Source: Medicines Authority (MT) Revision Year: 2022 Publisher: Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, France
Linked to perindopril:
Linked to amlodipine:
Linked to Coveram:
All contraindications related to each monocomponent, as listed above, should apply also to the fixed combination of Coveram.
All warnings related to each monocomponent, as listed below, should apply also to the fixed combination of Coveram.
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during therapy. In such cases, Coveram should promptly be discontinued and appropriate monitoring should be initiated and continued until complete resolution of symptoms has occurred. In those instances where swelling was confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely 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 facial angioedema and C-1 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 (see section 4.8).
The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of ACE inhibitors with NEP inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in a patient already taking an ACE inhibitor.
Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever).
There is an increased risk of hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors (see section 4.3). Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.
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.
Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of this product is not recommended.
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitors is considered essential, 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).
ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see sections 4.5 and 4.8). In patients at high risk of symptomatic hypotension, blood pressure, renal function and serum potassium should be monitored closely during treatment with Coveram. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
As with other ACE inhibitors, perindopril should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.
In cases of renal impairment (creatinine clearance <60 ml/min) an individual dose titration with the monocomponents is recommended (see section 4.2).
Routine monitoring of potassium and creatinine are part of normal medical practice for patients with renal impairment (see section 4.8).
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when perindopril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment.
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses 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 (see section 4.8).
ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients. As with other ACE inhibitors, perindopril may be 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.
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Coveram may block angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued one day prior to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril, ACE inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. Risk factors for the development of hyperkalemia include those with renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, intercurrent events, in particular dehydratation, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole) and especially aldosterone antagonists or angiotensinreceptor blockers. The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal arrhythmias. Potassium-sparing diuretics and angiotensinreceptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored. If concomitant use of perindopril and any of the above mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see section 4.5).
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group (see section 5.1). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).
Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.
All warnings related to each monocomponent, as listed above, should apply also to the fixed combination of Coveram.
Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucosegalactose malabsorption, or the total lactase deficiency should not take this medicinal product.
The concomitant use of Coveram with lithium, potassium-sparing drugs or potassium supplements, or dantrolene is not recommended (see section 4.5).
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).
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4). Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk for angioedema (see section 4.4).
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with Coveram. Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. The combination of these drugs increases the risk of hyperkalaemia. Therefore, the combination of Coveram with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.
In diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
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.
In patients other than diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.
It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with ACE inhibitor and angiotensin-receptor blocker is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g, by combining an ACE-inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure.
Risk of increased adverse effects such as angioneurotic oedema (angioedema).
Hyperkalaemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalaemic effects).
The combination of perindopril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is nonetheless indicated, they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart failure, see below.
Reversible increases in serum lithium concentrations and toxicity (severe neurotoxicity) have been reported during concurrent use of ACE inhibitors. The combination of perindopril with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended (see section 4.4).
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Patients on diuretics, and especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril.
In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE inhibitor, in which case a non-potassium-sparing diuretic can be thereafter reintroduced or the ACE inhibitor must be initiated with a low dosage and progressively increased.
In diuretic-treated congestive heart failure, the ACE inhibitor should be initiated at a very low dosage, possibly after reducing the dosage of the associated non-potassium-sparing diuretic. In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE inhibitor therapy.
With eplerenone or spironolactone at doses between 12.5 mg to 50 mg by day and with low doses of ACE inhibitors:
In the treatment of class II-IV heart failure (NYHA) with an ejection fraction <40%, and previously treated with ACE inhibitors and loop diuretics, risk of hyperkalaemia, potentially lethal, especially in case of nonobservance of the prescription recommendations on this combination.
Before initiating the combination, check the absence of hyperkalaemia and renal impairment.
A close monitoring of the kalaemia and creatininemia is recommended in the first month of the treatment once a week at the beginning and, monthly thereafter.
When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including perindopril.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
CYP3A4 inducers: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).
CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co administered with clarithromycin.
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.
