ZANIPRIL - PACKAGE LEAFLET - LEAFLETS

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Zanipril - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Enalapril (enalapril maleate), Lercanidipine (Lercanidipine hydrochloride)

Zanipril 10 mg / 10 mg film-coated tablets

Zanipril package inserts are available for pack sizes:

Zanipril 10 mg / 10 mg film-coated tablets
Zanipril 20 mg / 10 mg film-coated tablets

Indications Why is Zanipril used? What is it for?

Zanipril is the fixed combination of an ACE inhibitor (enalapril) and a calcium channel blocker (lercanidipine), two drugs that lower blood pressure.

Zanipril is indicated to treat high blood pressure (hypertension) in adult patients whose blood pressure has not been adequately controlled by the administration of 10 mg of lercanidipine alone. Zanipril is not indicated for the initial treatment of hypertension.

Contraindications When Zanipril should not be used

Do not take Zanipril:

If you are allergic to enalapril or lercanidipine or any of the other ingredients of this medicine (listed in section 6).
If you have ever had an allergic reaction to a type of medicine similar to those contained in Zanipril, eg. medicines called ACE inhibitors or calcium channel blockers.
If you have ever had swelling of the face, lips, mouth, tongue or larynx which caused difficulty in swallowing or breathing (angioedema) after taking a type of medicine called an ACE inhibitor, or without cause known or for hereditary cause.
If you have diabetes or kidney problems and are taking medicines containing aliskiren to lower your blood pressure.
If you are past the third month of pregnancy (also it is better to avoid Zanipril in the first months of pregnancy - see pregnancy section).
If you suffer from certain heart conditions such as:
- obstruction of blood flow from the heart, including narrowing of the aortic valve of the heart.
- untreated heart failure.
- chest pain that appears at rest or that gets progressively worse or happens more often (unstable angina).
- heart attack less than a month old.
If you have severe kidney problems, or if you are on dialysis.
If you have severe liver problems.
If you take drugs that inhibit liver metabolism such as:
- antifungals (e.g. ketoconazole, itraconazole).
- macrolide antibiotics (e.g. erythromycin, troleandomycin).
- antivirals (e.g. ritonavir).
If you are taking another medicine called cyclosporine at the same time (used after transplants to prevent organ rejection).
Along with grapefruit or grapefruit juice.

Precautions for use What you need to know before taking Zanipril

Talk to your doctor or pharmacist before taking Zanipril:

if you have low blood pressure (you will notice weakness or dizziness, especially when standing up)
if you have been very ill (excessive vomiting) or have recently had diarrhea
if you are on a low-sodium diet
if you have heart problems
if you have a disease involving the blood vessels in the brain
if you have kidney problems (including kidney transplant)
if you have liver problems
if you have blood problems, such as low or lack of white blood cells (leukopenia, agranulocytosis), low platelet count (thrombocytopenia) or low number of red blood cells (anemia)
if you have vascular collagen disease (e.g. lupus erythematosus, rheumatoid arthritis or scleroderma)
if you are a black patient you should be aware that black patients have a higher risk of an allergic reaction with swelling of the face, lips, tongue and throat with difficulty in swallowing and breathing when taking ACE inhibitors .
if you have diabetes
if a persistent dry cough appears
if you are taking potassium supplements, potassium-sparing agents or potassium-containing salt substitutes
if you are intolerant to certain sugars (lactose)
if you are taking any of the following medicines used to treat high blood pressure:
- an "angiotensin II receptor antagonist" (AIIRA) (also known as sartans - for example valsartan, telmisartan, irbesartan), particularly if you have diabetes-related kidney problems
- aliskiren.

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (such as potassium) in your blood at regular intervals.

See also information under the heading "Do not take Zanipril".

Tell your doctor if you are going to have treatment Tell your doctor that you are taking Zanipril if you are going to:

undergo surgery or anesthesia (including dental anesthesia)
follow a treatment to remove cholesterol from the blood called LDL apheresis
follow desensitization therapy to reduce the effect of allergies to bee or wasp stings.

Tell your doctor if you think you are (or may become) pregnant or are breast-feeding (see "Pregnancy, breast-feeding and fertility" section).

Children and adolescents

Do not give this medicine to children and adolescents under the age of 18 because there is no information on efficacy and safety.

Interactions Which drugs or foods can modify the effect of Zanipril

Zanipril must not be taken together with some medicines.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, even those obtained without a prescription. This is because when Zanipril is taken together with some medicines, its effect or that of other medicines may change, or some side effects may occur more frequently.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

drugs containing potassium (including salt substitutes in diets)
other medicines used to lower blood pressure, such as angiotensin II receptor blockers, diuretics (drugs that increase urine output) or a drug called aliskiren
lithium (a drug used to treat a certain type of depression)
medicines for depression called tricyclic antidepressants
medicines for mental problems called antipsychotics
non-steroidal anti-inflammatory drugs, including COX-2 inhibitors (drugs that reduce inflammation and can be used to help relieve pain)
some pain or arthritis medications including gold therapy
some cough and cold medications and weight loss medications containing a substance called a "sympathomimetic agent"
diabetes medications (including oral antidiabetic medications and insulin), astemizole or terfenadine (allergy medications)
amiodarone or quinidine (medicines to treat a fast heartbeat)
phenytoinocarbamazepine (drugs for epilepsy)
rifampicin (a drug to treat tuberculosis)
digoxin (a medicine to treat heart problems)
midazolam (a medicine that helps you sleep)
beta-blockers (medicines to treat high blood pressure and heart problems)
a medicine for ulcers and heartburn called cimetidine, taken in daily doses greater than 800 mg.

Your doctor may need to change your dose and / or take other precautions:

if you are taking an angiotensin II receptor antagonist (AIIRA) or aliskiren (see also information under "Do not take Zanipril" and "Warnings and precautions").

Zanipril with food, drink and alcohol

Take Zanipril at least 15 minutes before a meal.
Alcohol intake can increase the effects of Zanipril. For this reason it is recommended not to take alcohol or to minimize its consumption.
Do not take Zanipril with grapefruit or grapefruit juice.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Pregnancy and fertility

Tell your doctor if you think you are (or might get) pregnant. Your doctor will normally advise you to stop taking Zanipril before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Zanipril. Zanipril is not recommended during pregnancy, and it should not be taken after the third month, as it could cause serious harm to your baby if used after the third month of pregnancy.

Feeding time

Tell your doctor if you are breastfeeding or about to start breastfeeding. Breastfeeding babies (in the first few weeks after birth), and especially premature babies, is not recommended if you are taking Zanipril. In the case of an older baby, your doctor should inform you about the benefits and risks of taking Zanipril while breastfeeding, in comparison to other treatments.

