ENALAPRIL MALEATE/LERCANIDIPINE HYDROCHLORIDE 20 MG / 10 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Enalapril maleate/Lerca­nidipine hydrochloride 20 mg/10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg enalapril maleate and 10 mg lercanidipine hydrochloride.

Excipient with known effect: Each tablet contains 154 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Yellow colored, round, biconvex film coated tablets with debossing ‘LE2’ on one face and other face plain, approximate diameter of 12.10 mm and thickness of 4.80 mm.

4.1 Therapeutic indications

Treatment of essential hypertension in patients whose blood pressure is not adequately controlled by enalapril 20 mg alone.

Fixed combination Enalapril/Ler­canidipine tablets 20 mg/10 mg should not be used for initial treatment of hypertension.

4.2 Posology and method of administration

Patients whose blood pressure is not adequately controlled by treatment with enalapril 20 mg alone could either be titrated up to the higher dose of enalapril monotherapy or switched to Enalapril/Ler­canidipine tablets 20mg/10mg.

Individual dose titration with the components can be recommended. When clinically appropriate, direct switch from monotherapy to the fixed combination may be considered.

Posology

The recommended dose is one tablet once a day at least 15 minutes before meals.

Elderly patients:

The dose should depend on the patient's renal function (see „Use in renal impairment“).

Patients with renal impairment:

Enalapril/Ler­canidipine tablets is contraindicated in patients with severe renal dysfunction (creatinine clearance <30 ml/min) or in patients undergoing haemodialysis (see section 4.3 and 4.4). Particular caution is needed when initiating treatment in patients with mild to moderate renal dysfunction.

Patients with hepatic impairment:

Enalapril/Ler­canidipine tablets is contraindicated in severe hepatic dysfunction. Particular caution is needed when initiating treatment in patients with mild to moderate hepatic dysfunction.

Paediatric population:

There is no relevant use of Enalapril/Ler­canidipine in the paediatric population in the indication of hypertension.

Method of administration

Precautions to be taken before handling or administering the medicinal product:

Treatment should be preferably administered in the morning at least 15 minutes before breakfast.

This product should not be administered with grapefruit juice (see section 4.3 and 4.5).

4.3 Contraindications

Hypersensitivity to any ACE-inhibitor or dihydropyridine calcium channel blocker or to any of the excipients listed in section 6.1.

History of angioedema associated with ACE-inhibitor therapy.

Hereditary or idiopathic angioedema.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Left ventricular outflow tract obstruction.

Untreated congestive cardiac failure.

Unstable angina pectoris or recent (within 1 month) myocardial infarction.

Severe hepatic impairment.

Severe renal impairment (GFR < 30 ml/min), including patients undergoing dialysis

Co-administration with: o strong CYP3A4 inhibitors (see section 4.5) o ciclosporin (see section 4.5)

o grapefruit or grapefruit juice (see section 4.5)

o Concomitant use with sacubitril/val­sartan therapy. Enalapril must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see also sections 4.4 and 4.5).

The concomitant use of enalapril/ler­canidipine with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Symptomatic hypotension

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.

Sick-sinus syndrome

Lercanidipine should be administered with caution in patients with sick-sinus syndrome (without a pacemaker).

Left ventricular dysfunction

Although haemodynamic controlled studies revealed no impairment of ventricular function, care is required in patients with left ventricular dysfunction.

Ischaemic heart disease

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).

Use in renal impairment

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).

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.

Kidney transplantation

There is no experience in the use of lercanidipine or enalapril in patients who have recently undergone kidney transplantation. Treatment with Enalapril/Ler­canidipine tablets is therefore not recommended.

Hepatic failure

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.

Peritoneal Dialysis

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

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.

Hypersensitivi­ty/angioneuro­tic oedema

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.

Anaphylactoid Reactions during Hymenoptera Desensitisation

Rarely, patients receiving ACE-inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACEinhibitor therapy prior to each desensitisation.

Anaphylactoid Reactions during LDL Apheresis

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.

