Zaneril 10 Mg/10 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zaneril 10 mg/10 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 10 mg enalapril maleate (equivalent to 7.64 mg enalapril) and 10 mg lercanidipine hydrochloride (equivalent to 9.44 mg lercanidipine).
Excipients: one film-coated tablet contains 102.0 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
White, biconvex, round, tablets.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of essential hypertension in patients whose blood pressure is not adequately controlled by lercanidipine 10 mg alone.
Fixed combination Zaneril 10 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 lercanidipine 10 mg alone could either be titrated up to lercanidipine 20 mg monotherapy or switched to fixed combination Zaneril 10 mg/10 mg.
Individual dose titration with the components can be recommended. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.
The recommended dose is one tablet once a day at least 15 minutes before meals.
Treatment should be preferably administered in the morning. This product should not been administered with grapefruit (see section 4.3 and 4.5).
Elderly patients: The dose should depend on the patient's renal function (see "Use in renal impairment").
Children and adolescents under 18 years of age: Since there is no clinical experience in patients under 18 years of age, use in children and adolescents is not currently recommended.
Use in renal impairment: Zaneril 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.
Use in hepatic impairment: Zaneril is contraindicated in severe hepatic dysfunction. Particular caution is needed when initiating treatment in patients with mild to moderate hepatic dysfunction.
4.3 Contraindications
Zaneril must not be taken in:
• Hypersensitivity to a therapeutically active constituent (enalapril or lercanidipine), to any ACE-inhibitor or dihydropyridine calcium channel blocker or to any other constituent of this medicinal product
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
• Left ventricular outflow obstruction, including aortic stenosis
• Untreated congestive heart failure
• Unstable angina pectoris
• Within one month of a myocardial infarction
• Severe renal impairment (creatinine clearance < 30 ml/min), including patients undergoing haemodialysis
• Severe hepatic impairment
• Co-administration with:
o strong CYP3A4 inhibitors (see section 4.5) o ciclosporin (see section 4.5) o grapefruit juice (see section 4.5)
• A history of angioedema caused by previous therapy with an ACE-inhibitor
• Hereditary or idiopathic angioedema
4.4 Special warnings and precautions for use
Symptomatic hypotension
Particularly careful monitoring is required with enalapril in:
• severe hypotension with systolic blood pressure less than 90 mmHg
• decompensated heart failure
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
Particular caution is recommended in the use of lercanidipine in patients with sick-sinus syndrome (without a pacemaker).
Left ventricular dysfunction and ischaemic heart disease Although haemodynamic controlled studies revealed no impairment of ventricular function, caution must be exercised when treating patients with left ventricular dysfunction with calcium channel blockers. It has been suggested that patients with ischaemic heart disease show an elevated cardiovascular risk under treatment with some short-acting dihydropyridines. Although lercanidipine is long-acting, caution is advised in these patients.
In rare cases, some dihydropyridines can cause 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 under enalapril treatment is part of the normal medical care of these patients.
Reports of renal failure associated with the use of enalapril have been made especially in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If diagnosed promptly and treated appropriately, renal failure under enalapril treatment is usually reversible.
In some hypertensives with no pre-existing renal disease, the combination of enalapril with a diuretic can lead to an increase in blood urea and creatinine. Dosage reduction of enalapril and/or discontinuation of the diuretic may be necessary. In these cases, the possibility of an underlying renal artery stenosis should be considered (see section 4.4, Renovascular hypertension).
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney are particularly at risk of developing hypotension or renal failure under ACE-inhibitor therapy. In these patients, treatment should be initiated under close medical supervision with low doses and cautious titration. Renal function should be assessed at baseline and closely monitored during treatment.
Renal transplantation
There is no experience in the use of lercanidipine or enalapril in patients who have recently undergone renal transplantation. Therefore treatment of these patients with Zaneril is not recommended.
Hepatic failure
The antihypertensive effect of lercanidipine can be potentiated in patients with hepatic dysfunction.
Rarely, a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis (sometimes fatal) has been observed with ACE-inhibitor treatment. The mechanism of this syndrome is unclear. Patients who develop jaundice or a marked rise in liver enzymes with ACE-inhibitors must stop taking the ACE-inhibitor and should be given appropriate treatment.
