Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Recordati Ireland Limited, Raheens East, Ringaskiddy, Co. Cork, Ireland
Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving enalapril, symptomatic hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see section 4.5). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatremia or functional renal impairment. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of enalapril and/or diuretic is adjusted. Similar considerations may apply to patients with ischemic 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 normal saline. 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. In some patients with heart failure who have normal or low blood pressure, additional lowering of systematic blood pressure may occur with enalapril. This effect is anticipated and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or enalapril may be necessary.
Lercanidipine should be administered with caution in patients with sick-sinus syndrome (without a pacemaker).
Although haemodynamic controlled studies revealed no impairment of ventricular function, care is required in patients with left ventricular dysfunction.
It has been suggested that some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischaemic heart disease. Although lercanidipine is long-acting, caution is required in such patients. Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely, patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed (see section 4.8).
Particular caution is required with enalapril when initiating treatment in patients with mild to moderate renal impairment. Routine monitoring of serum potassium and creatinine are part of the normal medical practice for these patients. Renal failure has been reported in association with enalapril, mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure when associated with therapy with enalapril treatment is usually reversible.
Some hypertensive patients, with no apparent pre-existing renal disease, have developed increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. This situation should raise the possibility of underlying renal artery stenosis (see section 4.4, Renovascular hypertension).
There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE-inhibitor. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses and cautious titration and monitoring of renal function.
There is no experience in the use of lercanidipine or enalapril in patients who have recently undergone kidney transplantation. Treatment with Lercaril is therefore not recommended.
The antihypertensive effect of lercanidipine can be potentiated in patients with hepatic dysfunction.
Rarely, ACE-inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis 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 elevation of hepatic enzymes should discontinue the ACE-inhibitor and receive appropriate medical follow up.
Lercanidipine has been associated with the development of cloudy peritoneal effluent in patients on peritoneal dialysis. The turbidity is due to an increased triglyceride concentration in the peritoneal effluent. Whilst the mechanism is unknown, the turbidity tends to resolve soon after withdrawal of lercanidipine. This is an important association to recognise as cloudy peritoneal effluent can be mistaken for infective peritonitis with consequential unnecessary hospitalisation and empiric antibiotic administration.
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. Enalapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol, procainamide or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed severe infections which in few instances did not respond to intensive antibiotic therapy. If enalapril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any signs of infection.
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx, has been reported in patients treated with ACE-inhibitors, including enalapril. This may occur at any time during treatment. In such cases, enalapril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.
Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.
Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3ml to 0.5ml) and/or measures to ensure a patent airway, should be administered promptly.
Black patients receiving ACE-inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
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).
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of enalapril. Treatment with enalapril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and 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 vildagliptin in a patient already taking an ACE inhibitor.
Rarely, patients receiving ACE-inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each desensitisation.
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.
Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE-inhibitor, should be told to closely monitor for hypoglycaemia, especially during the first month of combined use (see section 4.5).
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 also be considered as part of the differential diagnosis of cough.
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril blocks angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
ACE inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalaemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5).
The combination of lithium and enalapril is generally not recommended (see section 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.
Inducers of CYP3A4 such as anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce lercanidipine plasma levels and therefore the efficacy of lercanidipine may be less than expected (see section 4.5).
As with other ACE-inhibitors, enalapril is apparently less effective in lowering blood pressure in black patients than in non-blacks, possibly because plasma renin levels are often lower in the black hypertensive population.
Lercaril is not recommended during pregnancy.
ACE-inhibitors, like enalapril, 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).
The use of lercanidipine is also not recommended during pregnancy or in women who might become pregnant (see section 4.6).
The use of Lercaril is not recommended during lactation (see section 4.6).
The safety and efficacy of this association has not been demonstrated in children.
Alcohol should be avoided because it may potentiate the effect of vasodilating antihypertensive drugs (see section 4.5).
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Lercaril.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.
