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1.25 mg tablet: oblong (8 mm by 4 mm), white tablet with 1.25 scoreline HMN on one side and company logo scoreline 1.25 on the other side
2.5 mg tablet: oblong (8 mm by 4 mm), yellow tablet with 2.5 scoreline HMR on one side and company logo scoreline 2.5 on the other side
5 mg tablet: oblong (8 mm by 4 mm), red with 5 scoreline HMP on one side and company logo scoreline 5.0 on the other side
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 increase in bradykinin activity probably contributes to the cardioprotective and endothelioprotective effects observed in animal experiments. It has not yet been established to what extent this is also responsible for certain unwanted effects (e.g. tickling cough).
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.
The prodrug ramipril undergoes an extensive hepatic first pass metabolism, which is essential for the formation of the sole active metabolite ramiprilat (hydrolysis, which occurs principally in the liver). In addition to this activation into ramiprilat, ramipril is glucuronized and transformed into ramipril diketopiperazine (ester). Ramiprilat is glucuronized as well and transformed into ramiprilat diketopiperazine (acid). As a result of this activation/metabolisation of the prodrug, approx. 20% of orally administered ramipril is bioavailable. The bioavailability of ramiprilat after oral administration of 2.5 and 5mg ramipril is approx. 45% compared with its availability after intravenous administration of the same doses.
Following oral administration of 10mg of radioactive labelled ramipril, approx. 40% of total radioactivity is excreted in faeces and approx. 60% in urine. After intravenous administration of ramipril, approx. 50 to 60% of the doses have been detected in urine (as ramipril and metabolites); approx. 50% were eliminated apparently by non-renal routes. Following intravenous administration of ramiprilat approx. 70% of the substance and its metabolites have been found in urine - indicating non-renal ramiprilat elimination of approx. 30%. After oral administration of 5mg ramipril in patients with drainage of the bile ducts, approximately the same amount of ramipril and its metabolites was excreted in urine and bile during the first 24 hours.
Approx. 80 to 90% of the metabolites in urine and bile have been identified as ramiprilat or ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazine represented approx. 10 to 20% of the total amount, whereas unmetabolised ramipril accounted for approx. 2%.
Studies in lactating animals have shown that ramipril passes into the milk.
Ramipril is rapidly absorbed after oral administration. As measured by the recovery of radioactivity in the urine, which represents only one of the elimination routes, absorption of ramipril is at least 56%. Administration of ramipril at the same time as food has no relevant effect on absorption.
Peak plasma concentrations of ramipril are reached within 1 hour after oral administration. The elimination half-life of ramipril is approx. 1 hour. Peak plasma concentrations of ramiprilat are reached 2 to 4 hours after oral administration of ramipril.
Plasma concentrations of ramiprilat decline in a polyphasic manner. The initial distribution and elimination phase has a half-life of approx. 3 hours. It is followed by an intermediate phase (half-life approx. 15 hours) and a terminal phase with very low plasma ramiprilat concentrations and a half-life of approx. 4 to 5 days.
This terminal phase is due to the slow dissociation of ramiprilat from the close but saturable binding to ACE.
Despite this long terminal phase, a single daily dose of 2.5mg ramipril or more yields steady state plasma concentrations of ramiprilat after approx. 4 days. The "effective" half-life, which is relevant for dosage, is 13 to 17 hours under multiple-dose conditions.
After intravenous administration the systemic distribution volume of ramipril is approx. 90 litres, and the relative systemic distribution volume of ramiprilat is approx. 500 litres. The protein-binding of ramipril and ramiprilat is approx. 73% and approx. 56% respectively.
In healthy subjects aged between 65 and 76 years ramipril and ramiprilat kinetics are similar to those in healthy young subjects.
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 persons with normal renal function.
When high doses (10mg) of ramipril are administered, impairment of hepatic function retards the activation of ramipril into ramiprilat, resulting in increased ramipril plasma levels, and slows down the elimination of ramiprilat.
As in healthy persons and patients with hypertension, there was also no relevant accumulation of ramipril and ramiprilat after oral administration of 5mg ramipril once daily over two weeks in patients with congestive heart failure.
Ramipril is not suitable for the treatment of hypertension resulting from primary hyperaldosteronism.
In patients aged 55 years and over with:
Treatment with ramipril 10mg daily was associated with a positive risk benefit for the following indications:
The dosage is based on the desired antihypertensive effect and on how the individual patient tolerates the medicine.