Hypoglycaemia

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

Cough has been reported with the use of ACE-inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACEinhibitor-induced cough should also be considered as part of the differential diagnosis of cough.

Surgery/anaesthesia

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.

Serum potassium

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).

Lithium

The combination of lithium and enalapril is generally not recommended (see section 4.5).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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

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).

Ethnic differences

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.

Pregnancy

Enalapril/Ler­canidipine 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).

Lactation

The use of Enalapril/Ler­canidipine tablets is not recommended during lactation (see section 4.6).

Paediatric population

The safety and efficacy of this association has not been demonstrated in children.

Alcohol

Alcohol should be avoided because it may potentiate the effect of vasodilating antihypertensive drugs (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction The antihypertensive effect of Enalapril/Ler­canidipine tablets could be potentiated by other blood pressure lowering drugs such as diuretics, betablockers, alpha-blockers and other substances.

In addition, the following interactions have been observed with one or other constituents of the combined product.

Enalapril maleate

Medicines increasing the risk of angioedema

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).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosteronesystem (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).

Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes

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 potassiumcontaining salt substitutes may lead to significant increases in serum potassium. Care should also be taken when enalapril is coadministered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sul­famethoxazole) as trimethoprim is known to act as a potassiumsparing 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.

Ciclosporin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Heparin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Diuretics (thiazides or loop diuretics)

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.

Other antihypertensive agents

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.

Lithium

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).

Tricyclic antidepressants/ Antipsychotics /Anaesthetics/Nar­cotics 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 (COX-2) Inhibitors

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.

Gold

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

Sympathomimetics may reduce the antihypertensive effects of ACE-inhibitors.

Antidiabetics

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

Alcohol enhances the hypotensive effect of ACE-inhibitors.

Acetylsalicylic acid, thrombolytics and B-blockers

Enalapril can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and B-blockers.

Lercanidipine

Contraindications of concomitant use 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).

Concomitant use not recommended

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).

Precautions including dose adjustment

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 P-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 P-blockers and may therefore occur with other drugs of this class. Consequently, lercanidipine may be safely administered with P-adrenoceptor blocking drugs, but dose adjustment may be required.

Digoxin

Co-administration of 20 mg lercanidipine in patients chronically treated with P- 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.

Concomitant use with other drugs

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, P-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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

For enalapril

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 ACEinhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

For lercanidipine

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).

For enalapril and lercanidipine in association

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).

Enalapril/Ler­canidipine tablets 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.

Breast-feeding

For enalapril

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.

For lercanidipine

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.

For enalapril and lercanidipine in association

Consequently, enalapril/ler­canidipine should not be used during breastfeeding.

Fertility

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.

4.7 Effects on ability to drive and use machines

Enalapril/Ler­canidipine tablets 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).

4.8 Undesirable effects

Summary of the safety profile

The safety of enalapril/ler­canidipine 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 enalapril/ler­canidipine 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 enalapril/ler­canidipine were cough (4.03%), dizziness (1.67%) and headache (1.67%).

Tabulated summary of adverse reactions

In the table below, adverse reactions reported in clinical studies with enalapril/ler­canidipine 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).

Undesirable effects occurring in one patient only are reported under the frequency rare.

Additional information on the individual components

Adverse reactions reported with one of the individual components (enalapril or lercanidipine) may be potential undesirable effect with enalapril/ler­canidipine as well, even if not observed in clinical trials or during the post-marketing period.

Enalapril alone

Among the adverse drug reactions reported for enalapril are:

Blood and lymphatic system disorders:

Uncommon: anaemia (including aplastic and haemolytic)

Rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases

Endocrine disorders:

Not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders:

Uncommon: hypoglycaemia (see section 4.4)

Psychiatric disorders:

Common: depression

Uncommon: confusion, nervousness, insomnia

Rare: dream abnormality, sleep disorders

Nervous system disorders:

Very common: dizziness

Common: headache, syncope, taste alteration

Uncommon: somnolence, paraesthesia, vertigo

Eye disorders:

Very common: blurred vision

Ear and labyrinth disorders:

Uncommon: tinnitus

Cardiac disorders:

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.

