Altace - Tritace (Brand) Ramipril

Description
Each tablet also contains methylhydroxypropylcellulose, sodium stearyl fumarate and pregelatinized starch as excipients.

Actions
Tritace is a long-acting ACE inhibitor. Ramiprilat, the active metabolite of ramipril, is an inhibitor of the enzyme dipeptidylcarboxypeptidase 1 (angiotensin-converting enzyme (ACE), kininase II).
Administration of Tritace results in a vasodilatation and, especially in hypertensive patients, in a reduction of blood pressure. The blood pressure-lowering effect of a single dose is evident within 1-2 hrs after drug intake, its peak effect occurs within 3-6 hrs. The effect of a single dose usually lasts for 24 hrs.
Pharmacology: Mechanism of Action: Ramipril is a potent and long-acting inhibitor of the angiotensin-converting enzyme (ACE). It is a prodrug which is hydrolyzed in the liver after absorption from the gastrointestinal tract to form the active angiotensin-converting inhibitor, ramiprilat.
Ramipril increases plasma renin activity and decreases plasma concentrations of angiotensin II and aldosterone. The beneficial haemodynamic effects are caused by ACE inhibition and the consequent reduction in angiotensin II results in dilation of peripheral vessels and reduction in vascular resistance.
The mechanism regulating blood pressure confirm that, while the circulating renin-angiotensin system (RAS) has a short-term effect on blood pressure and organ function, tissular RAS contributes in the long run to structural modifications of target organs especially the heart, kidney and vessels.
Angiotensin-converting enzyme is identical with kininase II, an enzyme responsible for the degradation of bradykinin.
There is evidence that ACE inhibition by ramipril interferes with the kallikrein-kinin system. It is assumed that this contributes both to the hypotensive and organ protective activity (blood vessel, heart and kidney) of ramipril.
Effects on Blood Pressure and Effects on the Renin-Angiotensin System: In all rat and dog models used (acute, chronic, anaesthetized and conscious), ramipril was an effective and potent antihypertensive agent.
Ramipril in single daily doses of 5 and 10 mg significantly lowered blood pressure in comparison with placebo. The maximum decrease was noted 4-8 hrs after administration. During a 4-week treatment, both supine and standing blood pressures decreased significantly at 2 and 4 weeks.
Serum concentrations of aldosterone and plasma levels of circulating angiotensin II were reduced for up to 12 hrs after drug intake and tended to return to pre-treatment levels after 24 hrs. Serum ACE activity was markedly suppressed for >24 hrs after a single acute dose of 5 mg of ramipril.
Influence on Diurnal Variations of Blood Pressure:
Single daily doses of 1.25-10 mg given in the morning reduced the blood pressure levels without influencing their circadian variation; no effect on heart rate could be observed.
Effects on Angiotensin-Converting Enzyme and Angiotensin II in Various Tissues: Ramipril caused a stronger pronounced ACE inhibition in the tissues of various organs than enalapril and perindopril.
In a human study, the converting enzyme activity was determined in tissue samples of renal cortex, heart, arteries and veins after an acute oral administration of ramiprilat 2.5 mg. The percent inhibition of converting enzyme activity in renal cortex was 99.7%, heart 35%, artery 97.5% and vein 60.9%.
Effects on Cardiac Arrhythmias: Single oral pre-treatment with ramipril 1 mg/kg attenuated the incidence and duration of re-perfusion arrhythmias in isolated perfused rat hearts and improved haemodynamics during re-perfusion.
Effects on Cardiac Function and Metabolism: Both oral pre-treatment with ramipril and perfusion with ramiprilat of isolated rat heart improved cardiodynamic parameters like coronary flow, left ventricular pressure and dp/dtmax which were increased in comparison to controls without significant changes in heart rate.
In the perfusate of pre-treated hearts, lactate dehydrogenase, creatinine kinase activities and lactate production were reduced. Myocardial tissue levels of glycogen and energy-rich phosphates eg, ATP and creatinine phosphate, were significantly increased, whereas lactate was decreased.
Effects on Cardiac Noradrenaline (NA): Ramiprilat, at therapeutic dose levels, inhibited the noradrenaline release in isolated perfused ischaemic rat hearts.