Recommended initial dose: 2.5mg ramipril once daily. Depending on the patient's response, the dose may be increased. It is recommended that the dose, if increased, be doubled at intervals of 2 to 3 weeks.
Usual maintenance dose: 2.5 to 5mg ramipril daily.
Maximum permitted daily dose: 10mg ramipril.
Instead of increasing the dose beyond 5mg ramipril daily, additional administration of e.g. a diuretic or a calcium antagonist may be considered.
In patients with impaired renal function with a creatinine clearance of 50 to 20ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25mg ramipril. The maximum permitted daily dose in this case is 5mg ramipril.
Where fluid or salt depletion have not been completely corrected, in cases of severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk (e.g. with relevant stenoses of the coronary vessels or those supplying the brain), a reduced initial dose of 1.25mg ramipril daily must be considered.
In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic at least 2 to 3 days or (depending on the duration of action of the diuretic) longer before starting treatment with ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25mg ramipril.
In patients with impaired liver function, the response to the treatment with ramipril may be either increased or reduced. Treatment in these patients must therefore be initiated only under close medical supervision. Maximum permitted daily dose in this case is 2.5mg ramipril.
Recommended initial dose: 1.25mg ramipril once daily. Depending on the patient's response, the dose may be increased. It is recommended that the dose, if increased, be doubled at intervals of 1 to 2 weeks. If a daily dose of 2.5mg ramipril or more is required, this may be taken as a single dose or as two divided doses.
Maximum permitted daily dose: 10mg ramipril.
In patients with impaired renal function with a creatinine clearance of 50 to 20ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25mg ramipril. The maximum permitted daily dose in this case is 5mg ramipril.
In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic at least 2 to 3 days or (depending on the duration of action of the diuretic) longer before starting treatment with ramipril, or at least to reducing the diuretic dose.
In patients with impaired liver function, the response to the treatment with ramipril may be either increased or reduced. Treatment in these patients must therefore be initiated only under close medical supervision. Maximum permitted daily dose in this case is 2.5mg ramipril.
Recommended initial dose: 5mg ramipril daily, divided into two single doses of 2.5mg each, one in the morning and one in the evening. If the patient does not tolerate this initial dosage it is recommended that 1.25mg be given twice daily for two days. In either event, depending on the patient's response, the dose may then be increased. It is recommended that the dose, if increased, be doubled at intervals of 1 to 3 days. At a later time, the total daily dose, initially divided, may be taken as one single daily dose.
Maximum permitted daily dose: 10mg ramipril.
Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be made to nevertheless treat these patients, it is recommended that therapy be started with the lowest possible daily dose (1.25mg ramipril once daily) and that the dosage be increased only with particular caution.
In patients with impaired renal function with a creatinine clearance of 50 to 20ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25mg ramipril. The maximum permitted daily dose in this case is 5mg ramipril.
Where fluid or salt depletion have not been completely corrected, in cases of severe hypertension, in patients in whom a hypotensive reaction would constitute a particular risk (e.g. with relevant stenoses of the coronary vessels or those supplying the brain), as well as in patients pre-treated with a diuretic, a reduced initial dose of 1.25mg ramipril daily must be considered.
In patients with impaired liver function, the response to the treatment with ramipril may be either increased or reduced. Treatment in these patients should therefore only be initiated under close medical supervision. Maximum permitted daily dose in this case is 2.5mg ramipril.
Ramipril tablets have to be swallowed whole with sufficient amounts of liquid (approx. 1/2 glass of water).
Ramipril may be taken before, during or after a meal.
Ramipril must not be used
Life-threatening anaphylactoid hypersensitivity reactions, sometimes progressing to shock, have been described in the course of dialysis with certain high-flux membranes (e.g. polyacrylonitril membranes) during ACE inhibitor therapy (see also the instructions of the membrane manufacturer). Concomitant use of ramipril and such membranes (e.g. for emergency dialysis or haemofiltration) must be avoided by using other membranes or changing over to a therapy without ACE inhibitors.
Similar reactions have been observed during low-density lipoprotein apheresis with dextran sulfate. This method must, therefore, not be used in patients treated with ACE inhibitors.
Treatment with ramipril requires regular medical supervision.
Generally, it is recommended that dehydration, hypovolaemia or salt depletion be corrected before initiating treatment (in patients with heart failure, however, this must be carefully weighed against the risk of volume overload). When these conditions have become clinically relevant, treatment with ramipril must only be started or continued if appropriate steps are taken concurrently to prevent an excessive fall in blood pressure and deterioration of renal function.