Neutropenia/agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients on ACE-inhibitors. Neutropenia is rare in patients with normal renal function and without particular risk factors. Enalapril should be used with extreme caution in patients with collagen vascular disease, those under treatment with immunosuppressants, allopurinol, procainamide or if several of these risk factors are present, especially in pre-existing impairment of renal function. Severe infections occurred in some of these patients, that in few cases did not respond to intensive antibiotic treatment. If enalapril is used in such patients, regular monitoring of leucocytes is advised and patients should be instructed to report any signs of infection to their doctor.
Hypersensitivity/angioneurotic oedema
Angioneurotic oedema with involvement of the face, extremities, lips, tongue, glottis and/or larynx, has been reported in patients treated with ACE-inhibitors, including enalapril. It may occur at any time during treatment. In such cases, enalapril must be stopped immediately. The patient is to be carefully monitored in order to ensure that the symptoms have fully resolved before discharge from the hospital. In cases where the swelling was limited to the face and lips, symptoms generally resolved without treatment. However, antihistamines were useful in relieving the symptoms.
Angioneurotic oedema with laryngeal involvement can be fatal. When the tongue, glottis or larynx are affected and are likely to cause respiratory obstruction, appropriate treatment must be instituted without delay (e.g. subcutaneous administration of adrenaline [diluted 1:1000]) and/or measures to ensure a patent airway.
A higher incidence of angioedema on ACE-inhibitors has been reported in black patients, when compared to non-black patients.
Patients with a history of angioedema not triggered by an ACE-inhibitor can be at a higher risk of developing angioedema if they are to receive an ACE-inhibitor (see also section 4.3).
Anaphylactoid reactions during desensitisation with insect venoms Life-threatening anaphylactoid reactions have occurred rarely during desensitisation therapy against insect venoms and concurrent use of an ACE-inhibitor. These reactions can be avoided by temporarily discontinuing the ACE-inhibitor prior to each desensitisation.
Anaphylactoid reactions during LDL-apheresis
Life-threatening anaphylactoid reactions have occurred rarely during a low density lipoprotein (LDL)-apheresis with dextran sulfate and concurrent use of an ACE-inhibitor. These reactions can be avoided by temporarily discontinuing the ACE-inhibitor prior to each apheresis.
Diabetics
Close monitoring of blood glucose should be undertaken in the first month of ACE-inhibitor treatment in diabetic patients treated with oral antidiabetics or insulin (see section 4.5).
Cough
Cough has been reported in connection with the use of ACE-inhibitors. Typically, the cough is non-productive, persistent and subsides after discontinuation of the therapy. A cough induced by ACE-inhibitor should also be considered in the differential diagnosis of cough.
Surgery/anaesthesia
In patients undergoing major surgery or anaesthesia with agents that reduce blood pressure, enalapril inhibits the formation of angiotensin II, that would otherwise occur due to a compensatory secretion of renin. If hypotension develops as a result of this mechanism, it can be corrected by volume expansion.
Hyperkalaemia
An increase in serum potassium has been observed in some patients on ACE-inhibitors including enalapril. Risk factors for hyperkalaemia are: renal failure, diabetes mellitus, concurrent treatment with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes as well as concurrent treatment with other drugs that can lead to an increase in serum potassium values (e.g. heparin). If concomitant use of one of the
above-mentioned substances is indicated, serum potassium should be regularly monitored.
Inducers of CYP3A4
CYP3A4 inducers such as anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin can reduce serum levels of lercanidipine so that the efficacy of the drug can be lower than expected (see section 4.5).
Other not recommended medications
This medicinal product is generally not recommended in combinations with lithium, potassium-sparing diuretics, potassium supplements and estramustine (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
Zaneril 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 planning to become pregnant (see section 4.6)
Lactation
The use of Zaneril is not recommended during lactation (see section 4.6). Pediatric use
The safety and efficacy of this association has not been demonstrated in controlled studies in children.
Alcohol
Alcohol should be avoided because it may potentiate the effect of vasodilator antihypertensives (see section 4.5).
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Zaneril.
4.5 Interaction with other medicinal products and other forms of interaction
The antihypertensive effect of Zaneril 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.
Enalapril maleate
Some active substances or therapeutic classes may favour the development of hyperkalaemia: potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II inhibitors, non-steroidal anti-inflammatory agents, heparins (low molecular weight or unfractionned), ciclosporin and tacrolimus, trimethoprim.