Driving and using machines

Avoid driving a vehicle or operating machinery if you experience dizziness, weakness, tiredness or sleepiness while taking this medicine.

Zanipril contains lactose.

If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicinal product.

Dosage and method of use How to use Zanipril: Dosage

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

Adults: the recommended dose is one tablet a day, taken at the same time each day, unless otherwise prescribed by your doctor. The tablet should preferably be taken in the morning, at least 15 minutes before breakfast. The tablet should be swallowed whole with a little water.

Patients with kidney problems / the elderly: Your doctor will decide the dose of medicine to take based on how your kidneys are working.

If you forget to take Zanipril

If you forget to take your tablet, skip the missed dose.
Take the next dose as usual.
Do not take a double dose to make up for a forgotten dose.

If you stop taking Zanipril

Do not stop taking this medicine until your doctor tells you to.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Zanipril

If you take more medicine than you should, consult your doctor or go to a hospital immediately. Take the box with you.

Taking an excessive dose of the drug can cause an excessive drop in blood pressure and the appearance of irregular heart rhythms or tachycardia.

Side Effects What are the side effects of Zanipril

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects may occur with the use of this medicine:

Certain side effects can be serious.

If any of the following occur, tell your doctor immediately:

Allergic reaction with swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing.

At the beginning of treatment with Zanipril you may feel weakness or dizziness or have blurred vision; this is caused by a sudden drop in blood pressure and if this happens it would help to lie down. If this causes you concern, talk to your doctor.

Side effects seen with Zanipril

Common (may affect up to 1 in 10 people)

Cough, feeling dizzy, headache.

Uncommon (may affect up to 1 in 100 people)

Changes in blood values such as a reduction in the number of blood platelets, an increase in the level of potassium in the blood, nervousness (anxiety), feeling dizzy on standing up, dizziness, rapid heartbeat, fast or irregular heartbeat (palpitations), sudden redness of the face, neck or upper chest (flushing), low blood pressure, abdominal pain, constipation, feeling sick (nausea), high liver enzyme levels, red skin, joint pain, increased frequency of "passing urine, feeling weak, tired, hot flashes, swollen ankles.

Rare (may affect up to 1 in 1,000 people)

Anemia, allergic reactions, ringing in the ears (tinnitus), fainting, dry throat, sore throat, indigestion, salty tongue sensation, diarrhea, dry mouth, enlarged gums, allergic reaction with swelling of the face, lips, tongue or throat with difficulty in swallowing and breathing, rash, hives, wake up at night to urinate, high urine output, impotence.

Additional side effects with enalapril or lercanidipine taken separately

Enalapril

Very common (affects more than 1 in 10 people)

Blurred vision.

Common (affects less than 1 in 10 people)

Depression, chest pain, heart rhythm changes, angina, shortness of breath, taste disturbance, increased blood creatinine levels (usually seen in a test).

Uncommon (affects less than 1 in 100 people)

Anemia (including aplastic and haemolytic anemia), sudden drop in blood pressure, confusion, insomnia or sleepiness, tingling or numbness in the skin, heart attack (possibly due to very low blood pressure in some high-risk patients, including those with problems with blood flow to the heart or brain), stroke (possibly due to very low blood pressure in high-risk patients), runny nose, sore throat and hoarseness, asthma, impaired bowel motility, inflammation of the pancreas, malaise, upset stomach (gastric irritation), ulcer, anorexia, increased sweating, itching or hives, hair loss, impaired kidney function, kidney failure, high level of protein in the urine (measured in a test), muscle cramps, general feeling of unwell (malaise), high temperature (fever), low blood sugar or sodium, high blood urea (all detected with a blood test).

Rare (affects less than 1 in 1,000 people)

Abnormal laboratory values such as reduced white blood cell count, decreased bone marrow function, autoimmune disease, altered dreams or sleep disturbances, Raynaud's phenomenon (where hands and feet can become very cold and white due to reduced blood flow blood), lung infiltrates, inflammation of the nose, pneumonia, liver problems such as decreased liver function, inflammation of the liver, jaundice (yellowing of the skin and / or whites of the eyes), increased bilirubin levels (measured with a blood test), erythema multiforme (red patches of different shapes on the skin), Stevens-Johnson syndrome (a serious skin condition where redness and peeling of the skin, blisters or sores, or peeling of the upper layer of the skin occur) , decreased urine output, enlargement of the mammary gland in humans.

Very rare (affects less than 1 in 10,000 people)

Swelling of the intestine (intestinal angioedema).

Lercanidipine

Rare (affects less than 1 in 1,000 people)

Angina pectoris (chest pain caused by insufficient blood supply to the heart), vomiting, heartburn, muscle pain.

Very rare (affects less than 1 in 10,000 people)

Chest pain.

Patients with pre-existing angina pectoris may experience increased frequency, duration or severity of attacks with the drug group to which lercanidipine belongs. Isolated cases of heart attack can be observed.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Talk to your doctor or pharmacist for more information on side effects. They both have a more complete list of side effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after the word EXP. The expiry date refers to the last day of that month.

Store in the original package to protect from light and moisture. Do not store above 25 ° C.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Zanipril contains

The active ingredients are enalapril maleate and lercanidipine hydrochloride.

Each film-coated tablet contains: 10 mg of enalapril maleate (equivalent to 7.64 mg of enalapril) and 10 mg of lercanidipine hydrochloride (equivalent to 9.44 mg of lercanidipine).

The other ingredients are:

Core: lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch type A, povidone K30, sodium hydrogen carbonate, magnesium stearate.
Film coating: 5 cP hypromellose, titanium dioxide (E171), talc, macrogol 6000

What Zanipril looks like and contents of the pack

Zanipril 10 mg / 10 mg are white, 8.5 mm circular biconvex film-coated tablets.

Zanipril 10 mg / 10 mg is available in packs of 7, 14, 28, 30, 35, 42, 50, 56, 90, 98 and 100 tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Zanipril can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

ZANIPRIL 10 MG / 10 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each film-coated tablet contains 10 mg of enalapril maleate (equivalent to 7.64 mg of enalapril) and 10 mg of lercanidipine hydrochloride (equivalent to 9.44 mg of lercanidipine).

Excipient with known effect: each tablet contains 102.0 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Film-coated tablet.

White, circular, biconvex tablets of 8.5 mm.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Treatment of essential hypertension in patients with blood pressure inadequately controlled by monotherapy with 10 mg lercanidipine.