Effects on Cardiac Hypertrophy: Ramipril was able to prevent the development or to cause regression of cardiac hypertrophy, even with a low dose of 10 mcg/kg which had no antihypertensive effects.
In a human study, 32 hypertensive patients were treated with 5 mg of ramipril daily for 3 months. At the end of the study, a significant reduction in the thickness of the left ventricle wall could be demonstrated. Furthermore, ramipril caused a decrease of the septum thickness and also of the posterior wall. The therapeutic aim of reducing diastolic blood pressure was achieved in all patients.
Effects on the Development of Endothelial Dysfunction Due to Hypercholesterolaemia: A study in hypercholesterolaemia-induced rabbits found that a low once-daily dose of ramipril may prevent the development of hypercholesterolaemia-induced endothelial dysfunction and delay or even prevent the development of atherosclerosis.
Effects on Renal Haemodynamics and Glomerular Filtration Rate (GFR): The effects of ramipril on renal haemodynamics and GFR were studied in essential hypertensives both with and without renal impairment. After 12 weeks of treatment, patients with normal renal function showed significant increase in renal plasma flow and decrease in renal vascular resistance, while the mean GFR was maintained. Patients with renal impairment documented a significant increase in the GFR and renal blood flow and a decrease in the renal vascular resistance.
Effects on Proteinuria: Hypertensive patients with glomerulonephritis and nephrotic syndrome received ramipril in low doses of 1.25 mg (alternate days) to 2.5 mg (once daily) for 24 weeks. During the treatment, both mean arterial blood pressure and proteinuria decreased significantly.
In a double-blind study, normotensive diabetic patients with persistent microalbuminuria were randomized into 2 groups. Patients received either 5 mg ramipril or 1.25 mg ramipril daily for 45 days. Urinary albumin excretion decreased with both treatments, independent of the hypotensive effect.
Effects in Diabetic Patient with Concomitant Mild to Moderate Hypertension: Both supine systolic and diastolic blood pressures decreased significantly in nondiabetic and diabetic hypertensives receiving ramipril, whereas blood glucose levels were not significantly altered in both groups.
Pharmacokinetics: Following oral administration, ramipril is rapidly absorbed from the gastrointestinal tract; peak plasma concentrations of ramipril are reached within 1 hr.
Ramipril is a prodrug, which is converted in the liver to its diacid metabolite, ramiprilat, by cleavage of an ester group. Peak plasma concentrations of ramiprilat are reached approximately 3 hrs after drug intake. Based on the urinary recovery of radiolabelled ramipril and its metabolites, the extent of absorption is estimated to 50-60%.
Food intake has no relevant influence on the extent of absorption.
Steady-state plasma concentrations of ramiprilat after once-daily dosing of the usual doses of ramipril are reached at about treatment day 4.
Ramipril is almost completely metabolized and the metabolites are excreted mainly via the kidneys.
In patients with impaired renal function, the elimination of ramipril and ramiprilat from plasma is delayed and the urinary excretion reduced. Therefore, it is recommended to adjust the ramipril dose according to the degree of impairment of renal function.
In patients with impaired liver function, the metabolization of the parent compound ramipril and therefore the formation of the bioactive metabolite ramiprilat is decelerated resulting in markedly elevated plasma ramipril levels due to a diminished activity of esterases in the liver. Therefore, treatment with ramipril should be initiated with a reduced dose in patients with impaired liver function.
The protein-binding of ramipril is about 73% and of ramiprilat about 56%.

Indications
Hypertension; congestive heart failure; reduction in mortality in patients after myocardial infarction; prevention of myocardial infarction, stroke or cardiovascular death and reduction of need for revascularization procedures in patients with an increased cardiovascular risk eg, manifest coronary heart disease (with or without a history of myocardial infarction), a history of stroke, or a history of peripheral vascular disease; prevention of myocardial infarction, stroke or cardiovascular death in diabetic patients; decreases rate of progression of renal insufficiency in non-diabetic and diabetic overt nephropathy; reduces albumin excretion in non-diabetic and diabetic incipient nephropathy.

Dosage
Dosage is based on the desired effect and on how the patient tolerates the drug. Therapy with Tritace is usually long-term; the physician determines the duration of treatment in each individual case.