The occurrence of hyperkalaemia may depend on the existence of associated risk factors.
This risk is increased in combination with the above-mentioned medicinal products.
Not recommended combinations Potassium-sparing diuretics or potassium supplements
ACE-inhibitors attenuate diuretic-induced potassium loss. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).
Lithium
Reversible increases in serum lithium concentrations and toxic effects have been reported during concomitant administration of lithium with ACE-inhibitors. Concomitant use of thiazide diuretics may increase serum lithium concentrations and hence enhance the risk of lithium toxicity with ACE-inhibitors. Use of enalapril with lithium is therefore not recommended, but if the combination is necessary, serum lithium levels must be carefully monitored (see section 4.4).
Estramustine:
Risk of increased adverse effects such as angioneurotic oedema (angioedema) (see section 4.4).
Combinations requiring precautions for use Antidiabetics
Epidemiological studies have suggested that concomitant administration of ACE-inhibitors and antidiabetic drugs (insulin, oral antidiabetics) may cause an increased blood glucose-lowering effect, with risk of hypoglycaemia. These cases are apparently more likely to occur in the first weeks of combined treatment and in patients with renal impairment.
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 correcting the volume depletion or giving salt, or by initiating therapy with a low dose of enalapril.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Chronic treatment with NSAIDs may reduce the antihypertensive effect of an ACE-inhibitor. NSAIDs and ACE-inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. This is usually reversible. Rarely, acute renal failure may occur, especially in patients with impaired renal function such as elderly or dehydrated patients.
Baclofen
Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.
Cyclosporin
Cyclosporin increases the risk of hyperkalaemia with ACE inhibitors.
Alcohol
Alcohol enhances the hypotensive effect with ACE inhibitors.
Combinations to be taken into account Amifostine
Increased antihypertensive effect.
Tricyclic antidepressants/neuroleptics/anaesthetics/narcotics Concomitant use of certain anaesthetic agents, tricyclic antidepressants and neuroleptics with ACE-inhibitors may lead to a further reduction in blood pressure (see section 4.4).
Corticosteroids, tetracosactide (systemic) (except hydrocortisone used as a substitute in Addison’s disease):
Reduced antihypertensive effect (corticosteroid-induced salt/volume retention).
Other antihypertensives
Concomitant use with other antihypertensives may increase the hypotensive effects of enalapril. Concomitant use of glyceryl trinitrate and other nitrates or other vasodilators may further reduce blood pressure.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide
Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.
Antacids
Antiacids induce decreased bioavailability of ACE inhibitors.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE-inhibitors. A decreased response to pressor amines (e.g adrenaline) is possible, but not sufficient to preclude their use.
Acetylsalicylic acid and thrombolytics
Enalapril can be administered without problems concomitantly with acetylsalicylic acid (in doses suitable for cardiovascular prophylaxis) and thrombolytics.
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.
Lercanidipine
Contraindicated combinations Inhibitors of CYP3A4
Since lercanidipine is metabolised by the enzyme CYP3A4, simultaneously administered inhibitors and inducers of CYP3A4 may interact with the metabolism and excretion of lercanidipine.
The combination of lercanidipine and strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) is contraindicated (see section 4.3).
An interaction study with ketoconazole, a strong inhibitor of CYP3A4, showed a marked rise in plasma levels of lercanidipine (a 15-fold increase in area under the drug concentration-time curve, AUC, and an 8-fold increase in Cmax of the eutomer S-lercanidipine).
Cyclosporin
Cyclosporin and lercanidipine must not be used together (see section 4.3). Increased plasma concentrations of both drugs have been observed following concurrent administration. A study in healthy young volunteers showed no changes in plasma lercanidipine levels when cyclosporin was taken 3 hours after ingestion of lercanidipine, but the AUC of cyclosporin rose by 27%. Coadministration of lercanidipine with cyclosporin caused a 3-fold rise in plasma lercanidipine levels and a 21% increase in AUC of cyclosporin.
Grapefruit juice
Lercanidipine should not be taken with grapefruit juice (see section 4.3).
As for other dihydropyridines, the metabolism of lercanidipine can be inhibited by the ingestion of grapefruit juice, resulting in a rise in the systemic availability of lercanidipine and increased hypotensive effect.