The fixed combination Zanipril 10 mg / 10 mg should not be used for the initial treatment of hypertension.

04.2 Posology and method of administration -

Patients with blood pressure inadequately controlled by 10 mg lercanidipine monotherapy have the option of taking 20 mg lercanidipine alone or switching to the fixed combination Zanipril 10 mg / 10 mg.

Individual titration of the components is recommended. If clinically appropriate, a direct switch from monotherapy to fixed combination can be considered.

Dosage

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

Senior citizens : the dose depends on the patient's renal function (see "Renal impairment").

Patients with renal insufficiency : Zanipril is contraindicated in patients with severe renal impairment (creatinine clearance hemodialysis (see sections 4.3 and 4.4). Particular caution is recommended when initiating treatment in patients with mild to moderate renal impairment.

Patients with hepatic insufficiency: Zanipril is contraindicated in severe hepatic insufficiency. Particular caution is recommended at the initiation of treatment in patients with mild to moderate hepatic impairment.

Pediatric population : There is no specific use of Zanipril in the pediatric population in the indication of hypertension.

Method of administration

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

- The treatment should preferably be administered in the morning at least 15 minutes before breakfast.

- This medicinal product must not be taken with grapefruit juice (see sections 4.3 and 4.5).

04.3 Contraindications -

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Zanipril should not be given in the following cases:

• hypersensitivity to an ACE inhibitor or dihydropyridine calcium channel blocker or to any of the excipients present in the medicine

• history of angioedema caused by previous therapy with an ACE inhibitor

• hereditary or idiopathic angioedema

• second and third trimester of pregnancy (see sections 4.4 and 4.6)

• in combination with aliskiren-containing products in patients with diabetes mellitus or renal insufficiency (GFR

• left ventricular ejection obstruction, including aortic stenosis

• untreated congestive heart failure

• unstable angina pectoris

• myocardial infarction less than a month ago

• severe renal insufficiency (creatinine clearance

• severe hepatic insufficiency

• concomitant treatment with:

or potent CYP3A4 inhibitors (see section 4.5)

o ciclosporin (see section 4.5)

o grapefruit juice (see section 4.5).

04.4 Special warnings and appropriate precautions for use -

Symptomatic hypotension

Symptomatic hypotension has rarely been observed in patients with uncomplicated hypertension. In hypertensive patients treated with enalapril, symptomatic hypotension is more likely to occur if the patient is hypovolaemic, for example in the case of therapy with diuretics, limitation salt in the diet, dialysis, diarrhea or vomiting (see section 4.5). Symptomatic hypotension has been observed in patients with heart failure, with or without associated renal insufficiency. This is more likely to occur in patients with more severe heart failure , following the use of high doses of loop diuretics, hyponatremia or renal insufficiency. In these patients, therapy should be initiated under medical supervision and patients should be followed closely in case of dose adjustment of enalapril and / or diuretics. Similar considerations apply to patients with cardiac ischaemia or cerebrovascular disease for whom excessive decrease in blood pressure could result in myocardial infarction or a cerebrovascular accident.

Should hypotension occur, the patient should be placed in the supine position and, if necessary, given intravenous saline infusion. A transient hypotensive response is not a contraindication to further doses, which can generally be given without difficulty as soon as blood pressure has increased after volume expansion.

In some heart failure patients with normal or low blood pressure, administration of enalapril may cause a further reduction in systemic blood pressure. This effect is expected and is generally not a reason for discontinuation of treatment. If hypotension becomes symptomatic. , dose reduction and / or discontinuation of the diuretic and / or enalapril may be necessary.

Sinus node dysfunction syndromes

Particular caution is recommended in the use of lercanidipine in patients with sinus node dysfunction syndromes (if a pacemaker is not implanted).

Left ventricular dysfunction and cardiac ischemia

Although controlled hemodynamic studies have shown no impairment of ventricular function, caution should be exercised in patients with left ventricular dysfunction during treatment with calcium channel blockers. Patients with cardiac ischaemia have been shown to have an elevated cardiovascular risk during treatment with some short-acting dihydropyridines. Although lercanidipine has a long duration of action, caution is required in such patients.

In rare cases, some dihydropyridines can cause precordial pain or angina pectoris. Very rarely, in patients with pre-existing angina pectoris, these attacks may occur with greater frequency, duration or severity. Isolated cases of myocardial infarction may be observed (see section 4.8).

Kidney failure

Particular caution is required during the initial phase of enalapril treatment in patients with mild to moderate renal impairment. Routine monitoring of serum potassium and creatinine are part of normal medical practice for these patients.

Renal failure has been reported in association with enalapril, especially in patients with severe cardiac dysfunction or underlying renal disease, including renal artery stenosis. If promptly recognized and adequately treated, renal failure when associated with renal therapy. enalapril is generally reversible.

Some hypertensive patients with no apparent pre-existing kidney disease have developed increased blood urea and creatinine levels when enalapril was administered concurrently with a diuretic. A dose reduction of enalapril and / or discontinuation of the diuretic may be required. This situation should raise the possibility of latent renal artery stenosis (see section 4.4, Renovascular hypertension).

Renovascular hypertension

There is an increased risk of hypotension and renal failure when patients with bilateral renal artery stenosis or artery stenosis of only one functioning kidney are treated with ACE inhibitors. serum creatinine In these patients, therapy should be initiated under close medical supervision, with reduced doses and careful titration and monitoring of renal function.

Kidney transplant

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

Hepatic insufficiency

The antihypertensive effect of lercanidipine may be enhanced in patients with hepatic insufficiency.

Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not known. Patients receiving ACE inhibitors who develop jaundice or marked elevation of liver enzymes should stop taking the ACE inhibitor and receive appropriate medical attention.

Neutropenia / agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no particular risk factors, neutropenia rarely occurs. Enalapril should be used with extreme caution in patients with vascular collagen disease, on immunosuppressive therapy, on allopurinol, procainamide or a combination of these complicating factors, particularly if there is pre-existing impaired renal function. Some of these patients have impaired renal function. developed severe infections which have sometimes failed to 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 advised of the need to report any signs of infection.

Hypersensitivity / angioneurotic edema

Cases of angioedema of the face, extremities, lips, tongue, glottis and / or larynx have been reported in patients treated with ACE inhibitors, including enalapril. This can occur at any time during therapy. In these cases, the use of enalapril should be discontinued promptly and appropriate monitoring instituted to ensure resolution of symptoms prior to patient discharge. Even in these cases where swelling of the tongue alone was involved, without respiratory distress, the patients may require prolonged observation as treatment with antihistamines and corticosteroids may not be sufficient.

