Active ingredients: Enalapril (enalapril maleate)
Naprilene 5 mg tablets
Naprilene 20 mg tablets
Why is Naprilene used? What is it for?
Naprilene contains the active ingredient enalapril.
Enalapril belongs to a group of medicines called angiotensin converting enzyme inhibitors (ACE inhibitors), and it works by widening blood vessels to make it easier for the heart to pump blood to all parts of the body.
Naprilene is indicated for:
- the treatment of high blood pressure (hypertension)
- the treatment of symptomatic heart failure (worsening of heart function)
- prevention of symptomatic heart failure. These symptoms include: shortness of breath, tiredness after light physical activity such as walking or swelling of the ankles and feet.
Contraindications When Naprilene should not be used
Do not take Naprilene:
- if you are allergic to enalapril, other angiotensin converting enzyme inhibitors (ACE inhibitors) or any of the other ingredients of this medicine (listed in section 6)
- if you have had allergic reactions with swelling of the face, lips, tongue and / or throat, with difficulty in swallowing and breathing) after previous treatment with other angiotensin converting enzyme inhibitors (ACE inhibitors)
- if you have hereditary or idiopathic angioedema (ie without an apparent cause)
- if you are more than three months pregnant (It is better to avoid Naprilene even in early pregnancy, see sections "Warnings and precautions" and "Pregnancy and breast-feeding")
- if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren (see section "Other medicines and Naprilene"
Precautions for use What you need to know before taking Naprilene
Talk to your doctor or pharmacist before taking Naprylene.
Tell your doctor:
- if you are elderly and have kidney problems, as the dose of Naprylene may need to be adjusted
- if you think you are pregnant or are planning to become pregnant because he will prescribe another medicine instead of Naprilene. Naprylene is not recommended in early pregnancy, and must not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if used at that stage (see section "Do not take Naprylene" and "Pregnancy and breastfeeding");
- if you have or have had vomiting and / or diarrhea;
- if you are being treated with diuretics (medicines that increase the amount of water and salts excreted by the kidneys);
- if you are taking a special type of diuretics called potassium-sparing diuretics, if you are using potassium supplements, medicines that increase potassium levels in your blood or potassium-containing salt substitutes (see section "Other medicines and Naprylene")
- if you are on a low sodium diet;
- if you have or have ever had liver problems (see section 2 "Do not take Naprylene");
- if you have "kidney failure or are undergoing hemodialysis (see section 2" Do not take Naprylene ");
- if you have a narrowing or blockage of the blood vessels that carry blood to the kidneys (bilateral renal artery stenosis or artery stenosis of the only functioning kidney);
- if you have kidney problems due to diabetes (diabetic nephropathy);
- if you have recently had a kidney transplant;
- if you have a collagen disease affecting your blood vessels (e.g. lupus erythematosus, rheumatoid arthritis), if you are being treated with medicines that suppress the immune response, if you are taking the medicines allopurinol or procainamide, or any combination of these conditions ;
- if you have ever had allergic reactions which may occur for example with swelling of the face, lips, mouth or throat (angioedema). Tell your doctor if you have had any airway surgery, especially if you have had this type of reaction in the past if you have blood disorders
- if you have heart or brain problems, especially:
- a "heart failure or a disease caused by reduced blood flow in the blood vessels of the heart (ischemic cardiovascular disease)
- a disease caused by impaired blood circulation in the brain (cerebrovascular disease)
- a narrowing of the valves of the heart (aortic stenosis), or a condition that causes thickening of the heart muscle (hypertrophic cardiomyopathy)
- if you have diabetes and are taking oral diabetes medicines or insulin
- 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 - eg 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 Naprylene".
- if you are to undergo treatment to reduce the effects of an 'allergy to bee or wasp stings (desensitization treatment) a desensitization process to reduce the effects of an' allergy.
- if you are to undergo treatment to remove cholesterol from your blood by means of machinery (low density lipoprotein apheresis - LDL)
- if you are due to have surgery or anesthesia (including at the dentist). Your doctor and / or anesthetist should be informed that you are being treated with Naprylene.
Tell your doctor during treatment with Naprylene:
- if you experience signs and symptoms of excessive blood pressure drop, for example feeling lightheaded or dizzy, particularly when taking the first dose of Naprilene and when increasing the dose. These episodes can occur in particular when standing up.
- if you have diabetes and notice hypoglycaemia.
- if you develop allergic reactions which may occur for example with swelling of the face, lips, mouth or throat. Black patients have a higher risk of developing these reactions.