The antihypertensive effect of Lercaril could be potentiated by other blood pressure-lowering drugs such as diuretics, beta-blockers, alpha-blockers and other substances.
In addition, the following interactions have been observed with one or other constituents of the combined product.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).
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).
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with enalapril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when enalapril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of enalapril 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.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating treatment with enalapril (see section 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of enalapril.
Concomitant use of these agents may increase the hypotensive effects of enalapril. Concomitant use with nitroglycerine and other nitrates, or other vasodilators, may further reduce blood pressure.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE-inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and enhance the risk of lithium toxicity with ACE-inhibitors. Use of enalapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE-inhibitors may result in further reduction of blood pressure (see section 4.4).
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and others antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE-inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
The co-administration of NSAIDs (including COX-2 inhibitors)and angiotensin II receptor antagonists or ACE-inhibitors exert an additive effect on the increase in serum potassium, and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function (such as the elderly or patients who are volume-depleted, including those on diuretic therapy). Therefore, the combination should be administered with caution in patients with compromised renal function. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
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 enalapril.
Sympathomimetics may reduce the antihypertensive effects of ACE-inhibitors.
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 (see sections 4.4 and 4.8).
Alcohol enhances the hypotensive effect of ACE-inhibitors.
Enalapril can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and β‑blockers.
Inhibitors of CYP3A4:
Lercanidipine is known to be metabolised by the CYP3A4 enzyme and therefore inhibitors of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine. An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the eutomer S-lercanidipine).
Co-prescription of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided (see section 4.3).
Ciclosporin:
Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3 hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of ciclosporin increased by 27%. However, the co-administration of lercanidipine with ciclosporin has caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC.
Ciclosporin and lercanidipine should not be administered together (see section 4.3).
Grapefruit or grapefruit juice:
As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit or grapefruit juice, with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should not be taken with grapefruit or grapefruit juice (see section 4.3).
Inducers of CYP3A4:
Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine) and rifampicin should be approached with caution since the antihypertensive effect may be reduced and blood pressure should be monitored more frequently than usual (see section 4.4).
Alcohol:
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see section 4.4).
Substrates of CYP3A4:
Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4 like terfenadine, astemizole, class III antiarrhythmic drugs, such as amiodarone, quinidine, sotalol.
Midazolam:
When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers, lercanidipine absorption was increased (by approximately 40%) and the rate of absorption was decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified.
Metoprolol:
When lercanidipine was co-administered with metoprolol, a β-blocker eliminated mainly by the liver, the bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This effect may be due to the reduction in hepatic blood flow caused by β-blockers and may therefore occur with other drugs of this class. Consequently, lercanidipine may be safely administered with β-adrenoceptor blocking drugs, but dose adjustment may be required.
Digoxin:
Co-administration of 20 mg lercanidipine in patients chronically treated with β-methyldigoxin showed no evidence of pharmacokinetic interaction. However, a mean increase of 33% in digoxin Cmax was observed, while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity.
Fluoxetine:
An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of an age of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the pharmacokinetics of lercanidipine.
Cimetidine:
Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the hypotensive effect of lercanidipine may be increased.
Simvastatin:
When a 20 mg dose of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the AUC of lercanidipine was not significantly modified, while simvastatin AUC increased by 56% and that of its active metabolite, β-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance. No interaction is expected when lercanidipine is administered in the morning and simvastatin in the evening, as indicated for such a drug.
Warfarin:
The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the pharmacokinetics of warfarin.
Diuretics and ACE inhibitors:
Lercanidipine has been safely administered with diuretics and ACE-inhibitors.
Other medications affecting blood pressure:
As for all antihypertensive medications, an increased hypotensive effects may be observed when lercanidipine is administered with other medications affecting blood pressure, such as alphablockers for the treatment of urinary symptoms, tricyclic antidepressants, neuroleptics. On the contrary, a reduction of the hypotensive effect may be observed with a concomitant use with corticosteroids.