Fatal events due to angioedema associated with laryngeal edema or tongue edema have been reported very rarely. Patients with involvement of the tongue, glottis, or larynx, especially those with a history of respiratory surgery, are more likely to experience airway obstruction.

If there is involvement of the tongue, glottis or larynx that could cause airway obstruction, appropriate therapy should be given promptly, which may include subcutaneous administration of adrenaline at a 1: 1000 dilution (0.3 ml to 0 , 5 ml) and / or take all necessary measures to ensure a patent airway.

A higher incidence of angioedema has been reported in black patients receiving ACE inhibitors than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema when administering an ACE inhibitor (see section 4.3).

Anaphylactoid reactions during hymenoptera desensitization

Rarely, patients receiving ACE inhibitors during desensitization with hymenoptera venom have experienced dangerous anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization treatment.

Anaphylactoid reactions during low density lipoprotein (LDL) apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate have experienced dangerous anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Hypoglycemia

In diabetic patients treated with oral antidiabetic agents or insulin, starting treatment with ACE inhibitors, they should be advised to carefully monitor for hypoglycaemia especially during the first month of concomitant use (see section 4.5).

Cough

Cough has been observed with the use of ACE inhibitors. This cough is usually non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Surgery / Anesthesia

In patients undergoing major surgery or during anesthesia with agents that cause hypotension, enalapril inhibits the formation of angiotensin II, secondary to a compensatory release of renin. If hypotension occurs and is considered to be a consequence of this mechanism, it can be corrected by expanding the volume.

Hyperkalemia

Elevation of serum potassium has been observed in some patients treated with ACE inhibitors, including enalapril. Risk factors for the development of hyperkalaemia include: renal failure, worsening of renal function, age (> 70 years), diabetes mellitus, concomitant events such as dehydration, acute heart failure, metabolic acidosis and concomitant intake of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes as well as "concomitant use of other drugs that may increase serum potassium levels (eg heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes in patients with impaired renal function can lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the agents mentioned above is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Lithium

The combined use 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 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 the 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 block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

CYP3A4 inducers

CYP3A4 inducers such as anticonvulsants (eg phenytoin, carbamazepine) and rifampicin may decrease the serum levels of lercanidipine and therefore the efficacy of the drug may be lower than expected (see section 4.5).

Ethnic differences

As with other ACE inhibitors, enalapril appears to be 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

The use of Zanipril is not recommended during pregnancy.

Treatment with ACE inhibitors, such as enalapril, should not be initiated during pregnancy. Unless administration of ACE inhibitors is considered essential, patients planning pregnancy should be switched to antihypertensive drug treatments. alternatives, which are safe to use during pregnancy.As soon as pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if necessary, 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 may be pregnant (see section 4.6).

Feeding time

The use of Zanipril is not recommended during lactation (see section 4.6).

Pediatric population

The safety and efficacy of this combination have not been demonstrated in children.

Alcohol

Alcohol intake should be avoided as it may potentiate the vasodilator effect of antihypertensive drugs (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Zanipril.

04.5 Interactions with other medicinal products and other forms of interaction -

The antihypertensive effect of Zanipril may be potentiated by other hypotensive drugs, such as diuretics, beta-blockers, alpha-blockers and other substances.

In addition, the following interactions with one or the other component of the association were observed.

Enalapril maleate

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

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events. such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).

Potassium-sparing diuretics or potassium supplements

ACE inhibitors attenuate diuretic induced potassium loss. Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may lead to a significant increase in serum potassium level. If concomitant use is indicated due to demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Diuretics (thiazides or loop diuretics)

Previous treatment with high-dose diuretics may result in hypovolaemia and a risk of hypotension when initiating therapy with enalapril (see section 4.4). The hypotensive effects may be reduced by discontinuation of the diuretic, by increasing blood volume or salt intake or starting therapy with a reduced dose of enalapril.

Other antihypertensives

Concomitant use with other antihypertensive agents may increase the hypotensive effects of enalapril. The concomitant use of nitroglycerin and other nitrates or vasodilators may lead to a further reduction in blood pressure.

Lithium

Reversible increases in serum concentrations and toxicity of lithium have been reported when co-administered with ACE inhibitors. Concomitant use of thiazide diuretics may further increase the serum lithium concentration, resulting in an increased risk of lithium toxicity with ACE inhibitors. The use of enalapril with lithium is not recommended, but if the combination is proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Tricyclic antidepressants / antipsychotics / anesthetics / narcotics

The concomitant use of some anesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in a further reduction in 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 effects of diuretics and other antihypertensive drugs. Consequently, NSAIDs and selective COX-2 inhibitors may attenuate the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors.

Concomitant use of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors exerts an additive effect on the increase in serum potassium, and may result in deterioration of renal function. These effects are generally reversible. In rare cases, acute renal failure may occur, especially in patients with impaired renal function (such as the elderly or patients with hypovolaemia, including patients treated with diuretics). Concomitant intake of the above mentioned drugs should therefore be managed with caution in patients with impaired renal function. Patients should be adequately hydrated and renal function after initiation of concomitant therapy should be monitored periodically.

Gold

Nitritoid reactions (symptoms include flushing, nausea, vomiting and hypotension) have been reported rarely in patients receiving therapy with injectable gold (sodium aurothiomalate) and concomitant administration of ACE inhibitors, including enalapril.

Sympathomimetic drugs

Sympathomimetic drugs can reduce the antihypertensive effects of ACE inhibitors.

Antidiabetic

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic drugs (insulin, oral hypoglycemic agents) may cause an increase in the hypoglycemic effect of the latter, with the risk of hypoglycaemia. These cases appear to occur more likely during the former. weeks of combined treatment and in patients with impaired renal function (see sections 4.4 and 4.8).

Alcohol

Alcohol potentiates the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and β-blockers

Enalapril can be safely administered together with acetylsalicylic acid (at cardiological doses), thrombolytics and beta-blockers.

Lercanidipine

CYP3A4 inhibitors

Since lercanidipine is metabolised by the CYP3A4 enzyme, concomitant administration of CYP3A4 inhibitors and inducers may interact with the metabolism and elimination of lercanidipine.

Co-administration of lercanidipine with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) is contraindicated (see section 4.3).

An interaction study with ketoconazole, a potent CYP3A4 inhibitor, showed a considerable increase in plasma levels of lercanidipine (a 15-fold increase in the area under the drug concentration / time curve, AUC, and an 8-fold increase in Cmax. for the S-lercanidipine eutomer).

Cyclosporine

Ciclosporin and lercanidipine must not be used together (see section 4.3).