- if you have a dry and persistent cough because it could be due to one of the active ingredients contained in Naprilene.
- if you have any signs of infection.
If you are a black patient it is important that you know that medicines like Naprylene may be less effective in lowering your blood pressure.
Children and adolescents
Naprylene should not be given to children and adolescents for indications other than the treatment of high blood pressure. Naprylene should not be given to infants and children with impaired renal function.
Interactions Which drugs or foods can modify the effect of Naprylene
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.
Tell your doctor if you are using or should use the following medicines:
- other medicines to lower blood pressure as they can further reduce blood pressure
- allopurinol (a gout medicine);
- procainamide (a medicine against heart rhythm disturbances)
- diuretics (medicines that increase the amount of water and salts excreted by the kidneys)
- medicines for depression (antidepressants)
- medicines used in severe psychiatric disorders (antipsychotics)
- medicines used for anesthesia
- medicines for diabetes eg. insulin and other oral medicines
- medicines which retain potassium or which may increase potassium levels: potassium supplements or salt substitutes containing potassium or medicines to lower blood pressure called potassium sparing products e.g. amiloride, triamterene, spironolactone
- lithium (medicine for mood disorders)
- non-steroidal anti-inflammatory drugs eg. l "acetylsalicylic acid
- medicines used to dissolve blood clots (thrombolytics)
- some cough and cold medicines and weight reduction medicines containing an agent called a "sympathomimetic"
- alcohol
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 Naprylene and" Warnings and precautions ")
Naprilene with food, drink and alcohol
Do not drink alcohol while taking Naprilene as a sharp drop in blood pressure can occur.
Food does not interfere with the absorption of Naprylene. Tablets can be taken before, during and after meals. Most people take Naprylene with a glass of water.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Naprilene is not recommended in early pregnancy, and must not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if used at that time. Tell your doctor if you think you are pregnant. or are planning to become pregnant because he will prescribe another medicine instead of Naprylene.
Feeding time
Tell your doctor if you are breastfeeding or about to start breastfeeding. Naprylene is not recommended while breastfeeding unless your doctor considers it strictly necessary. If you wish to breastfeed, your doctor may prescribe another treatment instead of Naprylene.
Driving and using machines
Naprilene may occasionally cause dizziness and tiredness, take special care if you have to drive or use machines.
Naprilene contains lactose (a milk sugar)
If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Naprylene: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Your doctor will work out the appropriate dose of Naprylene, based on your disease and the other medicines you are taking.
It is very important that you keep taking Naprilene for as long as your doctor tells you.
Do not take more tablets than your doctor has told you.
The tablets can be taken before, during and after meals. Most people take this medicine with a glass of water.
Use in adults
Treatment of hypertension
- The recommended starting dose is 5 to 20 mg per day in a single dose.
- The recommended dose in mild cases of high blood pressure is 5 to 10 mg.
- The usual dose for long-term therapy is 20 mg per day, once a day.
- The maximum dose for long-term therapy is 40 mg per day.
If you are being treated with a diuretic, your doctor will tell you to stop it 2-3 days before starting the treatment with Naprylene or will decide whether to start therapy with Naprylene with lower doses.
Treatment and prevention of symptomatic heart failure in patients with symptomatic left heart glass problems (asymptomatic left ventricular dysfunction)
- The recommended starting dose is 2.5 mg once daily. Your doctor will gradually increase the dose until the dose that is right for you is reached.
- The usual dose for long-term therapy is 20 mg per day, given in one or two doses.
- The maximum dose for long-term therapy is 40 mg per day in two separate administrations.
Tell your doctor if you feel lightheaded or dizzy when taking the first dose of Naprilene and when increasing the dose.
Use in children and adolescents
Your doctor will work out the appropriate dose of Naprylene, based on the child's illness and the other medicines you are taking.
Children and adolescents with a body weight between 20 and 50 kg
- The recommended starting dose is 2.5 mg per day, in a single dose. Your doctor may gradually increase the dose according to your child's needs.
- The maximum dose is 20 mg per day.
Children and adolescents with a body weight of 50 kg or more
- The recommended starting dose is 5 mg per day, in a single dose. The doctor may gradually increase the dose according to the needs of the child.
- The maximum dose is 40 mg per day.
Babies
Naprylene should not be used in infants.
Use in patients with kidney problems
Naprilene should not be used in children and adolescents with kidney problems. The interval between administration and doses of Naprylene should be reduced in patients with kidney problems.
If you forget to take Naprylene
If you forget your daily dose, take the next tablet at the usual time the following day.