There is a risk of increased tacrolimus blood levels when co administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
No drug interaction studies have been conducted with ciclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of ciclosporine were observed. Consideration should be given for monitoring ciclosporine levels in renal transplant patients on amlodipine, and ciclosporine dose reductions should be made as necessary.
Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.
Given the effects of the individual components in this combination product on pregnancy and lactation:
Coveram is not recommended during the first trimester of pregnancy. Coveram is contraindicated during the second and third trimesters of pregnancy.
Coveram is not recommended during lactation. A decision should therefore be made whether to discontinue nursing or to discontinue Coveram taking account the importance of this therapy for the mother.
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 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.
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 inhibitor 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).
The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.
There was no effect on reproductive performance or fertility.
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).
No studies on the effects of Coveram on the ability to drive and use machines have been performed. Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients suffer from dizziness, headache, fatigue, weariness or nausea, the ability to react may be impaired. Caution is recommended especially at the start of treatment.
The most commonly reported adverse reactions with perindopril and amlodipine given separately are: oedema, somnolence, dizziness, headache (especially at the beginning of the treatment), dysgeusia, paraesthesia, visual impairment (including diplopia), tinnitus, vertigo, palpitations, flushing, hypotension (and effects related to hypotension), dyspnoea, cough, abdominal pain, nausea, vomiting, dyspepsia, change of bowel habit, diarrheoa, constipation, prurit, rash, exanthema, joint swelling (ankle swelling), muscle spasms, fatigue, asthenia.
The following undesirable effects have been observed during clinical trials and/or post-marketing use with perindopril or amlodipine given separately and ranked under the MedDRA classification by body system and under the following frequency: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data).
| MedDRA System Organ Class | Undesirable Effects | Frequency | |
|---|---|---|---|
| Amlodipine | Perindopril | ||
| Infections and infestations | Rhinitis | Uncommon | Very rare |
| Blood and the lymphatic System Disorders | Eosinophilia | - | Uncommon* |
| Leukopenia/neutropenia (see section 4.4) | Very rare | Very rare | |
| Agranulocytosis or pancytopenia (see section 4.4) | - | Very rare | |
| Thrombocytopenia (see section 4.4) | Very rare | Very rare | |
| Haemolytic anaemia enzyme specific in patients with a congenital deficiency of G-6PDH (see section 4.4) | - | Very rare | |
| Immune System Disorders | Hypersensitivity | Very rare | Uncommon |
| Endocrine disorders | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | - | Rare |
| Metabolism and Nutrition Disorders | Hypoglycaemia (see sections 4.4 and 4.5) | - | Uncommon* |
| Hyperkalaemia, reversible on discontinuation (see section 4.4) | - | Uncommon* | |
| Hyponatraemia | - | Uncommon* | |
| Hyperglycaemia | Very rare | - | |
| Psychiatric disorders | Insomnia | Uncommon | - |
| Mood altered (including anxiety) | Uncommon | Uncommon | |
| Depression | Uncommon | - | |
| Sleep disorder | - | Uncommon | |
| Nervous System disorders | Somnolence (especially at the beginning of the treatment) | Common | Uncommon* |
| Dizziness (especially at the beginning of the treatment) | Common | Common | |
| Headache (especially at the beginning of the treatment) | Common | Common | |
| Dysgeusia | Uncommon | Common | |
| Tremor | Uncommon | - | |
| Hypoaesthesia | Uncommon | - | |
| Paraesthesia | Uncommon | Common | |
| Syncope | Uncommon | Uncommon* | |
| Confusional state | Rare | Very rare | |
