Vanicon 1,25 mg/ 2,5 mg/ 5 mg/ 10 mg CAPSULES

VANICON 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.

VANICON 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 VANICON. The diuretic should, if possible, be discontinued for two to three days before starting therapy with VANICON to reduce the likelihood of hypotension. If the diuretic therapy cannot be discontinued, the initial dose of VANICON should be 1,25 mg.

Hypertension: Administration of VANICON 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 VANICON, 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 VANICON in a single daily dose. The recommended initial dosage in patients not on diuretics is 2,5 mg VANICON once a day. Dosage should be increased to 5 mg VANICON and up to a maximum of 10 mg VANICON 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 VANICON 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 VANICON twice daily for two days. If well tolerated increase the dose to 5 mg VANICON twice daily. If patients are unable to tolerate VANICON 2,5 mg initially, 1,25 mg VANICON 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 VANICON once daily. Depending on how the patient tolerates VANICON, 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 VANICON.

• Sensitivity to ramipril or any of the components of VANICON.
• 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.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 ml/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride.
• Porphyria.
• Lithium therapy: Concomitant administration with VANICON may lead to toxic blood concentrations of lithium.
• Pregnancy and lactation (see u201cPREGNANCY AND LACTATIONu201d).
• VANICON is not recommended for use in children.

Should a woman become pregnant while receiving VANICON, 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).

VANICON 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 VANICON 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 VANICON 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 VANICON. 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 VANICON 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 VANICON may need to be withdrawn (see u201cCONTRA-INDICATIONSu201d).
• Hypotension in acute myocardial infarction u2013 Treatment with VANICON 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. VANICON 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 VANICON may cause an increase in serum potassium levels.
• Renovascular disease u2013 VANICON 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, VANICON 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 VANICON resulting in an increased risk of hyperkalaemia. These patients may require lower doses of VANICON.
• 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 VANICON, then VANICON 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 VANICON again.
• VANICON causes a higher rate of angioedema in black patients than in non-black patients.

Concomitant use of VANICON 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 VANICON 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 VANICON. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with VANICON.

Safety in pregnancy and lactation has not been established (see u201cCONTRA-INDICATIONSu201d). VANICON can cause foetal morbidity and death. VANICON crosses through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. The use of VANICON 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 VANICON 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 VANICON should take care to ensure that they do not become pregnant.

Treatment with VANICON 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.