Combinations requiring_precautions _ for use Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilator antihypertensives (see section 4.4).
Substrates of CYP3A4
Caution is required on the co-prescribing of lercanidipine with other substrates of CYP3A4 such as terfenadine, astemizole, Class III antiarrhythmics, e.g. amiodarone, quinidine.
Inducers of CYP3A4
Concurrent use of lercanidipine with CYP3A4 inducers such as anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin should be approached with caution, because the antihypertensive effect of lercanidipine can be reduced. Blood pressure must therefore be monitored more frequently than usual.
Digoxin
Co-administration of 20 mg lercanidipine in patients chronically treated with B-methyldigoxin showed no evidence of pharmacokinetic interaction. Healthy volunteers treated with digoxin after administration of 20 mg lercanidipine showed a mean increase in digoxin Cmax of 33%, whereas neither AUC nor renal clearance were significantly altered. Patients on concomitant digoxin should be closely monitored for clinical signs of digoxin toxicity.
Combinations to be taken into account Midazolam
In elderly volunteers the concurrent administration of oral midazolam 20 mg enhanced the absorption of lercanidipine (by about 40%) and decreased its rate of absorption (tmax was delayed from 1.75 to 3 hours). No changes in midazolam concentrations occurred.
Metoprolol
When lercanidipine was co-administered with metoprolol - a B-blocker predominantly eliminated by the liver - the bioavailability of metoprolol was unchanged, whereas the bioavailability of lercanidipine was reduced by 50%. This effect may be due to the reduction in hepatic blood flow caused by B-blockers and hence might also occur with other preparations of this class of drug. Nvertheless, lercanidipine can be safely used at the same time as blockers of B-adrenergic receptors.
Cimetidine
Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in plasma levels of lercanidipine, but caution is required at higher doses since the bioavailability of lercanidipine, and therefore its hypotensive effect, may be increased.
Fluoxetine
An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in healthy volunteers aged 65 ± 7 years (mean ± s.d.), showed no clinically relevant modification of the pharmacokinetics of lercanidipine.
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, whereas the AUC of simvastatin increased by 56% and that of its principal active metabolite, B-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance. No interaction is expected if lercanidipine is administered in the morning and simvastatin in the evening, as indicated for such a drug.
Warfarin
Co-administration of 20 mg lercanidipine to fasted healthy volunteers did not alter the pharmacokinetics of warfarin.
4.6 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 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 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 fetotoxicity (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 section 4.3s and 4.4).
For lercanidipine
Animal studies with lercanidipine have not shown teratogenic effects, but these have been observed with other dihydropyridine compounds.
No clinical data on exposed pregnancies are available for lercanidipine, therefore its use is not recommended during pregnancy or in women planning to become pregnant.
For enalapril and lercanidipine in association
Consequently, the use of Zaneril is not recommended during the first trimester of pregnancy and it is contraindicated from the second trimester of pregnancy onwards.
Lactation
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 Zaneril in breastfeeding 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 Zaneril 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
The excretion of lercanidipine in human milk is unknown.
For enalapril and lercanidipine in association
Consequently, the use of Zaneril is not recommended during lactation.
Fertility
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
Clinical experiences with Zaneril and its constituents suggest that impairment of the ability to drive a car or to operate machines is unlikely. However, caution is advised because dizziness, asthenia, fatigue and in rare cases somnolence may occur (see section 4.8).
4.8 Undesirable effects
The undesirable effects of the combined preparation are similar to those that have been observed with one or other of the constituents when given alone.
In controlled clinical trials using Zaneril 10 mg/10 mg and including 329 patients, undesirable effect were reported as shown in the following table.