Following the concomitant administration of lercanidipine and cyclosporine, an increase in plasma levels of both active substances was observed. A study in young healthy volunteers has shown that when cyclosporine is administered 3 hours after lercanidipine intake, the plasma levels of lercanidipine do not change, while the cyclosporine AUC increases by 27%. Co-administration of lercanidipine with cyclosporine caused a 3-fold increase in plasma levels of lercanidipine and a 21% increase in cyclosporine AUC.

Grapefruit juice

Lercanidipine must not be taken together with grapefruit juice (see section 4.3).

As with other dihydropyridines, lercanidipine is sensitive to the metabolic inhibition caused by grapefruit juice, with a consequent increase in its systemic availability and an increase in its hypotensive effect.

Alcohol

Alcohol intake should be avoided as it may potentiate the vasodilating effect of antihypertensive drugs (see section 4.4).

CYP3A4 substrates

Caution should be exercised when lercanidipine is taken together with other CYP3A4 substrates, such as terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone and quinidine.

CYP3A4 inducers

Concomitant administration of lercanidipine with inducers of CYP3A4 such as anticonvulsant drugs (eg phenytoin, carbamazepine) and rifampicin should be done with caution as the antihypertensive effect may be reduced and blood pressure should be monitored more frequently than usual.

Digoxin

In patients undergoing chronic treatment with β-methyldigoxine, co-administration of 20 mg of lercanidipine showed no pharmacokinetic interaction. Healthy volunteers treated with digoxin, following administration of 20 mg of lercanidipine, showed a mean increase of 33% in digoxin Cmax, while AUC and renal clearance were not significantly changed. Patients concomitantly treated with digoxin to detect any signs of digoxin toxicity.

Midazolam

In elderly volunteers, concomitant oral administration of 20 mg midazolam enhanced the absorption of lercanidipine (approximately 40%) and decreased its rate of absorption (delayed tmax from 1.75 to 3 hours). midazolam concentrations.

Metoprolol

When lercanidipine was co-administered with metoprolol - a β-blocker eliminated primarily by the liver - the bioavailability of metoprolol remained unchanged, while that of lercanidipine was reduced by 50%. This effect could be due to the reduction in hepatic blood flow caused by β-blockers, therefore it could also occur with other drugs of this class. Nevertheless, lercanidipine can be safely used concurrently with β-adrenergic receptor blockers.

Cimetidine

Plasma levels of lercanidipine are not significantly changed in patients receiving concomitant treatment with 800 mg cimetidine per day, however caution should be exercised with higher doses, as increases in both the bioavailability of lercanidipine and its hypotensive effect may occur.

Fluoxetine

An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in healthy volunteers aged 65 ± 7 years (mean ± sd), showed no clinically relevant change in the pharmacokinetic properties of lercanidipine.

Simvastatin

During repeated co-administration of a 20 mg dose of lercanidipine and 40 mg of simvastatin, the AUC of lercanidipine was not significantly changed, while the AUC of simvastatin increased by 56% and that of its main active metabolite, the β-hydroxy acid, by 28%. Such variations are unlikely to be of clinical relevance. No interaction is expected if lercanidipine is administered in the morning and simvastatin in the evening as indicated for this drug.

Warfarin

Co-administration of 20 mg of lercanidipine taken by fasted healthy volunteers does not alter the pharmacokinetics of warfarin.

Pediatric population

Interaction studies have only been performed in adults.

04.6 Pregnancy and breastfeeding -

Pregnancy

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 trimester of pregnancy (see section 4.4). paragraphs 4.3 and 4.4).

No definitive epidemiological evidence is available on the risk of teratogenesis following exposure to ACE inhibitors during the first trimester of pregnancy; however, a small increase in risk cannot be excluded. Unless administration of ACE inhibitors is considered. essential, patients planning to become pregnant should be switched to alternative antihypertensive drugs which are safe for use during pregnancy. As soon as pregnancy is diagnosed, discontinue treatment with ACE inhibitors immediately and, if necessary, initiate an alternative therapy.

Exposure to ACE inhibitor therapy during the second and third trimesters induces human foetotoxicity (decreased renal function, oligohydramnios, cranial ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3 ). Cases of maternal oligohydramnios have occurred, presumably indicating reduced fetal renal function and which can induce limb contractures, craniofacial deformations and development of pulmonary hypoplasia.

If exposure to ACE inhibitors has occurred after the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Children whose mothers have taken ACE inhibitors should be closely monitored for onset. hypotension (see sections 4.3 and 4.4).

Lercanidipine

Studies conducted on animals treated with lercanidipine did not show teratogenic effects, which were instead observed with the use of other dihydropyridine compounds.

No clinical data on exposure to lercanidipine in pregnancy are available, therefore use in pregnancy or in women of childbearing potential is not recommended unless effective contraceptive measures are in place.

Combination of enalapril and lercanidipine

There are no or few data on the use of the combination enalapril maleate / lercanidipine hydrochloride in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

The use of Zanipril is contraindicated in the second and third trimester of pregnancy. It is not recommended during the first trimester of pregnancy and in women of childbearing potential who are not using any contraception.

Feeding time

Enalapril

Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations appear to be clinically irrelevant, the use of enalapril in breastfeeding is not recommended for preterm infants and in the first few weeks after delivery due to the hypothetical risk of cardiovascular and renal effects and because there is insufficient clinical experience.

In older infants, if deemed necessary for the mother, enalapril can be taken during breastfeeding, but in this case the infant should be followed up for possible adverse effects.

Lercanidipine

The excretion of lercanidipine in human milk is unknown.

Combination of enalapril and lercanidipine

Consequently, Zanipril should not be used while breastfeeding.

Fertility

Reversible biochemical changes in the head of spermatozoa, which could impair fertilization, have been reported in some patients treated with calcium channel blockers. In the face of repeated unsuccessful in-vitro fertilization, and in the absence of other explanations, it is possible to attribute the cause to calcium channel blockers.

04.7 Effects on ability to drive and use machines -

Zanipril moderately affects the ability to drive or use machines. However, caution is advised as symptoms such as dizziness, asthenia, tiredness and in rare cases somnolence may occur (see section 4.8).

04.8 Undesirable effects -

Summary of the safety profile

The safety of Zanipril was evaluated in five double-blind controlled clinical studies and in two long-term open-label studies. In total, 1,141 patients received Zanipril at a dose of 10 mg / 10 mg, 20 mg / 10 mg and 20 mg / 20 mg. The undesirable effects of the combination are similar to those observed following a single administration of one or the other component. The most commonly reported adverse reactions during treatment with Zanipril were: cough (4.03%), dizziness (1.67%) and headache (1.67%).