Interaction studies have only been performed in adults.
The use of ACE-inhibitors (enalapril) is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE-inhibitors (enalapril) is contra-indicated 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). Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development. 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).
There are no data from the use of lercanidipine in pregnant women. Studies in animals have not shown teratogenic effects (see section 5.3), but these have been observed with other dihydropyridine compounds.
Lercanidipine is not recommended during pregnancy and in women of childbearing-potential not using contraception (see section 4.4).
There are no or limited amount of data from the use of enalapril maleate/lercanidipine HCl in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).
Lercaril should not be used in the second and third trimester of pregnancy. It is not recommended in the first trimester of pregnancy and in women of childbearing potential not using contraception.
Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of enalapril in breast-feeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of enalapril in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.
It is unknown whether lercanidipine/metabolite are excreted in human milk. A risk to the newborns/infants cannot be excluded. Lercanidipine should not be used during breast-feeding.
Consequently, Lercaril should not be used during breast-feeding.
No clinical data are available with lercanidipine. Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some patients treated by channel blockers. In cases where repeated in-vitro fertilisation is unsuccessful and where another explanation cannot be found, the possibility of calcium channel blockers as the cause should be considered.
Lercaril has minor influence on the ability to drive and use machines. However, caution should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur (see section 4.8).
The safety of Lercaril has been evaluated in five double-blind controlled clinical studies and in two long term open-label extension phases. In total, 1,141 patients have received Lercaril at a dose of 10 mg/10 mg, 20 mg/10 mg and 20 mg/20 mg. The undesirable effects observed with combination therapy have been similar to those already observed with one or the other of the constituents given alone. The most commonly reported adverse reactions during treatment with Lercaril were cough (4.03%), dizziness (1.67%) and headache (1.67%).
In the table below, adverse reactions reported in clinical studies with Lercaril 10 mg/10 mg, 20 mg/10 mg and 20 mg/20 mg and for which a reasonable causal relationship exists are listed by MedDRA system organ class and frequency: 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).
| Blood and lymphatic system disorders | |
| Uncommon: | Thrombocytopenia |
| Rare: | Haemoglobin decreased |
| Immune System Disorders | |
| Rare: | Hypersensitivity |
| Metabolism and nutrition disorders | |
| Uncommon: | Hyperkalaemia |
| Psychiatric disorders | |
| Uncommon: | Anxiety |
| Nervous system disorders | |
| Common: | Dizziness, headache |
| Uncommon: | Dizziness postural |
| Ear and labyrinth disorders | |
| Uncommon: | Vertigo |
| Rare: | Tinnitus |
| Cardiac Disorders | |
| Uncommon: | Tachycardia, palpitations |
| Vascular disorders | |
| Uncommon: | Flushing, hypotension |
| Rare: | Circulatory collapse |
| Respiratory, thoracic and mediastinal disorders | |
| Common: | Cough |
| Rare: | Dry throat, oropharingeal pain |
| Gastrointestinal disorders | |
| Uncommon: | Abdominal pain, constipation, nausea |
| Rare: | Dyspepsia, lip oedema, tongue disorder, diarrhoea, dry mouth, gingivitis |
| Hepatobiliary Disorders | |
| Uncommon: | ALT increased, AST increased |
| Skin and sub-cutaneous tissue disorders | |
| Uncommon: | Erythema |
| Rare: | Angioedema, swelling face, dermatitis, rash, urticaria |
| Musculoskeletal, connective tissue disorders | |
| Uncommon: | Arthralgia |
| Renal and urinary disorders | |
| Uncommon: | Pollakiuria |
| Rare: | Nocturia, polyuria |
| Reproductive System and Breast Disorders | |
| Rare: | Erectile dysfunction |
| General disorders and administration site conditions | |
| Uncommon: | Asthenia, fatigue, feeling hot, oedema peripheral |
Undesirable effects occurring in one patient only are reported under the frequency rare.