Treatment of Hypertension: It is recommended that Tritace is taken once daily, starting with a dose of 2.5 mg, and that the dose be doubled at intervals of 2-3 weeks if necessary, and depending on the patient's response.
The usual maintenance dose is 2.5-5 mg Tritace daily, whereas the maximum permitted daily dose is 10 mg.
Where fluid or salt deficiency has not been completely corrected, in cases of severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk (eg, with flow-reducing narrowing of the coronary heart vessels or those supplying the brain), a reduced initial dose of 1.25 mg Tritace must be considered.
In patients pre-treated with a drug that promotes fluid excretion (diuretic), consideration must be given to discontinuing the diuretic at least 2-3 days or (depending on the duration of action of the diuretic) longer before starting treatment with Tritace, or at least to reducing the diuretic dose. The physician will decide in each individual case whether such discontinuation or dose reduction is possible and how long it can last. The initial dose in patients previously treated with a diuretic is generally 1.25 mg Tritace.
Treatment of Congestive Heart Failure: The recommended initial dose is 1.25 mg Tritace 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 1-2 weeks. If a daily dose of ? (greater than or equal to) 2.5 mg Tritace is required, this may be taken as a single dose or as 2 divided doses.
The maximum permitted daily dose is 10 mg Tritace.
In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic at least 2-3 days or (depending on the duration of action of the diuretic) longer before starting treatment with Tritace, or at least to reducing the diuretic dose.
Treatment After Myocardial Infarction: The recommended initial dose is 5 mg Tritace daily divided into 2 single doses of 2.5 mg each, 1 in the morning and 1 in the evening. If the patient does not tolerate this initial dosage, it is recommended that 1.25 mg be given twice daily for 2 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 1-3 days.
At a later time, the total daily dose, initially divided, may be taken as a single daily dose.
The maximum permitted daily dose is 10 mg Tritace.
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 (1.25 mg Tritace once daily) and that the dosage be increased only with particular caution.
Where fluid or salt deficiency has not been completely corrected, in cases of severe hypertension, in patients in whom a hypotensive reaction would constitute a particular risk (eg, with flow-reducing narrowing of the coronary heart vessels or those supplying the brain), as well as in patients pre-treated with a drug that promotes fluid excretion (diuretic), a reduced initial dose of 1.25 mg Tritace daily must be considered.
Prevention of Myocardial Infarction, Stroke or Cardiovascular Death: The recommended initial dose is 2.5 mg once daily. Depending on the tolerability, the dose is gradually increased. The increase should be implemented by doubling the dose after 1 week. Three weeks later, it should be doubled again to the usual maintenance dose of 10 mg.
Patients with Impaired Renal and Liver Function: Treatment of hypertension, congestive heart failure and myocardial infarction: In patients with impaired renal function ie, a creatinine clearance between 50 and 20 mL/min/1.73 m2 body surface area, the initial dose is generally reduce to 1.25 mg Tritace. The maximum permitted daily dose is 5 mg Tritace in such cases.
When creatinine clearance cannot be measured, it can be calculated based on the serum creatinine level using the following formula (Cockcroft's equation):

In patients with impaired liver function, the response to the treatment with Tritace may either be increased or reduced. Treatment in these patients must therefore be initiated only under close medical supervision. Maximum permitted daily dose in this case is 2.5 mg Tritace.
Administration: The tablets are to be swallowed whole with a sufficient amount of liquid (approximately ? glass of water). They may be taken before, during or after a meal.



Contraindication
Hypersensitivity to ramipril or any of the excipients (see Description).
Patients with a history of angioneurotic oedema [risk of precipitating a life-threatening angioneurotic oedema (see Adverse Reactions)].
Flow-reducing narrowing (haemodynamically relevant stenosis) of the renal artery, bilateral or unilateral in the single kidney (risk of life-threatening fall in blood pressure and renal failure). Flow-reducing (haemodynamically relevant) left ventricular inflow or outflow impediment (eg, narrowing of the aortic or mitral valve of the heart, risk of life-threatening fall in blood pressure and renal failure).
Patients with low blood pressure or labile circulatory condition (risk of life-threatening fall in blood pressure).