Tabular summary of adverse reactions

In the table below, adverse reactions reported in clinical studies with administration of Zanipril 10 mg / 10 mg, 20 mg / 10 mg and 20 mg / 20 mg and for which a reasonable causal relationship has been established, are listed by MedDRA classification. : very common (> 1/10), common (≥1 / 100 to

Disorders of the blood and lymphatic system Uncommon: Thrombocytopenia Rare: Decrease in hemoglobin Disorders of the immune system Rare: Hypersensitivity Metabolism and nutrition disorders Uncommon: Hyperkalemia Psychiatric disorders Uncommon: Anxiety Nervous system disorders Common: Dizziness, headache Uncommon: Postural dizziness Ear and labyrinth disorders Uncommon: Vertigo Rare: Tinnitus Cardiac pathologies Uncommon: Tachycardia, palpitations Vascular pathologies Uncommon: Hot flashes, hypotension Rare: Circulatory collapse Respiratory, thoracic and mediastinal disorders Common: Cough Rare: Dry throat, oropharyngeal pain Gastrointestinal disorders Uncommon: Abdominal pain, constipation, nausea Rare: Dyspepsia, lip edema, tongue disorders, diarrhea, dry mouth, gingivitis Hepatobiliary disorders Uncommon: ALT increase, AST increase Skin and subcutaneous tissue disorders Uncommon: Erythema Rare: Angioedema, face edema, dermatitis, rash, urticaria Musculoskeletal and connective tissue disorders Uncommon: Arthralgia Renal and urinary disorders Uncommon: Pollakiuria Rare: Nocturia, polyuria Diseases of the reproductive system and breast Rare: Erectile dysfunction General disorders and administration site conditions Uncommon: Asthenia, fatigue, hot flashes, peripheral edema

Side effects occurring in only one patient are listed under the frequency rare.

Additional information on the individual components

Enalapril

The reported side effects for enalapril are:

Disorders of the blood and lymphatic system:

Uncommon: anemia (including aplastic and haemolytic forms)

Rare: neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow failure, 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)

Nervous system disorders and psychiatric disorders:

Common: headache, depression

Uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia, dizziness

Rare: abnormal dreams, sleep disturbances

Eye disorders:

Very common: blurred vision

Cardiac and vascular disorders:

Very common: dizziness

Common: hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia

Uncommon: orthostatic hypotension, palpitations, myocardial infarction or cerebrovascular accident *, possibly as a result of excessive hypotension in high-risk patients (see section 4.4)

Rare: Raynaud's phenomenon

* The incidence rates in clinical trials were comparable between those treated with placebo versus those with active control.

Respiratory, thoracic and mediastinal disorders:

Very common: cough

Common: dyspnoea

Uncommon: rhinorrhea, oropharyngeal pain and dysphonia, bronchospasm / asthma

Rare: pulmonary infiltrates, rhinitis, allergic alveolitis / eosinophilic pneumonia

Gastrointestinal disorders:

Very common: nausea

Common: diarrhea, abdominal pain, taste disturbance

Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcer

Rare: stomatitis / aphthous ulcerations, glossitis

Very rare: intestinal angioedema

Hepatobiliary disorders:

Rare: hepatic failure, hepatitis - both hepatocellular and cholestatic, hepatitis with necrosis, cholestasis (including jaundice)

Skin and subcutaneous tissue disorders:

Common: rash, hypersensitivity / angioedema: cases of angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx have 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 conditions: fever, serositis, vasculitis, myalgia / myositis, arthralgia / arthritis, positivity for ANA, elevated ESR, eosinophilia and leukocytosis. Possibility of the appearance of skin rashes, photosensitivity or other dermatological manifestations.

Renal and urinary disorders:

Uncommon: renal dysfunction, renal failure, proteinuria

Rare: oliguria

Diseases of the reproductive system and breast:

Uncommon: impotence

Rare: gynecomastia

General disorders and administration site conditions:

Very common: asthenia

Common: tiredness

Uncommon: muscle spasms, hot flashes, tinnitus, malaise, fever

Diagnostic tests:

Common: hyperkalaemia, blood creatinine increased

Uncommon: increased uremia, hyponatremia

Rare: increased liver enzymes, increased blood bilirubin.

Lercanidipine

The most commonly observed adverse drug reactions in controlled clinical trials include: headache, dizziness, peripheral edema, tachycardia, palpitations and hot flashes, all of which occurred in less than 1% of patients.

Disorders of the immune system:

Very rare: hypersensitivity

Psychiatric disorders:

Rare: somnolence

Nervous system disorders:

Uncommon: headache, dizziness

Cardiac pathologies:

Uncommon: tachycardia, palpitations

Rare: angina pectoris

Vascular pathologies:

Uncommon: hot flashes

Very rare: syncope

Gastrointestinal disorders:

Rare: nausea, dyspepsia, diarrhea, abdominal pain, vomiting

Skin and subcutaneous tissue disorders:

Rare: skin rashes

Musculoskeletal and connective tissue disorders:

Rare: myalgia

Renal and urinary disorders:

Rare: polyuria

General disorders and administration site conditions:

Uncommon: peripheral edema

Rare: asthenia, fatigue

Spontaneous reports received in post-marketing experience have reported very rarely (gingival hypertrophy, reversible increases in serum levels of hepatic transaminases, hypotension, urinary frequency and chest pain.

Some dihydropyridines may rarely cause localized precordial pain or angina pectoris. Very rarely, an increase in the frequency, duration or severity of these attacks may occur in patients with pre-existing angina pectoris. Isolated cases of myocardial infarction can occur.

There are no adverse effects of lercanidipine on blood glucose or serum lipid levels.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

In post-marketing experience, some cases of intentional overdose have been reported with the administration of enalapril / lercanidipine at doses of 100 to 1,000 mg each requiring hospitalization. Symptoms reported (decreased systolic blood pressure, bradycardia, restlessness, somnolence and flank pain) may also have been caused by the concomitant administration of high doses of other drugs (e.g. β-blockers).

Symptoms of overdose with enalapril and lercanidipine taken individually:

The most important symptoms of overdose reported with enalapril to date are marked hypotension (approximately six hours after ingestion of the tablets), concomitant with blockade of the renin-angiotensin system and stupor. Symptoms associated with ACE inhibitor overdose may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. After ingestion of enalapril 300 mg and 440 mg serum levels of enalaprilat have been reported 100 and 200 times higher, respectively. normally observed following therapeutic doses.

As with other dihydropyridines, lercanidipine overdose could cause excessive peripheral vasodilation with marked hypotension and reflex tachycardia.