Vascular disorders

Common: hypotension (including orthostatic hypotension)

Uncommon: flushing, orthostatic hypotension

Rare: Raynaud’s phe­nomenon

Respiratory, thoracic and mediastinal disorders:

Very common: cough

Common: dyspnoea

Uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eo­sinophilic pneumonia

Gastrointestinal disorders:

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

Hepatobiliary disorders:

Rare: hepatic failure, hepatitis – either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice)

Skin and subcutaneous tissue disorders:

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.

Musculoskeletal, connective tissue, bone disorders:

Uncommon: Muscle cramps

Renal and urinary disorders:

Uncommon: renal dysfunction, renal failure, proteinuria

Rare: oliguria

Reproductive system and breast disorders:

Uncommon: impotence

Rare: gynaecomastia

General disorders and administration site conditions:

Very common: asthenia

Common: fatigue,

Uncommon: malaise, fever

Investigations:

Common: hyperkalaemia, increases in serum creatinine

Uncommon: increases in blood urea, hyponatremia

Rare: elevation of liver enzymes, elevation of serum bilirubin.

Lercanidipine alone

The adverse drug reactions most commonly reported in clinical trials and in the postmarketing experience are peripheral oedema, headache, flushing, tachycardia and palpitations.

Immune system disorders

Rare: hypersensitivity

Nervous system disorders

Common: headache

Uncommon: dizziness

Rare: somnolence, syncope

Cardiac disorders

Common: tachycardia, palpitations

Rare: angina pectoris

Vascular disorders

Common: flushing

Uncommon: hypotension

Gastrointestinal disorders

Uncommon: nausea, dyspepsia, abdominal pain upper

Rare: vomiting, diarrhoea

Not known: gingival hypertrophy1, peritoneal cloudy effluent1

Hepatobiliary disorders:

Not known: serum transaminase increased1

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

Rare: urticaria

Not known: angioedema1

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

Renal and urinary disorders

Uncommon: polyuria

Rare: pollakiuria

General disorders and administration site conditions

Common: oedema peripheral

Uncommon: asthenia, fatigue

Rare: chest pain

1adverse reactions from spontaneous reporting in the worldwide postmarketing 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 of suspected adverse reactions

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 the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

No pharmacokinetic interactions have been observed on concurrent administration of enalapril and lercanidipine.

Pharmacokinetics of enalapril

Absorption

Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril maleate is approximately 60%. The absorption of oral enalapril is not affected by the presence of food in the gastrointesti­nal tract.

Distribution

Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin-converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur about 4 hours after an oral dose of enalapril maleate. The effective half life for accumulation of enalaprilat following multiple doses of oral enalapril is 11 hours. In subjects with normal renal function, steady-state serum concentrations of enalaprilat was reached after four days of treatment. Over the range of concentrations which are therapeutically relevant, enalaprilat binding to human plasma proteins does not exceed 60%.

Biotransformation

Apart from the conversion to enalaprilat, there is no evidence for significant metabolism of enalapril.

Elimination

Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and unchanged enalapril (about 20%).

Renal impairment

The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40–60 ml/min), the steady state AUC of enalaprilat was approximately twofold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance <30 ml/min), the AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed (see section 4.2).

Enalaprilate may be removed from the general circulation by haemodialysis. The dialysis clearance is 62 ml/min.

Lactation

After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7gg/L (range 0.54 to 5.9 gg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7gg/L (range 1.2 to 2.3gg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage. A woman who had been taking oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 pg/L 4 hours after a dose and peak enalaprilat levels of 0.75 pg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44pg/L and 0.63 pg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2pg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10mg in two mothers; enalapril levels were not determined.

Pharmacokinetics of lercanidipine

Absorption

Lercanidipine is completely absorbed after oral administration and peak plasma levels are reached after approximately 1.5 – 3 hours.

The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma concentration is the same and the peak plasma concentration and AUC are, on average 1.2 times higher for the (S)-enantiomer. The elimination half-lives of the two enantiomers are essentially the same. No interconversion of the two enantiomers is observed „in vivo“.

