrawn if hypotension persists (systolic blood pressure less than 89,93 mmHg for more than 1 hour).
• Bone marrow depression u2013 Increased risk of agranulocytosis and neutropenia.
• Diabetes mellitus u2013 Increased risk of hyperkalaemia, as well as hypoglycaemia may occur.
• Hyperkalaemia u2013 LIRACEN may cause an increase in serum potassium levels.
• Renovascular disease u2013 LIRACEN should not be used in patients with renovascular disease or suspected renovascular disease, but it may be used cautiously in severe resistant hypertension in such patients. In this instance, LIRACEN must only be used under the supervision of a specialist. Patients with peripheral vascular diseases or generalised atherosclerosis and the elderly may have asymptomatic renovascular disease (see u201cDOSAGE AND DIRECTIONS FOR USEu201d).
• Renal artery stenosis, bilateral or in one kidney or renal transplant u2013 Increased risk of renal function impairment may increase in blood urea and serum creatinine concentrations, which may be reversible upon discontinuation of therapy.
• Renal function impairment u2013 Decreased elimination of LIRACEN resulting in an increased risk of hyperkalaemia. These patients may require lower doses of LIRACEN.
• Anaphylactoid reactions have occurred in patients using ACE inhibitors during desensitising protocols involving for example, hymenoptera venom.
• Anaphylactoid reactions have been reported in patients exposed to either high-flux membrane dialysis or low-density lipoprotein apheresis with dextran sulphate absorption.
• Hypersensitivity/angioedema u2013 If angioedema of the extremities, face, lips, tongue, glottis and/or larynx is observed in patients treated with LIRACEN, then LIRACEN should be promptly discontinued. These patients should be monitored to ensure complete resolution of symptoms (see u201cCONTRA - INDICATIONSu201d).
• Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate emergency therapy should be administered. This may include the administration of epinephrine and/or the maintenance of a patent airway. Until complete and sustained resolution of symptoms has occurred, the patient should be under close medical supervision. These patients should never receive LIRACEN again.
• LIRACEN causes a higher rate of angioedema in black patients than in non-black patients.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, and amiloride may lead to hyperkalaemia which may be severe and lead to cardiac conduction abnormalities, dysarrythmias and cardiac arrest (see u201cCONTRA - INDICATIONSu201d).
• The metabolism of the parent compound ramipril and therefore the formation of the bioactive metabolite ramiprilat is decelerated in patients with impaired liver function. This results in markedly elevated plasma ramipril levels due to a diminished activity of esterases in the liver. In patients with impaired liver function, the use of LIRACEN is not recommended.
• Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischaemic heart disease or cerebrovascular disease.
• In volume depleted patients or patients with ischaemic heart disease or cerebrovascular disease, therapy should be monitored especially when the dose of LIRACEN or diuretic is adjusted.
• If hypotension occurs, the patient should be placed in the supine position and if necessary receive an intravenous infusion of 0,9 % saline.
• Increases in blood urea and serum creatinine have been seen in patients with no apparent pre-existing vascular disease, especially when LIRACEN has been given concomitantly with a diuretic. Dosage reduction or discontinuation of LIRACEN or the diuretic may be required.
• In patients undergoing surgery or during anaesthesia with agents producing hypotension, LIRACEN may block angiotensin II formation secondary to compensatory rennin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
• ACE-inhibitors such as LIRACEN have been shown to be less effective as anti-hypertensives in black patients than in white patients.

Concomitant use of LIRACEN with:

• Loop, thiazide or related diuretics u2013 u201cFirst dose hypotensionu201d may occur (see u201cDOSAGE AND DIRECTIONS FOR USEu201d).
• Diuretics, alcohol and hypotension-producing medications - The antihypertensive effect is additive. It may be necessary to adjust the dose during concurrent use or when one medicine is discontinued.
• Potassium sparing diuretics such as spironolactone, triamterene or amiloride or potassium supplements u2013 Concurrent administration may result in hyperkalaemia (see u201cCONTRA - INDICATIONSu201d). In patients with heart failure, potassium sparing diuretics should generally be stopped before starting LIRACEN therapy.
• Lithium u2013 Increases in lithium concentrations have been reported (see u201cCONTRA- INDICATIONSu201d).
• Indomethacin and nonsteroidal anti-inflammatory medicines (NSAIDs) u2013 reduce the antihypertensive effects of LIRACEN. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with LIRACEN.

Safety in pregnancy and lactation has not been established (see u201cCONTRA - INDICATIONSu201d). LIRACEN can cause foetal morbidity and death. LIRACEN crosses through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. The use of LIRACEN during first trimester of pregnancy has been associated with an increased risk of birth defects, in particular of the cardiovascular and the central nervous system. Oligohydramnios as well as hypotension, oliguria and anuria in newborns, have been reported after administration of ramipril, such as contained in LIRACEN during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (See u201cCONTRA - INDICATIONSu201d and u201cWARNINGSu201d). Teratogenicity has been shown in animals. Hypertensive women receiving LIRACEN should take care to ensure that they do not become pregnant.

Treatment with LIRACEN may impair the ability to drive or operate machinery, especially at the start of treatment, when changing over from other preparations and during concomitant use of alcohol.

Side-effects:

Blood and lymphatic system disorders: Less frequent: Decrease in white blood cell count, haemoglobin and haemocrit, bone marrow depression, anaemia, thrombocytopenia, agranulocytosis, haemolytic anaemia.

Immune system disorders: Less frequent: Hypersensitivity/angioedema reactions: Angioedema of the face, which may be fatal, extremities, lips, tongue, glottis and/or larynx and intestinal angioedema.

Metabolism and nutrition disorders: Less frequent: Hyperkalaemia, hyponatraemia, increases in blood urea, increases in serum creatinine.

Nervous system disorders: Frequent: Dizziness, headache, fatigue. Less frequent: Mood alterations, mental confusion, paraesthesia, vertigo, sleep disturbances.

Cardiac disorders: Less frequent: Myocardial infarction, palpitations, tachycardia and chest pain.

Vascular disorders: Less frequent: Orthostatic effects including hypotension, cerebrovascular accident.

Respiratory, thoracic and mediastinal disorders: Frequent: A dry cough has been reported. Less frequent: Bronchospasm, rhinitis, sinusitis.

Gastrointestinal disorders: Frequent: Nausea, diarrhoea. Less frequent: Abdominal pain, indigestion, dry mouth, pancreatitis, vomiting and taste disturbances.

Hepato-biliary disorders: Less frequent: Hepatitis (hepatocellular or cholestatic) jaundice, increase in serum bilirubin, increase in liver enzymes.

Skin and subcutaneous tissue disorders: Less frequent: Rash, urticaria, diaphoresis, alopecia, pruritus, psoriasis, severe skin disorders including pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme.

Musculoskeletal, connective tissue and bone disorders: Less frequent: Asthenia.

Renal and urinary disorders: Less frequent: Uraemia, oliguria, anuria, renal dysfunction, acute renal failure.

Reproductive system and breast disorders: Less frequent: Impotence.

General disorders and administrative site conditions: Less frequent: A symptom complex has been reported which may include fever, vasculitis, myalgia, arthritis/arthralgia, positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate, eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.

Severe hypotension, electrolyte disturbances and renal failure are symptoms of overdose. Treatment is symptomatic and supportive. Treatment should include volume expanders.