Treatment of cases of enalapril and lercanidipine overdose taken individually:

The recommended treatment for enalapril overdose is intravenous saline infusion. In the presence of hypotension, the patient should be placed in an anti-shock position. If available, angiotensin II infusion treatment may also be considered. / or intravenous catecholamines. If the ingestion of the tablets is recent, adequate measures should be taken to eliminate enalapril maleate (eg induction of vomiting, gastric lavage, administration of sorbents or sodium sulphate). Enalaprilat can be removed from the circulation by hemodialysis (see section 4.4). Pacemaker application is indicated in the case of therapy-resistant bradycardia. Continuously monitor vital signs, serum electrolytes and creatinine.

With lercanidipine in cases of severe hypotension, bradycardia and loss of consciousness, cardiovascular support via intravenous atropine may be necessary to counteract bradycardia.

Given the prolonged pharmacological action of lercanidipine, the cardiovascular status of patients who have taken an overdose should be monitored for at least 24 hours. There is no information on the usefulness of dialysis. Since the drug is highly lipophilic, plasma levels are very unlikely to be indicative of the duration of the risk phase. Dialysis may not be effective.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group:

ACE inhibitors and calcium channel blockers: enalapril and lercanidipine.

ATC code: C09BB02.

Zanipril is a fixed combination of an ACE inhibitor (enalapril) and a calcium channel blocker (lercanidipine), two antihypertensive drugs with complementary mechanisms of action to control blood pressure in patients with essential hypertension.

Enalapril

Enalapril maleate is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. The angiotensin converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressure-acting substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. . Inhibition of ACE results in a decrease in plasma angiotensin II levels, with an increase in plasma renin activity (due to the removal of the negative feedback exerted on renin release) and a decrease in aldosterone secretion.

Since ACE is identical to kininase II, enalapril can also inhibit the breakdown of bradykinin, a potent vasodilator peptide. However, the role of this mechanism in the therapeutic effects of enalapril is not yet known.

Although the mechanism by which enalapril lowers blood pressure is primarily attributed to suppression of the renin-angiotensin-aldosterone system, enalapril produces antihypertensive effects even in patients with reduced renin levels.

Administration of enalapril to hypertensive patients produces a reduction in both supine and standing blood pressure, without a significant increase in heart rate.

Symptomatic orthostatic hypotension is infrequent. In some patients, it may take several weeks of treatment to achieve optimal blood pressure control. Abrupt discontinuation of enalapril has not been associated with rapid rise in blood pressure.

The efficacy of inhibiting ACE activity normally begins 2 to 4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive activity is usually seen after 1 hour and maximal activity is achieved within 4 hours. - 6 hours after administration. The duration of the effect depends on the dose; however, at the recommended dose, the haemodynamic and antihypertensive effects persist for at least 24 hours.

From haemodynamic studies conducted in patients with essential hypertension, it was found that the reduction in blood pressure is associated with a reduction in peripheral arterial resistance, with an increase in cardiac output and no or minimal change in heart rate. An increase in renal blood flow occurred after administration of enalapril, while the glomerular filtration rate remained unchanged. There were no signs of water or sodium retention. However, in patients with reduced glomerular filtration rate prior to treatment, this rate is generally increased.

Decreases in albuminuria, urinary IgG excretion and total proteinuria have been observed in short-term clinical studies in diabetic and non-diabetic renal patients after administration of enalapril.

Two large randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA Nephron-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE inhibitor with an antagonist of the angiotensin II receptor.

ONTARGET is a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus associated with evidence of organ damage. VA NEPHRON-D is a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy. These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties. ACE inhibitors and angiotensin II receptor antagonists should therefore not be used concurrently in patients. with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) is a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Lercanidipine

Lercanidipine is a calcium channel blocker of the dihydropyridine group and inhibits the flow of calcium across the cell membrane of smooth and cardiac muscle. The mechanism of its antihypertensive action is due to a direct relaxing effect on vascular smooth muscle, with a consequent reduction in total peripheral resistance. Despite its short plasma half-life, lercanidipine, thanks to its high partition coefficient in the membrane, has a prolonged antihypertensive activity and does not cause negative inotropic effects due to its high vascular selectivity.

Since lercanidipine-induced vasodilation occurs gradually, acute hypotension with reflex tachycardia has only rarely occurred in hypertensive patients.

As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its (S) -enantiomer.

Enalapril / Lercanidipine

The combination of these two substances has an additive antihypertensive effect which reduces blood pressure more than the use of the single components.

- Zanipril 10 mg / 10 mg

In a double-blind phase III clinical study in 342 patients inadequately controlled on 10 mg lercanidipine monotherapy (PAD, diastolic blood pressure, sitting 95-114 mmHg and PAS, systolic blood pressure, 140-189 mmHg ), after 12 weeks of double-blind treatment, the reduction in systolic blood pressure was 5.4 mmHg greater with the enalapril 10 mg / lercanidipine 10 mg combination compared to lercanidipine 10 mg monotherapy (-7.7 mmHg vs - 2.3 mmHg, p 140/90 mmHg: titration was performed in 133 of 221 patients and PAD was normalized after titration in 1/3 of cases.

- Zanipril 20 mg / 10 mg

In a double-blind phase III clinical study in 327 patients inadequately controlled by enalapril 20 mg monotherapy (PAD, sitting diastolic blood pressure 95-114 mmHg and PAS, systolic blood pressure 140-189 mmHg), i patients treated with enalapril 20 mg / lercanidipine 10 mg achieved a significantly greater reduction in systolic and diastolic blood pressure than that seen in patients remaining on monotherapy, both for PAS (-9.8 vs -6.7 mmHg, p = 0.013) and for PAD (-9.2 vs -7.5 mmHg, p = 0.015). The percentage of patients who responded to treatment with combination therapy was non-statistically significantly higher than monotherapy for both PAD (53% vs 43%, p = 0.076) and PAS (41% vs 33% , p = 0.116), as well as the percentage of patients in combination therapy with normalized pressure for PAD (48% vs 37%, p = 0.055) and for PAS (33% vs 28) was higher in a non-statistically significant measure. %, p = 0.325).

- Zanipril 20 mg / 20 mg

In a randomized, double-blind, placebo-controlled, active-controlled factorial study of 1,039 patients with moderate hypertension (blood pressure measured in the sitting position in the PAD study: 100-109 mmHg, PAD home blood pressure PAS ≥ 85 mmHg), the patients receiving enalapril 20 mg / lercanidipine 20 mg had significantly greater reductions in PAS and PAD, both measured at home and measured in the practice, compared to placebo (p

05.2 "Pharmacokinetic properties -

No pharmacokinetic interactions were observed during concomitant administration of enalapril and lercanidipine.

