ZANERIL

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

Elderly:

The dose should depend on the patient's renal function (see "Use in renal impairment"). 4). Particular caution is needed when initiating treatment in patients with mild to moderate renal dysfunction.

Hepatic impairment:

Zaneril 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 Zaneril in the paediatric population for 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.

5).

Summary of the safety profile The safety of Zaneril 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 Zaneril 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. 67%). Tabulated summary of adverse reactions In the table below, adverse reactions reported in clinical studies with Zaneril 10 mg/10 mg, 20 mg/10 mg and 20 mg/20 mg and for which a reasonable causal relationship exists are listed by MedDRA system organ class and frequency: very common (> 1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000) not known (cannot be estimated from the available data).

Blood and lymphatic system disorders Uncommon:

Thrombocytopenia Rare: Haemoglobin decreased Immune System Disorders Rare: Hypersensitivity Metabolism and nutrition disorders Uncommon: Hyperkalaemia Psychiatric disorders Uncommon: Anxiety Nervous system disorders Common: Dizziness, headache Uncommon: Dizziness postural Ear and labyrinth disorders Uncommon: Vertigo Rare: Tinnitus Cardiac Disorders Uncommon: Tachycardia, palpitations Vascular disorders Uncommon: Flushing, hypotension Rare: Circulatory collapse Respiratory, thoracic and mediastinal disorders Common: Cough Rare: Dry throat, oropharingeal pain Gastrointestinal disorders Uncommon: Abdominal pain, constipation, nausea Rare: Dyspepsia, lip oedema, tongue disorder, diarrhoea, dry mouth, gingivitis Hepatobiliary Disorders Uncommon: ALT increased, AST increased Skin and sub-cutaneous tissue disorders Uncommon: Erythema Rare: Angioedema, swelling face, dermatitis, rash, urticaria Musculoskeletal, connective tissue disorders Uncommon: Arthralgia Renal and urinary disorders Uncommon: Pollakiuria Rare: Nocturia, polyuria Reproductive System and Breast Disorders Rare: Erectile dysfunction General disorders and administration site conditions Uncommon: Asthenia, fatigue, feeling hot, oedema peripheral Undesirable effects occurring in one patient only are reported under the frequency rare.

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

4) * Incidence rates were comparable to those in the placebo and active control groups in the clinical trials. 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 […]

Symptomatic hypotension Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. g. 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. 8). 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. 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 Zaneril 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 […]

1. • History of angioedema associated with ACE-inhibitor therapy. • Hereditary or idiopathic angioedema. 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. 5) • Concomitant use with sacubitril/valsartan therapy. 5). 1).