Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Aventis Pharma Ltd., 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK Or trading as Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK
ACE inhibitors such as ramipril or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/AIIRAs 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/AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
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:
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).
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
The initial phase of treatment requires special medical supervision.
See section 4.2.
It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.
Renal function should be assessed before and during treatment and dose 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 has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8). This risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) may be increased in patients taking concomitant medications which may cause angioedema such as mTOR (mammalian target of rapamycin) inhibitors (e.g. temsirolimus, everolimus, sirolimus), vildagliptin or neprilysin (NEP) inhibitors (such as racecadotril). The combination of ramipril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see sections 4.3 and 4.5).
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).
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 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).
Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatraemia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.
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).
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 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.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see sections 4.3 and 4.4). Treatment with ramipril must not be started until 36 hours after taking the last dose of sacubitril/valsartan. Sacubitril/valsartan must not be started until 36 hours after the last dose of TRITACE.
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.
Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim and in fixed dose combination with sulfamethoxazole, 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.
mTOR inhibitors or DPP-IV inhibitors:
An increased risk of angioedema is possible in patients taking concomitant medications such as mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be used when starting therapy (see section 4.4).
Neprilysin (NEP) inhibitors:
An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and NEP inhibitor such as racecadotril (see section 4.4).
Sacubitril/valsartan:
The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema.
TRITACE is not recommended during the first trimester of pregnancy (see section 4.4) and is contraindicated during the second and third trimesters of pregnancy (see section 4.3).
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.
ACE inhibitor/Angiotensin II Receptor Antagonist (AIIRA) therapy exposure 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 “Preclinical safety data”). Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4).
Because insufficient information is available regarding the use of ramipril during breast-feeding (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.
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.
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 (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| Common | Uncommon | Rare | Very rare | Not known | |
|---|---|---|---|---|---|
| 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 | ||
| Immune system disorders | Anaphylactic or anaphylactoid reactions, antinuclear antibody increased | ||||
| Endocrine disorders | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | ||||
| Metabolism and nutrition disorders | Blood potassium increased | Anorexia, decreased appetite | Blood sodium decreased | ||
| Psychiatric disorders | Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence | Confusional state | Disturbance in attention | ||
| 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 | ||||
| Cardiac disorders | Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral | ||||
| Vascular disorders | Hypotension, orthostatic blood pressure decreased, syncope | Flushing | Vascular stenosis, hypoperfusion, vasculitis | Raynaud’s phenomenon | |
| 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 | |
| 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). | ||
| 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 | |||
| 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 | ||||
| Reproductive system and breast disorders | Transient erectile impotence, libido decreased | Gynaecomastia | |||
| General disorders and administration site conditions | Chest pain, fatigue | Pyrexia | Asthenia |
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” (ie, ≥1/100 to <1/10) in paediatric, and “uncommon” (i.e. ≥1/1,000 to <1/100) in adult population.
Conjunctivitis “common” (ie, ≥1/100 to <1/10) in paediatric and “rare” (i.e. ≥1/10,000 to <1/1,000) in adult population.
Tremor and urticaria “uncommon” (.ie. ≥1/1,000 to <1/100) in paediatric population and “rare” (i.e. ≥1/10,000 to <1/1,000) in adult population.
The overall safety profile for ramipril in paediatric patients does not differ significantly from the safety profile in adults.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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