Pharmacokinetic properties of enalapril

Absorption

Oral enalapril is rapidly absorbed and peak serum concentration is reached within one hour of administration. Based on the amount excreted in the urine, the rate 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

After absorption, oral enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. The peak serum concentration of enalaprilat occurs approximately 4 hours after an oral dose of enalapril maleate. The effective accumulation half-life of enalaprilat following multiple doses of oral enalapril is 11 hours. Steady-state concentration of enalaprilat was reached after four days of treatment.

In the therapeutically relevant concentration range, the binding of enalaprilat to human plasma proteins does not exceed 60%.

Biotransformation

Other than conversion to enalaprilat, there is no significant evidence of enalapril metabolism.

Elimination

Enalaprilat is eliminated primarily by the kidney. The major constituents in the urine are enalaprilat, which accounts for 40% of the dose, and unchanged enalapril (approximately 20%).

Kidney failure

The exposure to enalapril and enalaprilat increases 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 twice that of patients with normal renal function after administration of 5 mg once daily. In the presence of severe renal insufficiency (creatinine clearance ≤ 30 ml / min), the AUC is increased approximately 8-fold. At these levels of renal insufficiency, the effective half-life of enalaprilat after multiple doses of enalapril maleate is prolonged and the time to steady state is increased (see section 4.2).

Enalaprilat can be removed from the general circulation by hemodialysis. Dialysis clearance is 62 mL / min.

Feeding time

After a single 20 mg oral dose administered postpartum to five women, the mean peak plasma enalapril in milk was 1.7 mcg / L (range 0.54-5.9 mcg / L) between 4 and 6 o'clock. hours after administration. The mean plasma peak of enalaprilat was 1.7 mcg / l (range 1.2 to 2.3 mcg / l); the spikes occurred at different times throughout the 24 hours. Using data from peak milk levels, the estimated maximum intake of an exclusively breastfed infant would be approximately 0.16% of the maternal weight-adjusted dose. A woman taking enalapril at a dose of 10 mg per day orally for 11 months has a peak enalapril milk plasma of 2 mcg / l 4 hours after dosing and a peak enalaprilat plasma of 0.75 mcg / l approximately 9 hours after dosing. The total amount of enalapril and enalaprilat detected in milk over 24 hours was 1.44 mcg / l and 0.63 mcg / l respectively. Levels of enalaprilat in milk were undetectable (

Pharmacokinetic properties of lercanidipine

Absorption

Lercanidipine is completely absorbed after oral administration and the plasma peak is reached after approximately 1.5 - 3 hours.

The two enantiomers of lercanidipine show a similar plasma level profile: the time required to obtain the maximum plasma concentration is identical, the maximum plasma concentration and AUC are, on average, 1.2 times higher for the (S) enantiomer. The elimination half-life of the two enantiomers is essentially the same. No "in vivo" interconversion of the enantiomers was observed.

Due to the elevated first pass metabolism, the absolute bioavailability of lercanidipine administered orally to fed patients is approximately 10%; it is reduced to one third when administered to healthy volunteers in the fasted state.

The oral availability of lercanidipine increases 4-fold when taken up to 2 hours after a high-fat meal. Therefore, the drug should be taken before meals.

Distribution

Distribution from plasma to tissues and organs is rapid and extensive.

The degree of binding of lercanidipine to plasma proteins exceeds 98%. In patients with severe renal or hepatic dysfunction, plasma protein levels are reduced and the free fraction of the drug may increase.

Biotransformation

Lercanidipine is extensively metabolised by CYP3A4; the drug was not found in urine or faeces. It is mainly converted to inactive metabolites and approximately 50% of the dose is excreted in the urine.

Experiments "in vitro"with human liver microsomes have shown that lercanidipine exerts a modest inhibition of the two enzymes CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher than those reached at peak in plasma after administration of a dose of 20 mg.

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. For this reason, at therapeutic doses it is not expected that the lercanidipine inhibits the biotransformation of drugs metabolised by CYP3A4 or CYP2D6.

Elimination

Elimination occurs essentially by biotransformation.

A mean terminal elimination half-life of 8-10 hours was calculated and, due to the high binding to lipid membranes, the therapeutic activity has a duration of 24 hours. No accumulation was found after repeated administration.

Linearity / non-linearity

Oral administration of lercanidipine leads to plasma levels not directly proportional to dose (non-linear kinetics). After 10, 20, or 40 mg, peak plasma concentrations of 1: 3: 8 and AUC of 1: 4: 18 were observed, indicating progressive saturation of first pass metabolism. Consequently, availability increases with increasing dose.

Additional information on special populations

In elderly patients and in patients with mild to moderate renal or hepatic impairment, the pharmacokinetic behavior of lercanidipine was similar to that observed in the general patient population. Higher levels of the drug (approximately 70%) were found in patients with severe renal insufficiency or in dialysis patients. In patients with moderate to severe hepatic impairment, an increase in the systemic bioavailability of lercanidipine is likely as the drug is normally extensively metabolised in the liver.

05.3 Preclinical safety data -

Enalapril / lercanidipine combination

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

For the two components (enalapril and lercanidipine), the following data are available.

Enalapril

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

Reproductive toxicity studies indicate that enalapril has been shown to have no effects on fertility and reproductive functions in rats and to develop no teratogenic effects. A study in female rats, given doses before mating and during gestation, showed a higher mortality of small rats during lactation. The compound crosses the placenta and is excreted in milk. The category of ACE inhibitors has been shown to induce adverse effects on final fetal development, resulting in fetal death and effects. cases of fetotoxicity, intrauterine growth retardation and patency of the arterial duct have been reported. These developmental anomalies are partially attributed to a "direct action of ACE inhibitors on the renin-angiotensin system of the fetus. and partly to ischemia due to maternal hypotension, as well as to decreases in blood flow fetal-placental blood and the passage of oxygen / nutrients to the fetus.

Lercanidipine

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

The important effects observed in long-term studies in rats and dogs were related, directly or indirectly, to the known effects of high doses of calcium channel blockers, which mainly reflect an exaggerated pharmacodynamic activity.

Treatment with lercanidipine did not affect fertility or general reproductive functions in rats, however, when administered at high doses, it induced pre- and post-implantation losses and delayed fetal development. There was no evidence of teratogenesis in rats and rabbits, but other dihydropyridines showed teratogenic effects in animals. When given in high doses (12 mg / kg / day) during labor, lercanidipine induced dystocia.

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