Due to the high first-pass metabolism, the absolute bioavailability of oral lercanidipine in non-fasted conditions is about 10% However, the bioavailability on ingestion by healthy volunteers under fasting conditions is reduced to 1/3.

Oral availability of lercanidipine increases 4-fold when it is ingested up to 2 hours after a high-fat meal. Hence the drug should be taken before meals.

Distribution

Distribution from plasma into tissues and organs is rapid and extensive. The degree of plasma protein binding of lercanidipine exceeds 98%. Since plasma protein levels are reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be higher.

Biotransformation

Lercanidipine is extensively metabolised by CYP3A4; no parent substance is found either in urine or faeces. It is predominantly converted into inactive metabolites and approximately 50% of the dose is excreted in the urine.

In vitro experiments with human liver microsomes have demonstrated that lercanidipine shows slight inhibition of the two enzymes CYP3A4 and CYP2D6 at concentrations 160– and 40-times higher than the peak plasma levels achieved after administration of the 20 mg dose.

Furthermore, interaction studies in humans have shown that lercanidipine does not modify the plasma levels of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6. Therefore, at therapeutic doses, lercanidipine is not expected to inhibit the biotransformation of drugs metabolised by CYP3A4 or CYP2D6.

Elimination

Elimination essentially occurs through biotransformation.

A mean terminal elimination half-life of 8–10 hours was calculated, and due to the high binding to lipid membranes, therapeutic activity lasts for 24 hours. No accumulation was shown after repeated administration.

Linearity/non-linearity

Oral administration of lercanidipine results in plasma levels that are not directly proportional to the dose (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations were in the ratio of 1:3:8 and areas under the plasma concentration time curves in the ratio of 1:4:18, suggesting a progressive saturation of first pass metabolism. Accordingly, availability increases with dosage elevation.

Additional information on special , populations

It has been shown that the pharmacokinetic behaviour of lercanidipine in elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic impairment is similar to that observed in the general patient population. Patients with severe renal dysfunction or dialysis-dependent patients showed higher concentrations of the drug (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is probably increased because the drug is normally extensively metabolised in the liver.

5.3 Preclinical safety data

Enalapril /lercanidipine combination

Potential toxicity of the fixed combination of enalapril and lercanidipine was studied in rats after oral administration for up to 3 months and in two genotoxicity tests. The combination did not alter the toxicological profile of the two individual components.

The following data exist for the two individual components, enalapril and lercanidipine.

Enalapril

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Reproductive toxicity studies suggest that enalapril has no effects on fertility and reproductive performance in rats, and is not teratogenic. In a study in which female rats were dosed prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The compound has been shown to cross the placenta and is excreted in milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal renin angiotensin system and partly due to ischemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.

Lercanidipine

Non -clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

The relevant effects which have been observed in long term studies in rats and dogs were related, directly or indirectly, to the known effects of high doses of Caantagonist, predominantly reflecting exaggerated pharmacodynamic activity.

Treatment with lercanidipine had no effect on fertility or general reproductive performance in rats, but at high doses induced pre- and post- implantation losses and delay in foetal development. There was no evidence of any teratogenicity effect in rats and rabbits, but other dihydropyridines have been found to be teratogenic in animals.

Lercanidipine induced dystocia when administered at high dose (12 mg/kg/day) during labour.

The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in breast milk have not been investigated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Lactose monohydrate

Microcrystalline cellulose

Sodium hydroxide

Crospovidone

Colloidal anhydrous silica

Povidone

Talc

Magnesium stearate

Film-coating:

Opadry yellow contains

Hypromellose (E464)

Talc

Macrogol (E1521)

Titanium dioxide (E171)

Quinoline yellow aluminium lake (E104)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

18 months

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

Alu – Alu blister packs containing 7, 10, 14, 15, 20, 28, 30, 35, 42, 50, 56, 60, 84, 90, 98 and 100 film-coated tablets.

Not all pack sizes may be marketed.