Do not take a double dose to make up for a forgotten tablet.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
If you stop taking Naprilene
Do not stop taking this medicine unless 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 an overdose of Naprylene
In case of accidental ingestion of an overdose of Naprylene, notify your doctor immediately or go to the nearest hospital.
Ingestion of an excessive dose may cause lightheadedness or dizziness due to a sudden or excessive drop in blood pressure, excessive thirst, cough, confusion, shortness of breath, anxiety, decreased amount of urine, changes in the heartbeat .
Side Effects What are the side effects of Naprylene
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Naprylene and contact your doctor immediately if you develop:
- swelling of the face, lips, tongue and / or throat which may cause difficulty in breathing or swallowing
- swelling of the hands, feet or ankles
- urticaria
Very common (may affect more than 1 in 10 people)
- Blurred vision
- Dizziness
- Cough
- Nausea
- Muscle weakness
Common (may affect up to 1 in 10 people)
- Diarrhea, abdominal pain
- Alteration of taste
- Headache
- Tiredness
- Depression
- Fainting
- Increased levels of potassium in the blood
- Reduction in blood pressure
- Heart attack or cerebrovascular accident (TIA, "mini-stroke")
- Heart rhythm disturbances
- Chest pain (angina pectoris)
- Chest pain
- Difficulty in breathing
- Rashes on the skin, allergic reactions
- Swelling of the face, tongue, lips and extremities with difficulty in swallowing or breathing
- Increase in blood creatinine levels
Uncommon (may affect up to 1 in 100 people)
- Anemia
- Flushes
- Muscle cramps
- Whistling and ringing in the ears
- Low blood sugar levels (hypoglycemia)
- Nervousness, confusion, insomnia, sleepiness
- Changes in the sensation of the limbs or other parts of the body (paraesthesia)
- Dizziness
- Reduction in blood pressure when standing up (orthostatic hypotension)
- Palpitations
- Sore throat, voice change (hoarseness), runny nose, bronchospasm / asthma
- Impaired intestinal motility (ileus)
- Inflammation of the pancreas (pancreatitis), vomiting, difficult digestion, constipation, loss of appetite, stomach irritation, dry mouth, stomach injury (peptic ulcer), hives, itching, sweating
- Hair loss
- Impaired kidney function, including kidney failure, accumulation of substances in the blood that should be excreted via the kidneys (uremia), presence of proteins in the urine
- Reduction of sodium levels in the blood
- Impotence
- General feeling of not feeling well (malaise), fever
Rare (may affect up to 1 in 1,000 people)
- Reduction of white blood cells
- Reduction in the number of platelets in the blood
- Reduction in the number of all blood cells (pancytopenia)
- Bone marrow depression - a decrease in the number of blood cells caused by a malfunction in the system that produces blood cells
- Enlarged lymph nodes
- Autoimmune Diseases
- Decrease in blood cell levels (hematocrit) and hemoglobin levels
- Abnormality of dreams, sleep disturbances
- Poor blood circulation in the limbs (Raynaud's phenomenon)
- Lung problems, including pneumonia, allergy-induced alveolitis, cold
- Inflammation of the mucous membrane of the mouth, mouth ulcers and canker sores, inflammation of the tongue.
- Liver problems including liver failure, inflammation of the liver (hepatitis), yellowing of the skin, mucous membranes and eyes (jaundice), inflammation of the gallbladder and death of liver cells which can be potentially fatal
- Increase in liver enzyme levels (sign of liver damage)
- Increase in bilirubin levels
- Severe allergic reactions with high fever, appearance of red patches on the skin (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), peeling skin rash (erythroderma), appearance of small fluid-filled blisters on the skin (pemphigus)
- Reduction of urine elimination
- Breast enlargement in males
Very rare (may affect up to 1 in 10,000 people)
- Swelling from fluid accumulation of the intestine
Undesirable effects with frequency not known (frequency cannot be estimated from the available data)
- Set of symptoms including:
- fever
- inflammation of a particular type of membrane that lines some organs (serositis)
- inflammation of blood vessels
- pain in muscles, joints and bones
- Elevated ESR (visible in blood tests)
- increase in the number of particular types of white blood cells in the blood (eosinophilia, leukocytosis)
- skin reactions including skin reactions to sunlight
- An endocrine disorder consisting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has also been reported.
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.
This medicine does not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry date refers to the last day of that month.
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 Naprilene contains
Naprilene 5 mg tablets
- The active ingredient is enalapril maleate. Each tablet contains 5 mg of enalapril maleate.
- The other ingredients are sodium bicarbonate, lactose monohydrate, maize starch, pregelatinised starch, magnesium stearate.