The incidence of selected listed adverse reactions frequently observed with enalapril and lercanidipine monotherapies, is shown in the table below, as reported in a double-blind, randomised, factorial clinical study:
| Placebo (n=113) | E20 (n=111) | L20 (n=113) | E20/L20 (n=116) | |
|---|---|---|---|---|
| Subject with any ADR | 5.3% | 10.8% | 8.8% | 8.6% |
| Cough | 1.8% | 3.6% | - | 1.7% |
| Dizziness | - | 1.8% | - | 0.9% |
| Headache | 0.9% | 0.9% | 1.8% | 0.9% |
| Oedema peripheral | 0.9% | - | 1.8% | - |
| Tachycardia | - | 1.8% | 3.5% | 0.9% |
| Palpitations | - | 0.9% | 0.9% | - |
| Flushing | - | - | 1.8% | 0.9% |
| Rash | - | 0.9% | 0.9% | - |
| Fatigue | - | - | - | 0.9% |
Adverse reactions reported with one of the individual components (enalapril or lercanidipine) may be potential undesirable effect with Lercaril as well, even if not observed in clinical trials or during the post-marketing period.
Among the adverse drug reactions reported for enalapril are:
Uncommon: anaemia (including aplastic and haemolytic)
Rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases
Not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Uncommon: hypoglycaemia (see section 4.4)
Common: depression
Uncommon: confusion, nervousness, insomnia
Rare: dream abnormality, sleep disorders
Very common: dizziness
Common: headache, syncope, taste alteration
Uncommon: somnolence, paraesthesia, vertigo
Very common: blurred vision
Uncommon: tinnitus
Common: chest pain, rhythm disturbances, angina pectoris, tachycardia
Uncommon: palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high risk patients (see section 4.4)
* Incidence rates were comparable to those in the placebo and active control groups in the clinical trials.
Common: hypotension (including orthostatic hypotension)
Uncommon: flushing, orthostatic hypotension
Rare: Raynaud’s phenomenon
Very common: cough
Common: dyspnoea
Uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma
Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia
Very common: nausea
Common: diarrhoea, abdominal pain
Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer
Rare: stomatitis/aphthous ulcerations, glossitis
Very rare: intestinal angioedema
Rare: hepatic failure, hepatitis – either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice)
Common: rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4)
Uncommon: diaphoresis, pruritus, urticaria, alopecia
Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma
A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.
Uncommon: muscle cramps
Uncommon: renal dysfunction, renal failure, proteinuria
Rare: oliguria
Uncommon: impotence
Rare: gynaecomastia
Very common: asthenia
Common: fatigue
Uncommon: malaise, fever
Common: hyperkalaemia, increases in serum creatinine
Uncommon: increases in blood urea, hyponatremia
Rare: elevation of liver enzymes, elevation of serum bilirubin.
The adverse drug reactions most commonly reported in clinical trials and in the post-marketing experience are peripheral oedema, headache, flushing, tachycardia and palpitations.
Rare: hypersensitivity
Common: headache
Uncommon: dizziness
Rare: somnolence, syncope
Common: tachycardia, palpitations
Rare: angina pectoris
Common: flushing
Uncommon: hypotension Gastrointestinal disorders:
Uncommon: nausea, dyspepsia, abdominal pain upper
Rare: vomiting, diarrhoea
Not known: gingival hypertrophy1, peritoneal cloudy effluent1
Not known: serum transaminase increased1
Uncommon: rash, pruritus
Rare: urticaria
Not known: angioedema1
Uncommon: myalgia
Uncommon: polyuria
Rare: pollakiuria
Common: oedema peripheral
Uncommon: asthenia, fatigue
Rare: chest pain
1 adverse reactions from spontaneous reporting in the worldwide post-marketing experience
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed. Lercanidipine does not appear to have any adverse effect on blood sugar or serum lipid levels.
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
