Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Sanofi-Aventis Ireland Limited T/A SANOFI, Citywest Business Campus, Dublin 24, Ireland
Angioedema occurring during treatment with an ACE inhibitornecessitates immediatediscontinuation of the medicinal product.Angioedemamay involve the tongue, glottis or larynx (e.g. swelling of the airways or tongue, with or without respiratory impairment) and, if so, may necessitate emergency measures.
Angioedema of the face, extremities, lips, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors. Emergency therapy should be given including, but not necessarily limited to, immediate subcutaneous adrenalin solution 1:1000 (0.3 to 0.5 ml) or slow intravenous adrenalin 1 mg/ml (observe dilution instructions) with control of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C1-esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Compared with non-black patients, a higher incidence of angioedema has been reported in black patients treated with ACE inhibitors.
This risk of angioedema 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).
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.
Renal function should be monitored, particularly in the initial weeks of treatment with ACE inhibitors. Caution should be observed in patients with an activated renin-angiotensin system.
Patients with mild to moderately impaired renal function (creatinine clearance 20-60 ml/min) and patients already on diuretic treatment: For dosage see the respective monoproducts.
Hyperkalaemia has been observed in some patients treated with ACE inhibitors, including ramipril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, age (>70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium-retaining diuretics; or other active substances increasing potassium (e.g. heparin, trimethoprim and in fixed dose combination with sulfamethoxazole, tacrolimus, ciclosporin); or condition 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 secretion (SIADH) and subsequent hyponatremia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels be monitored regularly in older people and in other patients at risk of hyponatremia.
It may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.
There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral renal artery stenosis.
There is no experience regarding the administration of Triapin in patients with a recent kidney transplantation.
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progress to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
For dosage see respective monoproducts.
Hypotension may occur in patients undergoing major surgery or during treatment with anaesthetic agents that are known to lower blood pressure. If hypotension occurs, it may be corrected by volume expansion.
ACE inhibitors should be used with caution in patients with haemodynamically relevant left-ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve, obstructive cardiomyopathy). The initial phase of treatment requires special medical supervision.
In some patients, symptomatic hypotension may be observed after the initial dose, mainly in patients with heart failure (with or without renal insufficiency) treated with high doses of loop diuretics, in hyponatraemia or in reduced renal function. Therefore, Triapin should only be given to such patients after special considerations and after the doses of the individual components have been carefully titrated. Triapin should only be given if the patient is in a stable circulatory condition (see section 4.3). In hypertensive patients without cardiac and renal insufficiency, hypotension may occur especially in patients with decreased blood volume due to diuretic therapy, salt restriction, diarrhoea or vomiting.
Patients who would be at particular risk from an undesirably pronounced reduction in blood pressure (e.g. patients with coronary or cerebrovascular insufficiency)should be treated with ramipril and felodipine in a free combination. If satisfactory and stable blood pressure control is achieved with the doses of ramipril and felodipine included in Triapin, the patient can be switched to this combination. In some cases, felodipine may cause hypotension with tachycardia, which may aggravate angina pectoris.
Triapin may cause agranulocytosis and neutropenia. These undesirable effects have also been shown with other ACE inhibitors, rarely in uncomplicated patients but more frequently in patients with some degree of renal impairment, especially when it is associated with collagen vascular disease (e.g. systemic lupus erythematodes, scleroderma) and therapy with immunosuppressive agents. Monitoring of white blood cell counts should be considered for patients who have collagen vascular disease, especially if the disease is associated with impaired renal function. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Should symptoms such as fever, swelling of the lymph nodes, and/or inflammation of the throat occur in the course of therapy with Triapin, the treating physician must be consulted and the white blood picture investigated immediately.
During treatment with an ACE inhibitor a dry cough may occur which disappears after discontinuation.
Concomitant treatment with ACE inhibitors and antidiabetics (insulin and oral antidiabetics) may lead to an enhanced hypoglycaemic effect with the risk of hypoglycaemia. This effect may be most pronounced at the beginning of treatment and in patients with impaired renal function.
Felodipine is metabolised by CYP3A4. Therefore, combination with medicinal products which are potent CYP3A4 inhibitors or inducers should be avoided. For the same reason, the concomitant intake of grapefruit juice should be avoided (see section 4.5).
The combination of lithium and ACE inhibitors is not recommended. (see section 4.5).
Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces should be avoided since it may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-flux (e.g. polyacrylonitrile) membranes and low-density lipoprotein apheresis with dextran sulphate.
Increased likelihood and greater severity of anaphylactic and anaphylactoid reactions to insect venom (e.g. bee and wasp) as for other ACE inhibitors.
Patients planning pregnancy should be changed to alternative antihypertensive 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).
As with other angiotensin converting enzyme inhibitors, ramipril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
No experience is available. Triapin should not be given to these patient groups.
Mild gingival enlargement has been reported in patients taking felodipine with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful dental hygiene.
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product contains macrogolglycerol hydroxystearate (polyoxyl hydrogenated castor oil). It may cause stomach upset and diarrhea.
This medicinal product contains less than 1 mmol sodium (23mg) 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 Triapin.
Felodipine is a CYP3A4 substrate. Medicinal products that induce or inhibit CYP3A4 will have large influence on felodipine plasma concentrations.