Naprilene 20 mg tablets
- The active ingredient is enalapril maleate. Each tablet contains 20 mg of enalapril maleate.
- The other ingredients are sodium bicarbonate, lactose monohydrate, maize starch, pregelatinised starch, red iron oxide, yellow iron oxide, magnesium stearate.
Description of Naprilene's appearance and contents of the pack
Naprilene 5 mg tablets
Each pack contains a blister of 28 tablets of 5 mg.
Naprilene 20 mg tablets
Each pack contains a blister of 14 or 28 tablets of 20 mg.
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.
01.0 NAME OF THE MEDICINAL PRODUCT -
NAPRILENE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Naprilene 5 mg tablets
Each tablet contains: enalapril maleate 5.00 mg.
Excipient with known effect: one tablet contains lactose monohydrate 196.3 mg.
Naprilene 20 mg tablets
Each tablet contains: enalapril maleate 20.00 mg.
Excipient with known effect: one tablet contains 146.72 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Divisible tablets.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
• Treatment of hypertension.
• Treatment of symptomatic heart failure.
• Prevention of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 35%).
(see section 5.1 Pharmacodynamic properties)
04.2 Posology and method of administration -
Dosage
Food does not interfere with the absorption of Naprylene. Dosage should be individualized according to the patient profile (see section 4.4) and blood pressure response.
Hypertension
The starting dosage is 5 mg up to a maximum of 20 mg, depending on the degree of hypertension and the patient's condition (see below). Naprilene is given once a day. For mild hypertension the recommended starting dose is 5 to 10 mg. Patients with an intensely activated renin-angiotensin-aldosterone system (e.g., those with renovascular hypertension, salt and / or volume-depleted, heart failure or severe hypertension) may experience an excessive drop in blood pressure after the initial dose. An initial dose of 5 mg or less is recommended in such patients and the initiation of therapy should take place under close medical supervision.
Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril. A starting dose of 5 mg or less is recommended in such patients. If possible, diuretic therapy should be discontinued for 2-3 days prior to initiating therapy with Naprylene. Renal function and serum potassium should be monitored.
The usual maintenance dose is 20 mg / day. The maximum maintenance dose is 40 mg / day.
Heart failure / asymptomatic left ventricular dysfunction
In the management of symptomatic heart failure, Naprylene is used in conjunction with diuretics and, where appropriate, digitalis or beta-blockers (see sections 4.3, 4.4, 4.5 and 5.1). The starting dose of Naprilene in patients with symptomatic heart failure or asymptomtic left ventricular dysfunction is 2.5 mg, and should be administered under close medical observation to determine the initial effect on blood pressure. initiation of Naprilene therapy for heart failure, or after its effective treatment, the dose should be gradually increased, based on patient tolerability, up to the usual maintenance dose of 20 mg, administered as a single dose or divided into 2 doses This dose titration can be performed over a period of 2-4 weeks The maximum dose is 40 mg given in two divided doses.
Suggested Titration of the Dosage of Naprylene
in Patients with Heart Failure / Asymptomatic Left Ventricular Dysfunction
* Adequate precautions should be followed in patients receiving diuretics and those with impaired renal function (see section 4.4).
Blood pressure and renal function should be monitored closely both before and after the initiation of treatment with Naprylene (see section 4.4) as hypotension and (more rarely) subsequent renal failure have been reported. In patients treated with diuretics, the dosage should be reduced if possible before starting treatment with Naprylene. The onset of hypotension following the initial dose of Naprylene does not imply that hypotension will recur during chronic therapy with Naprylene and does not preclude continued use of the drug. serum potassium and renal function were also monitored.
Dosage in renal insufficiency
In general, the intervals between enalapril dosing should be prolonged and / or the dosage reduced.
* See section 4.4 - Patients on hemodialysis
Enalapril is dialysable. Dosage on days when patients are not on dialysis should be adjusted according to blood pressure response.
Elderly patients
Dosage should be in line with the renal function of the elderly patient (see section 4.4 - Impaired renal function).
Pediatric population
Experience with the use of Naprylene in clinical trials in pediatric hypertensive patients is limited (see sections 4.4, 5.1 and 5.2).
For patients who are able to swallow tablets, the dosage should be individualized according to the patient profile and blood pressure response. The recommended starting dose is 2.5 mg in patients 20 to
Naprylene is not recommended in neonates and pediatric patients with glomerular filtration rate
04.3 Contraindications -
• Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to other ACE inhibitors.
• History of angioedema associated with ACE inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Second and third trimester of pregnancy (see sections 4.4 and 4.6).