The MedDRA system organ class and frequency convention has been followed: 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).
|
Frequency System organ class |
Common (>1/100 to <1/10) |
Uncommon (>1/1000 to <1/100) |
|
Immune system disorders |
Hypersensitivity* | |
|
Nervous system disorders |
Dizziness |
Headache |
|
Ear and labyrinth disorders |
Vertigo, including |
|
vertigo positional | ||
|
Cardiac disorders |
Palpitations Tachycardia* | |
|
Vascular disorders |
Hypotension* Circulatory collapse* | |
|
Respiratory, thoracic and mediastinal disorders |
Cough |
Dry throat* |
|
Gastrointestinal disorders |
Abdominal pain upper* Nausea* | |
|
Skin and sub-cutaneous tissue disorders |
Dermatitis* Erythema* Lip oedema* Urticaria* | |
|
Musculoskeletal and connective tissue disorders |
Arthralgia* | |
|
Renal and urinary disorders |
Polyuria* Pollakiuria* | |
|
Reproductive system and breast disorders |
Erectile dysfunction* | |
|
General disorders and administration site conditions |
Fatigue Asthenia* | |
|
Investigations |
Hemoglobin decreased* | |
|
Note: * in 1 patient only | ||
Additional information on the individual components.
Enalapril alone
Among the adverse drug reactions reported for enalapril are:
Blood and lymphatic system disorders:
Uncommon: anaemia (including aplastic and haemolytic forms)
Rare: neutropenia, thrombocytopenia, agranulocytosis, bone marrow failure, pancytopenia, lymphadenopathy
Immune system disorders:
Common: hypersensitivity, angioedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported (see section
4.4)
Rare: autoimmune disorder
Metabolism and nutrition disorders:
Uncommon: hypoglycaemia (see section 4.4), anorexia
Psychiatric disorder:
Common: depression
Uncommon: confusional state, somnolence, insomnia, nervousness Rare: abnormal dreams, sleep disorders
Nervous system disorders:
Very common: dizziness Common: headache Uncommon: paraesthesia
Eye disorders:
Very common: vision blurred
Ear and labyrinth disorder:
Uncommon: vertigo, tinnitus
Cardiac disorders:
Common: myocardial infarction, possibly secondary to excessive hypotension in high-risk patients (see section 4.4), arrhythmia, angina pectoris, tachycardia Uncommon: palpitations
Vascular disorders:
Common: hypotension, syncope, cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients (see section 4.4)
Uncommon: flushing, orthostatic hypotension Rare: Raynaud's phenomenon
Respiratory, thoracic and mediastinal disorders:
Very common: cough Common: dyspnoea
Uncommon: rhinorrhoea, pharyngolaryngeal pain and dysphonia,
bronchospasm/asthma
Rare: lung infiltration, rhinitis, alveolitis, allergic/eosinophilic pneumonia
Gastrointestinal disorders:
Very common: nausea
Common: diarrhoea, abdominal pain, dysgeusia
Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, stomach
discomfort, dry mouth, peptic ulcer
Rare: stomatitis, aphthous stomatitis, glossitis
Very rare: intestinal angioedema
Hepatobiliary disorders:
Rare: hepatic failure, hepatitis - either hepatitis cholestatic or hepatic necrosis, cholestasis (including jaundice)
Skin and subcutaneous tissue disorders:
Common: rash
Uncommon: hyperhidrosis, pruritus, urticaria, alopecia
Rare: erythema multiforme, Stevens-Johnson syndrome, dermatitis exfoliative,
toxic epidermal necrolysis, pemphigus
A symptom complex has been reported which may include some or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthral gi a/ arthriti s, positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.
Musculoskeletal and connective tissue disorders:
Uncommon: muscle spasms
Renal and urinary disorders:
Uncommon: renal impairment, renal failure, proteinuria Rare: oliguria
Reproductive system and breast disorders:
Uncommon: erectile dysfunction Rare: gynaecomastia
General disorders and administration site conditions:
Very common: asthenia Common: fatigue, chest pain Uncommon: malaise
Investigations:
Common: blood potassium increased, blood creatinine increased Uncommon: blood urea increased, blood sodium decreased Rare: haemoglobin decreased, haematocrit decreased, hepatic enzyme increased, blood bilirubin increased.
Lercanidipine alone
Adverse reactions occurred in approximately 1.8% of patients treated.
The adverse drug reactions most commonly reported in controlled clinical trials were headache, dizziness, oedema peripheral, tachycardia, palpitations and flushing, with each occurring in less than 1% of patients.