Medicinal products that increase the metabolism of felodipine through induction of cytochrome P450 3A4 include carbamazepine, phenytoin, phenobarbital and rifampin as well as St John’s wort (Hypericum perforatum). During concomitant administration of felodipine with carbamazepine, phenytoin, phenobarbital, AUC decreased by 93% and Cmax by 82%. A similar effect is expected with St John’s wort. Combination with CYP3A4 inducers should be avoided.
Potent inhibitors of cytochrome P450 3A4 include azole antifungals, macrolide antibiotics, telithromycin and HIV protease inhibitors. During concomitant administration of felodipine with itraconazole, Cmax increased 8-fold and AUC 6-fold. During concomitant administration of felodipine with erythromycin, Cmax and AUC increased approximately 2.5-fold. Combination with potent CYP3A4 inhibitors should be avoided.
Grapefruit juice inhibits cytochrome P450 3A4. Concomitant administration of felodipine with grapefruit juice increased felodipine Cmax and AUC approximately 2-fold. The combination should be avoided.
Excretion of lithium may be reduced by ACE inhibitors, leading to lithium toxicity. Lithium levels must, therefore, be monitored.
Potentiation of the antihypertensive effect of Triapin is to be anticipated.
Increased likelihood of haematological reactions.
Attenuation of the effect of ramipril is to be expected. Furthermore, concomitant treatment with ACE inhibitors and such medicinal products may lead to an increased risk of worsening of the renal function and an increase in serum potassium.
These may reduce the antihypertensive effect of Triapin. Particularly close blood pressure monitoring is recommended.
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).
An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and NEP inhibitor such as racecadotril(see section 4.4).
The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema.
Concomitant treatment with ACE inhibitors and antidiabetic agents may cause a pronounced hypoglycaemic effect with the risk of hypoglycaemia. This effect is most pronounced at the beginning of treatment.
Concomitant administration of felodipine and oral theophylline reduces theophylline absorption by approximately 20%. This is probably of minor clinical importance.
Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.
Potassium salts, heparin, potassium-retaining diuretics and other active substances causing hyperkalaemia (e.g trimethoprim and in fixed dose combination with sulfamethoxazole, tacrolimus, ciclosporin). Hyperkalaemia may occur, therefore, close monitoring of serum potassium is required (see section 4.4).
Increased dietary salt intake may attenuate the antihypertensive effect of Triapin.
Increased vasodilatation. The antihypertensive effect of Triapin may increase.
Triapin is contra-indicated (see section, 4.3) in pregnancy.
Calcium antagonists may inhibit contractions of the uterus during labour. Definite evidence that labour is prolonged in full-term pregnancy is lacking. Risk of foetal hypoxia may occur if the mother is hypotensive and perfusion of the uterus is reduced due to redistribution of the blood-flow through peripheral vasodilatation. In animal experiments, calcium antagonists have caused embryotoxic and/or teratogenic effects, especially in the form of distal skeletal malformations in several species.
Appropriate and well-controlled studies with ramipril have not been done in humans. ACE inhibitors cross the placenta and can cause foetal and neonatal morbidity and mortality when administered to pregnant women. 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 fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also section 5.3). Should exposure to ACE inhibitor 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).
In animals, ramipril is excreted in milk. No information is available on whether or not ramipril is excreted in human breast-milk. Felodipine is excreted in human breast-milk.
Women must not breast-feed during treatment with Triapin (see section 4.3).
No data on male and female fertility in patients are available (see section 5.3).
Some undesirable effects (e.g. some symptoms of reduction in blood pressure such as dizziness) may be accompanied by an impairment of the ability to concentrate and react. This may constitute a risk in situations where these abilities are of special importance, e.g., when driving a car or operating machinery.
The frequencies used in the tables throughout this section are: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000, <1/1000) and very rare (<1/10 000), not known (cannot be estimated from the available data).
The following undesirable effects may occur in connection with felodipine treatment:
| Frequencies/ Organ System | Very Common | Common | Uncommon | Rare | Very rare |
|---|---|---|---|---|---|
| Immune system disorders | Hypersensitivity reactions | ||||
| Metabolism and nutrition disorders | Hyperglycaemia | ||||
| Psychiatric disorders | Impotence/ sexual dysfunction | ||||
| Nervous system disorders | Headache | Dizziness, paraesthesiae | Syncope | ||
| Cardiac disorders | Tachycardia, palpitations | ||||
| Vascular disorders | Flush | Hypotension | Leucocytoclastic vasculitis | ||
| Gastrointestinal disorders | Nausea, abdominal pain | Vomiting | Gingival hyperplasia, gingivitis | ||
| Hepatobiliary disorders | Increased liver | ||||
| Skin and subcutaneous tissue disorders | Rash, pruritus | Urticaria | Photosensitivity reactions, angioedema | ||
| Musculoskeletal and connective tissue disorders | Arthralgia, myalgia | ||||
| Renal and urinary disorders | Pollakisuria | ||||
| General disorders and administration site conditions | Peripheral oedema | Fatigue | Fever |
The following undesirable effects may occur in connection with ramipril treatment:
| Frequencies/ Organ System | 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 | ||||
| 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 | |||
| Endocrine disorders | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | ||||
| 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 |
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 HPRA Pharmacovigilance. Website: www.hpra.ie.
Not applicable.
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