The following patient groups must be monitored with particular care during treatment with ramipril because an undesirably pronounced fall in blood pressure and possibly subsequent deterioration of renal function is more likely:
Particularly careful monitoring is also necessary in patients who would be at particular risk from an undesirably pronounced fall in blood pressure (e.g. patients with haemodynamically relevant stenoses of the coronary arteries or of the blood vessels supplying the brain).
In order to assess the extent of an acute fall in blood pressure and, where necessary, to permit corrective action to be taken, blood pressure must be repeatedly measured generally after the first dose and after every first increased dose of ramipril as well as after the first dose and when increasing the dose of an additional diuretic until no further acute relevant fall in blood pressure has to be anticipated.
In the event of an excessive fall in blood pressure, it may be necessary to lay the patient flat with legs raised, and to implement fluid or volume replacement as well as other measures.
It is recommended, particularly in the initial weeks of treatment, that renal function be monitored. Particularly careful monitoring is required in patients with renovascular disease (e.g. renal artery stenosis that is still haemodynamically irrelevant or haemodynamically relevant unilateral renal artery stenosis), in patients with pre-existing impairment of renal function or in kidney transplant patients.
It is recommended that serum potassium be monitored regularly. More frequent monitoring of serum potassium is necessary in patients with impaired renal function. Monitoring must be very frequent in patients treated concurrently with potassium-retaining diuretics (e.g. spironolactone), or with potassium salts.
Regular monitoring of serum sodium is necessary in patients undergoing concurrent diuretic therapy.
It is recommended that the white blood cell count be monitored so that a possible leucopenia can be detected. More frequent monitoring is advised in the initial phase of treatment and in the risk groups cited in the ADVERSE EFFECTS section.
Insufficient experience has been gained concerning the use of ramipril in children, in patients with severe impairment of renal function (creatinine clearance below 20ml/min per 1.73 m2 body surface area), and in dialysis patients.
Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable.
If the patient intends to become pregnant, treatment with ACE inhibitors must be halted, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with ramipril must be replaced as soon as possible, but in any event during the first trimester of pregnancy, by a treatment regimen without ACE inhibitors, i.e. also without ramipril. Otherwise there is a risk of harm to the foetus.
If treatment with ramipril is necessary during lactation, the patient must not breast-feed in order to prevent the infant from ingesting small quantities of ramipril with breast milk.
Lowering the blood pressure may impair the patient's ability to concentrate and react and hence, for example, the ability to drive or operate machinery. This applies to a greater extent at the start of treatment or after consumption of alcohol.
At the start of treatment in particular, symptoms such as lightheadedness - sometimes accompanied by concentration disturbances - and impaired reactions, fatigue, weakness and dizziness may occur as a result of vasodilatation, or as a result of the lowering of raised blood pressure even to the desired level. Other symptoms including tachycardia, palpitations, disturbed orthostatic regulation, nausea, sweating, tinnitus, disturbed hearing, disturbed vision, headache, anxiety, drowsiness and somnolence may supervene following an excessive reduction in blood pressure. Then syncope may also occur.
In rare instances, cardiac arrhythmias may occur and may also be caused, for example, by an excessive reduction in blood pressure.
An undesirably pronounced fall in blood pressure may occur particularly after the initial dose and after every first increased dose of ramipril, but also after the first dose or when increasing the dose of an additional diuretic. A pronounced fall in blood pressure, sometimes progressing to shock, may be more likely in patients with
Perfusion disturbances due to vascular stenoses may be exacerbated during treatment with ramipril. Mainly in patients with coronary heart disease or a haemodynamically relevant stenosis of blood vessels supplying the brain myocardial ischaemia (e.g. with ensuing angina pectoris and myocardial infarction) or cerebral ischaemia (e.g. with ensuing transient ischaemic attack or stroke) may occur, particularly as a result of an excessive fall in blood pressure.
Once an adequate blood pressure and fluid balance have been regained, treatment with ramipril can generally be continued.
During treatment with ramipril, there may be a deterioration in renal function, under certain circumstances progressing to acute renal failure, particularly
As signs of impaired renal function, serum creatinine and serum urea may increase, particularly if diuretics are administered concurrently. Pre-existing proteinuria may deteriorate. Particularly in patients with diabetic nephropathy, however, renal protein excretion may also be reduced.