Life-threatening, rapid-onset and allergy-like (anaphylactoid) hypersensitivity reactions, sometimes progressing to circulatory shock, have been described in the course of dialysis with certain high-flux membranes (eg, polyacrylonitril membranes) during ACE inhibitor therapy. Concomitant use of Tritace and such membranes, eg 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.
Use in pregnancy & lactation: Tritace must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided where therapy with ACE inhibitors is indispensable.
If the patient becomes pregnant during treatment, medication with Tritace must be replaced at the earliest possible stage, but in any event during the 1st trimester of pregnancy, by a treatment regimen without ACE inhibitors, ie also without Tritace. Otherwise there is a risk of harm to the foetus.
If treatment with Tritace is necessary during lactation, the patient must not breastfeed in order to prevent the infant from ingesting small quantities of ramipril with breast milk.

Precautions
Treatment with Tritace requires regular medical supervision.
Generally, it is recommended that dehydration, reduced blood volume (hypovolaemia) or salt deficiency be corrected before initiating treatment (in patients with heart failure, however, this must be carefully weighed against the risk of volume overload). When such a condition has become clinically relevant, treatment with Tritace must be started or continued only if appropriate steps are taken concurrently to prevent an excessive fall in blood pressure and deterioration of renal function (see Dosage & Administration).
The following patient groups must be monitored with particular care during treatment with Tritace, because an undesirably pronounced fall in blood pressure and possibly a subsequent deterioration of renal function is more likely:
Patients with severe, and particularly with malignant hypertension; patients heart failure, particularly if severe or if treated with other substances with blood pressure-lowering potential; patients in whom fluid or salt deficiency exist or may develop; patients pre-treated with drugs that promote fluid excretion (diuretics); patients with haemodynamically relevant renal artery stenosis.
Particularly careful monitoring is also necessary in patients who would be at particular risk from an undesirably pronounced fall in blood pressure (eg, 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, if necessary, to take countermeasures, blood pressure must be repeatedly measured, generally after the 1st dose and after every first increased dose of Tritace, until no further relevant acute fall in blood pressure has to be anticipated. This also applies after the 1st dose of an additional diuretic and when increasing its dose.
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.
Renal function should be monitored, particularly in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal vascular disease (eg, with renal artery stenosis that is still haemodynamically irrelevant or haemodynamically relevant unilateral renal artery stenosis), in patients with preexisting impairment of renal function, and in kidney transplant patients.
Serum potassium should be monitored regularly. More frequent monitoring of serum potassium is required in patients with impaired renal function; monitoring must be very frequent in patients treated concurrently with potassium-retaining diuretics (eg, spironolactone) or with potassium salts.
Regular monitoring of serum sodium is necessary in patients undergoing concurrent diuretic therapy.
White blood cell counts should be monitored so that a possible excessive reduction in white blood cells (leucopenia) can be detected. More frequent monitoring is recommended in the initial phase of treatment and in the risk groups (see Adverse Reactions).
The blood picture must be checked in the event of possible signs of leucopenia-induced immunodeficiency (eg, fever, lymph node enlargement, tonsillitis). It must also be checked in the event of possible signs of a bleeding tendency due to an excessive reduction in blood platelets, eg brownish red pin-point spots (petechiae) or areas of brownish red discoloration (sometimes rash-like) in the skin or mucous membranes (purpura), or bleeding from the gums, which is difficult to control.
In the event of swelling, eg in the facial region (eg, lips, eyelids) or the tongue, or in the event of swallowing or breathing difficulty, the possibility of angioneurotic oedema must be considered. Patients must inform their physician immediately in such circumstances and omit the next scheduled dose of Tritace for the time being. Angioneurotic oedema of the tongue, throat or larynx (possible symptoms, eg difficulty in swallowing or breathing) may become life-threatening and necessitate emergency measures.
Insufficient experience has been gained concerning the use of Tritace in children, in patients with severe impairment of renal function (creatinine clearance <20 mL/min/1.73 m2 body surface area), and in dialysis patients.
Effects on the Ability to Drive or Operate Machinery: Lowering the blood pressure may impair the patient's ability to concentrate and react and hence, eg the ability to drive, cross the road safely or operate machinery. This applies to a greater extent at the start of treatment or after consumption of alcohol.

