1. Name Of The Medicinal Product
Tritace 10mg Tablets
2. Qualitative And Quantitative Composition
Tablets
Each tablet contains ramipril 10 mg.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Tablets 10mg
White to almost white, oblong tablets with a score-line.
Upper stamp: HMO/HMO
The tablet can be divided into equal halves.
4. Clinical Particulars
4.1 Therapeutic Indications
- 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 (see section 5.1).
- 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 (see section 5.1),
• Manifest glomerular non diabetic nephropathy as defined by macroproteinuria
- 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.
4.2 Posology And Method Of Administration
Oral use.
It is recommended that TRITACE is taken each day at the same time of the day.
TRITACE can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2).
TRITACE has to be swallowed with liquid. It must not be chewed or crushed.
Adults
Diuretic-Treated patients
Hypotension may occur following initiation of therapy with TRITACE; 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 TRITACE (see section 4.4).
In hypertensive patients in whom the diuretic is not discontinued, therapy with TRITACE should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of TRITACE should be adjusted according to blood pressure target.
Hypertension
The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.
TRITACE may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.
Starting dose
TRITACE 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 (see section 4.4).
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 TRITACE is 10 mg daily. Usually the dose is administered once daily.
Cardiovascular prevention
Starting dose
The recommended initial dose is 2.5 mg of TRITACE 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 TRITACE 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 TRITACE 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 TRITACE 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 TRITACE after one or two weeks and then to 10 mg TRITACE 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
Starting dose:
The recommended initial dose is 1.25 mg of TRITACE 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
TRITACE 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 (see section 5.2):
- if creatinine clearance is
- 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 few hours after haemodialysis is performed.
Patients with hepatic impairment (see section 5.2)
In patients with hepatic impairment, treatment with TRITACE must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg TRITACE.
Elderly
Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.
Paediatric population
The safety and efficacy of ramipril in children has not yet been established. Currently available data for TRITACE are described in sections 4.8, 5.1, 5.2 & 5.3 but no specific recommendation on posology can be made.
4.3 Contraindications
- Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)
- 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 (see section 4.5)
- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney
- Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.
4.4 Special Warnings And Precautions For Use
Special populations
Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor 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 should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
- 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 failure
- patients with haemodynamically relevant left ventricular 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 out 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.
- Elderly patients
See section 4.2.
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 (see section 4.2). 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 (see section 4.8).
In case of angioedema, TRITACE 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 TRITACE (see section 4.8). 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 TRITACE should be considered prior to desensitization.
Hyperkalaemia
Hyperkalaemia has been observed in some patients treated with ACE inhibitors including TRITACE. 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 (see section 4.5).
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 (see sections 4.5 and 4.8).
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 nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 (see section 4.3). 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 (see section 4.2 for diuretics)
Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of TRITACE: 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 (see section 4.4).
Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level 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 TRITACE 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.
4.6 Pregnancy And Lactation
Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor 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 should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Lactation
Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), Tritace is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects On Ability To Drive And Use Machines
Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).
This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.
4.8 Undesirable Effects
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 (
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|
Common
|
Uncommon
|
Rare
|
Very rare
|
Not known
|
Cardiac disorders
|
|
Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral
|
|
|
|
Blood and lymphatic system disorders
|
|
Eosinophilia
|
White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased
|
|
Bone marrow failure, pancytopenia, haemolytic anaemia
|
Nervous system disorders
|
Headache, dizziness
|
Vertigo, paraesthesia, ageusia, dysgeusia,
|
Tremor, balance disorder
|
|
Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia
|
Eye disorders
|
|
Visual disturbance including blurred vision
|
Conjunctivitis
|
|
|
Ear and labyrinth disorders
|
|
|
Hearing impaired, tinnitus
|
|
|
Respiratory, thoracic and mediastinal disorders
|
Non-productive tickling cough, bronchitis, sinusitis, dyspnoea
|
Bronchospasm including asthma aggravated, nasal congestion
|
|
|
|
Gastrointestinal disorders
|
Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting
|
Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth
|
Glossitis
|
|
Aphtous stomatitis
|
Renal and urinary disorders
|
|
Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased
|
|
|
|
Skin and subcutaneous tissue disorders
|
Rash in particular maculo-papular
|
Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis
|
Exfoliative dermatitis, urticaria, onycholysis,
|
Photosensitivity reaction
|
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia
|
Musculoskeletal and connective tissue disorders
|
Muscle spasms, myalgia
|
Arthralgia
|
|
|
|
Metabolism and nutrition disorders
|
Blood potassium increased
|
Anorexia, decreased appetite,
|
|
|
Blood sodium decreased
|
Vascular disorders
|
Hypotension, orthostatic blood pressure decreased, syncope
|
Flushing
|
Vascular stenosis, hypoperfusion, vasculitis
|
|
Raynaud's phenomenon
|
General disorders and administration site conditions
|
Chest pain, fatigue
|
Pyrexia
|
Asthenia
|
|
|
Immune system disorders
|
|
|
|
|
Anaphylactic or anaphylactoid reactions, antinuclear antibody increased
|
Hepatobiliary disorders
|
|
Hepatic enzymes and/or bilirubin conjugated increased,
|
Jaundice cholestatic, hepatocellular damage
|
|
Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).
|
Reproductive system and breast disorders
|
|
Transient erectile impotence, libido decreased
|
|
|
Gynaecomastia
|
Psychiatric disorders
|
|
Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence
|
Confusional state
|
|
Disturbance in attention
|
Paediatric Population
The safety of ramipril was monitored in 325 children and adolescents, aged 2-16 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:
Tachycardia, nasal congestion and rhinitis, “common” (i.e.
Conjunctivitis “common” (i.e.
Tremor and urticaria “uncommon” (i.e.
The overall safety profile for ramipril in paediatric patients dose not differ significantly from the safety profile in adults.
4.9 Overdose
Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.
Mechanism of action
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 average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.
Pharmacodynamic effects
Antihypertensive properties:
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.
Heart failure:
In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.
Clinical efficacy and safety
Cardiovascular prevention/Nephroprotection;
A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.
The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).
The HOPE Study: Main Results;
|
Ramipril
|
Placebo
|
relative risk
(95% confidence interval)
|
p-value
|
|
%
|
%
|
|
|
All patients
|
n=4,645
|
N=4,652
|
|
|
Primary combined events
|
14.0
|
17.8
|
0.78 (0.70-0.86)
|
<0.001
|
Myocardial infarction
|
9.9
|
12.3
|
0.80 (0.70-0.90)
|
<0.001
|
Death from cardiovascular causes
|
6.1
|
8.1
|
0.74 (0.64-0.87)
|
<0.001
|
Stroke
|
3.4
|
4.9
|
0.68 (0.56-0.84)
|
<0.001
|
|
|
|
|
|
Secondary endpoints
|
|
|
|
|
Death from any cause
|
10.4
|
12.2
|
0.84 (0.75-0.95)
|
0.005
|
Need for Revascularisation
|
16.0
|
18.3
|
0.85 (0.77-0.94)
|
0.002
|
Hospitalisation for unstable angina
|
12.1
|
12.3
|
0.98 (0.87-1.10)
|
NS
|
Hospitalisation for heart failure
|
3.2
|
3.5
|
0.88 (0.70-1.10)
|
0.25
|
Complications related to diabetes
|
6.4
|
7.6
|
|