The reduction in angiotensin II formation and aldosterone secretion may cause, or contribute to a decline in serum sodium and an increase in serum potassium concentration, the latter being encountered mainly in patients with impaired renal function (e.g. due to diabetic nephropathy) or when potassium-retaining diuretics are administered concomitantly.
Initially, an increase in urinary output may occur which can be seen in connection with an improvement of cardiac performance.
Angioneurotic oedema occur rarely during treatment with ramipril, are due to ACE inhibitors and necessitate immediate discontinuation of ramipril therapy; any further therapy with other ACE inhibitors is also ruled out in such cases. Angioneurotic oedema, for example, of the tongue, throat or larynx may become life-threatening and necessitate emergency measures. Milder non-angioneurotic oedema, e.g. involving the ankle, are also possible.
In addition the following cutaneous or mucosal reactions may occur:
Reddening of skin areas with accompanying heat sensation, conjunctivitis, pruritus and reactions such as urticaria, maculopapular and lichenoid exanthema and enanthema, erythema multiforme, alopecia and precipitation or intensification of Raynaud's phenomenon. With other ACE inhibitors psoriasiform or pemphigoid exanthema and enanthema, hypersensitivity of the skin to light and onycholysis have been observed.
In the event of pruritus with urticaria, the patient must inform a physician immediately.
The likelihood and the severity of anaphylactic and anaphylactoid reactions may be increased under the influence of ACE inhibitors. This must be considered when desensitization is performed.
Due possibly to ACE inhibition a dry (non-productive) tickling cough frequently occurs. This is often worse at night and when the patient is lying down and occurs more frequently in women and non-smokers. In some cases a change over to another ACE inhibitor is successful. However, the cough may force patients to stop taking ACE inhibitors altogether.
Also possibly due to ACE inhibition rhinitis, sinusitis, bronchitis and, especially in patients with tickling cough, bronchospasm may occur.
In the event dyspnoea develops or worsens, the patient must inform a physician immediately.
Reactions in the digestive tract may develop, e.g. dryness of the mouth, irritation or inflammation of the oral mucosa, digestive disturbances, constipation, diarrhoea, nausea and vomiting, gastritis-like stomach pain, upper abdominal discomfort (sometimes with increased levels of pancreatic enzymes), pancreatitis, increases in hepatic enzymes and/or serum bilirubin, cholestatic jaundice, other forms of impaired liver function and - in some instances life-threatening - hepatitis.
The following blood picture changes may occur: a mild to severe reduction in the red blood cell count and haemoglobin content (in isolated instances also due to haemolytic anaemia), blood platelet count and white cell count (even presenting as neutropenia). Agranulocytosis, bone marrow depression and pancytopenia have been seen with other ACE inhibitors.
Such changes of the blood picture are more likely to occur in patients with impaired renal function and in patients with concomitant collagen disease (e.g. lupus erythematosus or scleroderma) or in patients treated with other agents that may cause changes of the blood picture. See also under INTERACTIONS and WARNINGS AND PRECAUTIONS.
Disorders of balance, headache, nervousness, restlessness, tremor, sleep disturbance, confusion, loss of appetite, depressed mood, feeling of anxiety, paraesthesiae, taste change (e.g. metallic taste), taste reduction and sometimes even loss of taste, muscle cramps as well as erectile impotence and reduced libido may occur. Vasculitis, myalgia, arthralgia, fever and eosinophilia may also occur. Raised titres of antinuclear antibodies have been seen with other ACE inhibitors.
The following interactions with other substances or materials must be considered when ramipril is used concurrently:
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood picture: Increased likelihood of blood picture changes.
Antidiabetic agents (e.g. insulin and sulfonylurea derivatives): Possibility of increased blood sugar reduction. It is suspected that ACE inhibitors potentiate the insulin sensitivity of the tissue.
Antihypertensive agents (e.g. diuretics) and other substances with antihypertensive potential (e.g. nitrates, tricyclic antidepressants, anaesthetics): Potentiation of the antihypertensive effect is to be anticipated (concerning diuretics see also under WARNINGS AND PRECAUTIONS, ADVERSE EFFECTS and DOSAGE AND ADMINISTRATION).
Potassium salts, potassium-retaining diuretics, heparin: Rise in serum potassium concentration is to be anticipated. Potassium salts are not recommended for concurrent administration with ramipril (see also under WARNINGS AND PRECAUTIONS).