Adverse Reactions
Blood Pressure: At the start of treatment in particular, symptoms, eg lightheadedness, sometimes accompanied by concentration disturbances, as well as impaired reactions, fatigue, weakness and dizziness may occur even as a result of vasodilatation (dilatation of smaller blood vessels) or as a result of the lowering of raised blood pressure to the desired level.
Other symptoms including rapid heart rate (tachycardia), palpitations, circulatory problems (eg, weakness or feeling faint) on standing (disturbed orthostatic regulation), nausea, sweating, noises in the ears (tinnitus), hearing disorders, visual disorders, headache, anxiety, drowsiness and extreme sleepiness (somnolence) may supervene following an excessive reduction in blood pressure. Then temporary loss of consciousness (syncope) may also occur.
In rare instances, cardiac arrhythmias may occur and may also be caused, eg 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 Tritace, but also after the 1st dose of an additional drug that promotes fluid excretion (diuretic) and when increasing its dose.
A pronounced fall in blood pressure, sometimes progressing to life-threatening circulatory shock, may be more likely in patients with severe and particularly malignant hypertension, heart failure, particularly if severe or if treated with other substances with blood pressure-lowering potential, previous diuretic therapy, fluid or salt deficiency (as a result of insufficient fluid or salt intake, or as a result of, eg diarrhoea, vomiting or excessive sweating in cases where salt and fluid replacement is inadequate), blood flow-reducing narrowing (haemodynamically relevant stenosis) of the renal artery.
Perfusion disturbances due to narrowing (stenoses) of blood vessels may be exacerbated during treatment with Tritace. Mainly in patients with coronary heart disease or flow-reducing (haemodynamically relevant) narrowing of blood vessels supplying the brain, life-threatening insufficient perfusion of the heart muscle or of the brain (myocardial or cerebral ischaemia) may occur, particularly as a result of an excessive fall in blood pressure. This may be complicated by angina pectoris or myocardial infarction, and by transient loss of brain function (transient ischaemic attack) or stroke. Once an adequate blood pressure has been regained, treatment with Tritace can generally be continued.
Kidney and Salt Balance: During treatment with Tritace, there may be a deterioration in renal function, under certain circumstances progressing to life-threatening acute renal failure. This applies particularly in patients with diseases of the blood vessels of the kidney (renovascular disease, eg haemodynamically relevant renal artery stenosis), in kidney transplant patients, and in conjunction with a more pronounced fall in blood pressure, mainly in patients with concomitant heart failure.
As a symptom of impaired renal function, serum creatinine and urea (substances eliminated by the kidney) may increase, particularly if drugs that promote fluid excretion (diuretics) are administered concurrently.
Preexisting pronounced urinary excretion of proteins (proteinuria) may increase under treatment with Tritace. However, renal protein excretion may also be reduced, particularly in patients with diseases of the kidney due to diabetes (diabetic nephropathy).
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 (eg, due to diabetic nephropathy) or when potassium diuretics are administered concomitantly.
Initially, an increase in urinary output may occur which can be seen in connection with an improvement of cardiac performance.
Skin, Blood Vessels, Anaphylactic and Anaphylactoid Reactions: Angioneurotic oedema occur rarely during treatment with Tritace due to the desired ACE inhibition, and necessitate immediate discontinuation of Tritace therapy; other ACE inhibitors are also ruled out in such cases.
Angioneurotic oedema may manifest itself, ie swelling in the region of the extremities, face (ie, eyelids, lips), tongue, throat or larynx (noticeable, eg difficulty in swallowing or breathing). Angioneurotic oedema, ie of the tongue, throat or larynx may become life-threatening and necessitate emergency measures.
Mild non-angioneurotic oedema, eg involving the ankle, are also possible.
In addition, the following cutaneous and mucosal reactions may occur: Reddening of skin areas with accompanying heat sensation, conjunctivitis, itching, urticaria, other skin or mucosal eruptions (maculopapular and lichenoid exanthema and enanthema), erythema multiforme, sometimes pronounced hair loss (alopecia) and precipitation or intensification of Raynaud's phenomenon (attacks of circulatory disturbances characterized by, eg whiteness of fingers or toes). With other ACE inhibitors, other types of skin and mucosal reactions (psoriasiform and pemphigoid exanthema and enanthema), hypersensitivity of the skin to light and loosening of the nails (onycholysis) have been observed. In the event of itching with urticaria, the patient must inform a physician immediately.