Immune system disorders Very rare: hypersensitivity
Psychiatric disorders Rare: somnolence
Nervous system disorders Uncommon: headache, dizziness
Cardiac disorders
Uncommon: tachycardia, palpitations Rare: angina pectoris
Vascular disorders Uncommon: flushing Very rare: syncope
Gastrointestinal disorders
Rare: nausea, dyspepsia, diarrhoea, abdominal pain, vomiting
Skin and subcutaneous tissue disorders Rare: rash
Musculoskeletal and connective tissue disorders Rare: myalgia
Renal and urinary disorders Rare: polyuria
General disorders and administration site conditions Uncommon: oedema peripheral Rare: asthenia, fatigue
From spontaneous reports in post-marketing experience, the following adverse reactions have been reported very rarely (<1/10000): gingival hypertrophy, reversible increases in serum levels of hepatic transaminases, hypotension, urinary frequency and chest pain.
Some dihydropyridines may rarely lead to precordial localised 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 occur.
Lercanidipine does not appear to have any adverse effect on blood sugar or serum lipid levels.
4.9 Overdose
Up to the present time, no cases of Zaneril overdose have been reported.
The likeliest symptoms of overdose are severe hypotension, bradycardia, reflex tachycardia, shock, stupor, electrolyte disturbances and renal failure.
Management of overdose:
Treatment is principally directed towards elimination of the poison and restoration of stable cardiovascular conditions. Following oral ingestion, copious gastric lavage - possibly combined with intestinal irrigation - is indicated.
Experiences of enalapril overdose
Limited data are available on overdose in humans.
Symptoms:
The most prominent features of overdose reported to date are marked hypotension (beginning some six hours after ingestion of the tablets), concomitant with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose of ACE-inhibitors may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation,
tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril respectively.
Treatment:
The recommended treatment of overdosage is intravenous infusion of saline solution. If hypotension occurs, the patients should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. If the tablets were ingested recently, measures to eliminate enalapril maleate should be taken (e.g. vomiting, gastric lavage, administration of absorbents or sodium sulfate). Enalaprilat can be removed from the circulation by haemodialysis (see section
4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine should be continuously monitored.
Experiences of lercanidipine overdose Symptoms:
As with other dihydropyridines, overdose might be expected to cause excessive peripheral vasodilatation with marked hypotension and reflex tachycardia.
In post-marketing experience, three cases of an overdose have been reported (150 mg, 280 mg and 800 mg of lercanidipine respectively had been ingested in an attempt to commit suicide). The first patient developed sleepiness. The second patient developed cardiogenic shock with severe myocardial ischaemia and mild renal failure. The third patient showed vomiting and hypotension.
All patients recovered without sequelae.
Treatment:
In the above mentioned cases, treatment consisted respectively in: gastric lavage; high-dose catecholamines, furosemide, digitalis and parenteral plasma expanders; activated charchoal, laxatives and intravenous dopamine.
In the case of severe hypotension, bradycardia and unconsciousness, cardiovascular support can be helpful, with intravenous atropine to counteract the bradycardia.
In view of the prolonged pharmacological action of lercanidipine, the cardiovascular status of patients who have taken an overdose must be monitored for at least 24 hours. There is no information about the value of dialysis. Since the drug is highly lipophilic, it is very unlikely that plasma levels will be indicative of the duration of the risk phase. Dialysis may not be effective.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers: enalapril and lercanidipine.
ATC code: C09BB02
Zaneril 10 mg/10 mg is a fixed combination of an ACE-inhibitor (enalapril 10 mg) and a calcium channel blocker (lercanidipine 10 mg).
In a pivotal phase III, double blind, add-on clinical trial conducted in 342 non responders to lercanidipine 10 mg (defined as SDBP 95-114 and SSBP 140-189 mmHg), the reduction in trough SSBP was 5.4 mmHg greater with the combination enalapril 10 mg/lercanidipine 10 mg than with lercanidipine 10 mg alone after 12 weeks of double-blind treatment (-7.7 mmHg vs -2.3 mmHg, p<0.001). Also the reduction in trough SDBP was 2.8 mmHg greater with the combination as compared to the monotherapy (-7.1 mmHg vs -4.3 mmHg, p<0.001). Responder rates resulted significantly higher with combination therapy than with monotherapy: 41% vs 24% (p< 0.001) for SSBP and 35% vs 24% (p=0.032) for SDBP. A significantly higher percentage of patients on combination treatment experienced normalization of SSBP (39% vs 22%, p<0.001) and of SDBP (29% vs 19%, p=0.023) compared with patients on monotherapy. In the open-label long term follow-up phase of this study a titration to the combination enalapril 20 mg/lercanidipine 10 mg was allowed if BP remained >140/90 mmHg: titration occurred in 133/221 patients and SDBP normalized after titration in 1/3 of these cases.