Lithium salts: Other ACE inhibitors - and therefore also presumably ramipril - reduce the excretion of lithium salts. This may lead to increased serum lithium levels and increase the risk of cardiotoxic and neurotoxic effects of lithium.
Nonsteroidal anti-inflammatory agents (e.g. acetylsalicylic acid and indomethacin): In case of concurrent administration of ACE inhibitors - and therefore also presumably ramipril - with these substances attenuation of the effect of ramipril must be anticipated.
High-flux dialyser membranes, dextran sulfate: Life-threatening anaphylactoid hypersensitivity reactions, sometimes progressing to shock, have been described in the course of dialysis with certain high-flux membranes (e.g. polyacrylonitril membranes) during ACE inhibitor therapy. Similar reactions have been observed during low-density lipoprotein apheresis with dextran sulfate. See also under CONTRAINDICATIONS.
Alcohol: Ramipril may potentiate the effect of alcohol.
Salt: Increased dietary salt intake may attenuate the antihypertensive effect of ramipril.
The following symptoms may occur: e.g. severe hypotension, shock, electrolyte disturbances, and renal failure.
The treatment given depends on how and when the medicine was taken and on the type and severity of symptoms. Steps must be taken to eliminate ramipril which has not yet been absorbed (e.g. gastric lavage, administration of adsorbants, sodium sulfate; if possible during the first 30 minutes). Vital and organ functions must be monitored under intensive care conditions, and safeguarded if necessary. In case of hypotension administration of catecholamines and angiotensin II must be considered in addition to volume and salt substitution.
No experience is available concerning the efficacy of forced diuresis, altering urine pH, haemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or haemofiltration is nevertheless considered, see also under CONTRAINDICATIONS.
The preparation must not be used after the expiry date printed on the pack.
Keep medicines out of the reach of children.
Store below 25° Centigrade.
Prescription Medicine.
28 tablets (blister pack)
With an LD50 in excess of 10,000mg/kg body weight in mice and rats and in excess of 1000mg/kg body weight in beagle dogs, oral administration of ramipril has been found to be devoid of acute toxicity.
Studies involving chronic administration have been conducted in rats, dogs and monkeys. In rats, daily doses of the order of 40g/kg body weight led to shifts in plasma electrolytes and to anaemia. At daily doses of 3.2mg/kg body weight and higher there was some evidence of changes in renal morphology (distal tubular atrophy). However, these effects can be explained in pharmacodynamic terms and are characteristic of the substance class. Daily doses of 2mg/kg body weight have been tolerated by rats without toxic effects. Tubular atrophy is encountered in rats, but not in dogs and monkeys.
As an expression of the pharmacodynamic activity of ramipril (a sign of increased renin production as a reaction to reduced angiotensin II formation), pronounced enlargement of the juxtaglomerular apparatus has been noted in the dog and monkey - especially at daily doses of 250mg/kg body weight and higher. Indications of plasma electrolyte shifts and changes in blood picture have also been found in the dog and monkey. Dogs and monkeys tolerated daily doses of 2.5mg/kg body weight and 8mg/kg body weight 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 foetal period and lactation produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at daily doses of 50mg/kg body weight and higher.
When ACE inhibitors have been administered to women in the second and third trimester of pregnancy, there have been reports of harmful effects on the foetus and newborn child, including - sometimes in conjunction with oligohydramnios (presumably as an expression of impaired foetal renal function) - craniofacial deformities, pulmonary hypoplasias, foetal limb contractures, hypotension, anuria, reversible and irreversible renal failure as well as death. Prematurity, intrauterine growth retardation and persistence of Botallo's duct have also been reported in humans, although it is uncertain whether these phenomena are a consequence of exposure to ACE inhibitors.
Toxicology studies have yielded no indication that ramipril possesses any immunotoxic effects.
Extensive mutagenicity testing using several test systems has yielded no indication that ramipril possesses mutagenic or genotoxic properties.
Long-term studies in rat and mouse have yielded no indication of a tumorigenic effect. Renal tubules with oxyphilic cells and tubules with oxyphilic cellular hyperplasia in rats are regarded as response to functional alterations and morphological changes, and not as a neoplastic or pre-neoplastic response.
Aventis Pharma Limited
56 Cawley St
Ellerslie
AUCKLAND
Telephone: (09) 580 1810
Fax: (09) 580 1811
March 2005