| Hypertonia | Very rare | - | |
| Neuropathy peripheral | Very rare | - | |
| Cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients (see section 4.4) | - | Very rare | |
| Extrapyramidal disorder (extrapyramidal syndrome) | Not known | - | |
| Eye Disorders | Visual impairment | Common | Common |
| Diplopia | Common | - | |
| Ear and labyrinth disorders | Tinnitus | Uncommon | Common |
| Vertigo | - | Common | |
| Cardiac Disorders | Palpitations | Common | Uncommon* |
| Tachycardia | - | Uncommon* | |
| Angina pectoris (see section 4.4) | - | Very rare | |
| Myocardial infarction, possibly secondary to excessive hypotension in high risk patients (see section 4.4) | Very rare | Very rare | |
| Arrythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) | Uncommon | Very rare | |
| Vascular Disorders | Flushing | Common | Rare* |
| Hypotension (and effects related to hypotension) | Uncommon | Common | |
| Vasculitis | Very Rare | Uncommon* | |
| Raynaud’s phenomenon | - | Not known | |
| Respiratory, Thoracic and Mediastinal Disorders | Dyspnoea | Common | Common |
| Cough | Uncommon | Common | |
| Bronchospasm | - | Uncommon | |
| Eosinophilic pneumonia | - | Very rare | |
| Gastro-intestinal Disorders | Gingival hyperplasia | Very rare | - |
| Abdominal pain | Common | Common | |
| Nausea | Common | Common | |
| Vomiting | Uncommon | Common | |
| Dyspepsia | Common | Common | |
| Change of bowel habit | Common | - | |
| Dry mouth | Uncommon | Uncommon | |
| Diarrheoa | Common | Common | |
| Constipation | Common | Common | |
| Pancreatitis | Very rare | Very rare | |
| Gastritis | Very rare | - | |
| Hepato-biliary Disorders | Hepatitis, jaundice | Very rare | - |
| Hepatitis either cytolitic or cholestatic (see section 4.4) | - | Very rare | |
| Hepatic enzymes increased (mostly consistent with cholestasis) | Very rare | - | |
| Skin and Subcutaneous Tissue Disorders | Quincke’s oedema | Very rare | - |
| Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see section 4.4) | Very rare | Uncommon | |
| Erythema multiform | Very rare | Very rare | |
| Alopecia | Uncommon | - | |
| Purpura | Uncommon | - | |
| Skin discolouration | Uncommon | - | |
| Hyperhidrosis | Uncommon | Uncommon | |
| Prurit | Uncommon | Common | |
| Rash, exanthema | Uncommon | Common | |
| Urticaria (see section 4.4) | Uncommon | Uncommon | |
| Photosentivity reactions | Very rare | Uncommon* | |
| Pemphigoid | - | Uncommon* | |
| Psoriasis aggravation | - | Rare | |
| Stevens-Johnson Syndrome | Very rare | - | |
| Exfoliative dermatitis | Very rare | - | |
| Toxic epidermal necrolysis | Not known | - | |
| Musculoskeletal and Connective Tissue Disorders | Joint swelling (ankle swelling) | Common | - |
| Arthralgia | Uncommon | Uncommon* | |
| Myalgia | Uncommon | Uncommon* | |
| Muscle spasms | Common | Common | |
| Back pain | Uncommon | - | |
| Renal and Urinary Disorders | Micturition disorder, nocturia, pollakiuria | Uncommon | - |
| Renal failure | - | Uncommon | |
| Acute renal failure | - | Rare | |
| Anuria/Oliguria | - | Rare* | |
| Reproductive System and Breast Disorders | Erectile dysfunction | Uncommon | Uncommon |
| Gynaecomastia | Uncommon | - | |
| General Disorders and Administration Site Conditions | Oedema | Very common | - |
| Oedema peripheral | - | Uncommon* | |
| Fatigue | Common | - | |
| Chest pain | Uncommon | Uncommon* | |
| Asthenia | Common | Common | |
| Pain | Uncommon | - | |
| Malaise | Uncommon | Uncommon* | |
| Pyrexia | - | Uncommon* | |
| Investigations | Weight increased, weight decreased | Uncommon | - |
| Blood urea increased | - | Uncommon* | |
| Blood creatinine increased | - | Uncommon* | |
| Blood bilirubin increase | - | Rare | |
| Hepatic enzyme increase | - | Rare | |
| Haemoglobin decreased and haematocrit decreased | - | Very rare | |
| Injury, poisoning and procedural complications | Fall | - | Uncommon* |
* Frequency calculated from clinical trials for adverse events detected from spontaneous report
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 ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal.
Not applicable.
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