Enalapril maleate is the maleate salt of enalapril, a derivative of two aminoacids, L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the vasopressor agent angiotensin II. After absorption, enalapril is hydrolysed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to the removal of negative feedback of renin release) and decreased aldosterone secretion.
Since ACE is identical to kininase II, enalapril may also inhibit the degradation of bradykinin, a potent vasodepressor peptide. However the role of this mechanism in the therapeutic effects of enalapril is still not understood.
Although the mechanism by which enalapril reduces blood pressure is primarily attributed to suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low renin levels.
Administration of enalapril to hypertensive patients reduces both supine and standing blood pressure, without a significant increase in heart rate.
Symptomatic postural hypotension is rare. In some patients it may take a few weeks of treatment before optimal blood pressure control is achieved. Abrupt withdrawal of enalapril is not associated with an rapid increase in blood pressure.
Effective inhibition of ACE activity normally occurs 2 to 4 hours after oral administration of a single dose of enalapril. Onset of the antihypertensive action was usually seen after one hour with maximum reduction of blood pressure observed 4 to 6 hours after administration. The duration of action is dose-related, but with recommended doses, antihypertensive and haemodynamic effects have been shown to persist for at least 24 hours.
Haemodynamic studies in patients with essential hypertension showed that the blood pressure reduction was associated with a decrease in peripheral arterial resistance and an increase in cardiac output; there was little or no change in heart rate. Following administration of enalapril, renal blood flow increased whilst glomerular filtration rate remained unchanged. There were no signs of sodium or water retention. However in patients with a low glomerular filtration rate prior to treatment, this rate was usually increased.
Decreases in albuminuria and urinary excretion of IgG and total protein were seen after ingestion of enalapril in short-term clinical studies in diabetic and non-diabetic patients with renal disease.
Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of the antihypertensive action is based on a direct relaxant effect on vascular smooth muscle, thus lowering total peripheral resistance. Due to its high membrane partition coefficient, lercanidipine has a prolonged antihypertensive action, and is devoid of negative inotropic effects because of its high vascular selectivity.
Since the vasodilatation produced by lercanidipine has a gradual onset, acute hypotension with reflex tachycardia has only been rarely observed in hypertensive patients.
As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its (S)-enantiomer.
5.2 Pharmacokinetic properties
No pharmacokinetic interactions have been observed on concurrent administration of enalapril and lercanidipine.
Pharmacokinetics of enalapril
Absorbtion
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 3 to 4 hours after an oral dose of enalapril maleate. The effective half-life for accumulation of enalapril following concentrations of enalaprilat was reached after four days of treatment.
Over the range of concentrations which are therapeutically relevant, enalapril 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 dialisys clearance is 62 ml/min.
Lactation
After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7pg/L (range 0.54 to 5.9 pg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7pg/L (range 1.2 to 2.3pg/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 concentrationtime 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
Preclinical 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 fetal development, resulting in fetal death and congenital effects, in particular affecting the skull. Fetotoxicity, 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 fetal renin angiotensin system and partly due to ischemia resulting from maternal hypotension and decreases in fetal-placental blood flow and oxygen/nutrients delivery to the fetus.
Lercanidipine
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 Ca-antagonist, predominantly reflecting exaggerated pharmacodynamic activity.
Lercanidipine showed no genotoxicity or evidence of carcinogenic hazard. 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 fetal 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 starch glycolate Povidone
Sodium hydrogen carbonate Magnesium stearate
Film-Coating: Hypromellose Titanium dioxide (E171) Talc
Macrogol 6000
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture. Do not store above 25°C.
6.5 Nature and contents of container
Polyamide-aluminium-PVC/aluminium blister
Packs of 7, 14, 28, 30, 35, 42, 50, 56, 90, 98 and 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Recordati Pharmaceuticals Limited,
200 Brook Drive,
Green Park,
Reading,
RG2 6UB United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 25046/0007
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/06/2008
10 DATE OF REVISION OF THE TEXT
06/04/2016