The likelihood and the severity of anaphylactoid reactions (sometimes life-threatening rapid-onset allergic or allergy-like reactions) may be increased under the influence of ACE inhibitors. This may be considered when desensitization is performed.
Respiratory Tract: A dry (nonproductive), tickling cough occurs frequently. This is possibly due to ACE inhibition. This is often worse at night and when the patient is lying down, and occurs more frequently in women and nonsmokers. In some cases, a changeover to another ACE inhibitor is successful. However, the cough may force patients to stop taking ACE inhibitors altogether. Also due to ACE inhibition, nasal catarrh (rhinitis), sinusitis, bronchitis and, especially in patients with tickling cough, bronchospasm may occur. In the event of difficulty in breathing, the patient must inform a physician immediately.
Digestive Tract: Reactions in the digestive tract may develop, eg 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, jaundice due to impaired excretion of bile pigment (cholestatic jaundice), other forms of impaired liver function and, in some instances, life-threatening hepatitis.
Blood Picture: The following changes in blood picture 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 and white cell counts, sometimes even involving only certain white blood cells (neutropenia). Agranulocytosis, bone marrow depression (impaired blood cell formation) and pancytopenia (excessive reduction in the number of all blood cells) have been observed with other ACE inhibitors.
Such changes of the blood picture, which are sometimes life-threatening, are more likely to occur in patients with impaired renal function, in patients with concomitant connective tissue disease (collagen vascular disease, eg lupus erythematosus or scleroderma), or in patients treated with other drugs that may cause changes in the blood picture (see Interactions and Precautions).
Other Adverse Reactions: Disturbances of balance, headache, nervousness, restlessness, tremor, sleep disorders, confusion, loss of appetite, depressed mood, feeling of anxiety, abnormal sensations (paraesthesiae), taste change (eg, metallic taste), taste reduction and sometimes even loss of taste, muscle cramps and, as is generally possible in unusually low blood pressure and as a possible consequence of other adverse reactions, erectile impotence and reduced sexual desire (decreased libido) may occur.
Inflammation of blood vessels (vasculitis), muscle and joint pains (myalgia and arthralgia), fever or eosinophilia (increase in the number of certain white blood cells) may occur. Raised titres of antinuclear antibodies have been seen in addition with other ACE inhibitors.



Drug Interaction
The following interactions must be considered when Tritace is administered simultaneously with certain other drugs, substances or materials:
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may alter the blood picture increase the likelihood of blood picture changes.
When antidiabetic agents (eg, insulin and sulfonylurea derivatives) are used concurrently, the possibility of increased blood-sugar reduction must be considered.
When antihypertensive agents (eg, diuretics), or other substances with antihypertensive potential (eg, nitrates, tricyclic antidepressants, anaesthetics) are used concomitantly, potentiation of the antihypertensive effect has to be anticipated [concerning anaesthetics and diuretics (see Precautions, Adverse Reactions and Dosage & Administration)].
When potassium supplements, potassium-retaining diuretics or heparin are given concurrently, a rise in serum potassium concentration has to be anticipated. Potassium salts should not be administered simultaneously with Tritace (concerning potassium-retaining diuretics, see Precautions).
Other ACE inhibitors, and 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.
When ACE inhibitors, and therefore also presumably Tritace, are administered simultaneously with certain drugs for the control of pain and inflammation (nonsteroidal anti-inflammatory drugs, eg acetylsalicylic acid and indomethacin), attenuation of the antihypertensive effect as well as development of acute renal failure has to be anticipated.
Life-threatening anaphylactoid hypersensitivity reactions, sometimes progressing to shock, have been described in the course of dialysis with certain high-flux membranes (eg, polyacrylonitril membranes) during ACE inhibitor therapy. Similar reactions have been observed during low-density lipoprotein apheresis with dextran sulfate (see Contraindications).
Tritace may potentiate the effect of alcohol.
Increased dietary salt intake may attenuate the antihypertensive effect of Tritace (see Precautions and Adverse Reactions).

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