• The concomitant use of Naprylene with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR
04.4 Special warnings and appropriate precautions for use -
Symptomatic hypotension
Symptomatic hypotension has rarely been reported in patients with uncomplicated hypertension.In hypertensive patients on Naprylene therapy, hypotension is more likely to occur if the patient is volume depleted, eg those treated with diuretics, patients on a low-sodium diet, hemodialysis patients, patients with diarrhea or vomiting (see sections 4.5 and 4.8). Symptomatic hypotension has been observed in patients with heart failure, with or without associated renal failure. This is more 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 initiated under medical supervision and patients should be followed closely whenever the dose of naprilene and / or the diuretic is adjusted.
Similar considerations can be applied to patients with ischemic heart disease or with a "cerebrovascular disease, in which an excessive drop in blood pressure could lead to myocardial infarction or a cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, be given intravenous saline infusion. A transient hypotensive response is not a contraindication to further doses, which can usually be given without difficulty once blood pressure has re-increased after volume expansion.
Treatment with Naprylene can lead to a further lowering of blood pressure in some patients suffering from heart failure with normal or low blood pressure. This effect is expected and generally it is not necessary to suspend the treatment. If hypotension becomes symptomatic, a reduction in dosage and / or discontinuation of the diuretic and / or Naprylene is necessary.
Aortic or mitral valve stenosis / hypertrophic cardiomyopathy
Like all vasodilators, ACE inhibitors should be used with caution in patients with valvular and left ventricular outflow tract obstruction and should be avoided in case of cardiogenic shock and significant haemodynamic obstruction.
Impaired renal function
In case of impaired renal function (creatinine clearance
Renal failure has been reported in association with enalapril and has mainly occurred in patients with severe heart failure and underlying renal disease, including renal artery stenosis. If recognized early and adequately treated, associated renal failure to enalapril therapy is usually reversible.
Some hypertensive patients with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril was given concomitantly with a diuretic. Dosage reductions of enalapril and / or discontinuation of the diuretic may be required. This circumstance should involve the possibility of a stenosis of the basic renal artery (see section 4.4, renovascular hypertension).
Renovascular hypertension
In patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney treated with ACE inhibitors, there is an increased risk of hypotension and renal failure. Loss of renal function can occur even with only minor changes in serum creatinine. In these patients, therapy should be initiated under the same medical supervision with low doses, careful titration and monitoring of renal function.
Kidney transplant
There is no clinical experience regarding the administration of Naprylene in patients with recent kidney transplantation. Treatment with Naprylene is therefore not recommended.
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 taking ACE inhibitors and developing jaundice or marked elevations in liver enzymes should discontinue the ACE inhibitor and undergo appropriate medical follow-up.
Neutropenia / agranulocytosis
Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. In patients with normal and uncomplicated renal function, neutropenia occurs rarely. Enalapril should be used with extreme caution in patients with vascular collagen disease, immunosuppressive therapy, allopurinol or procainamide treatments or a combination of these complications, especially if there is pre-existing renal impairment. Some of these patients have impaired renal function. developed serious infections which in some cases have not responded to intensive antibiotic therapy.When enalapril is used in these patients, periodic monitoring of leukocytes is advised and patients should be instructed to report any signs of infection.
Hypersensitivity / angioneurotic edema
Angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including naprylene. This can occur at any time during treatment. In such cases, Naprilene should be promptly discontinued and appropriate monitoring instituted to ensure complete regression of symptoms before the patient is discharged. Even in cases where the edema is limited to the tongue alone, without respiratory distress, patients may require prolonged observation as treatment with antihistamines and cortisones may not be sufficient.
Very rarely, deaths have been reported due to angioedema associated with laryngeal edema or tongue edema. Airway obstruction is likely to occur in patients with involvement of the tongue, glottis or larynx, especially if they have a positive history of airway surgery.
If the tongue, glottis or larynx is affected, and an airway obstruction is likely to occur, appropriate therapy such as epinephrine 1: 1000 subcutaneously (0.3 to 0.5 ml) should be promptly administered and / or the maintenance of the airway patency must be ensured.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema than non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema during treatment with an ACE inhibitor (see also 4.3).
Anaphylactoid reactions during desensitization to hymenoptera
Rarely, patients on ACE inhibitor therapy have reported life-threatening anaphylactoid reactions during desensitization with hymenoptera venom. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization.
Anaphylactoid reactions in the course of LDL apheresis
Rarely, some patients on ACE inhibitor therapy who underwent low-density lipoprotein (LDL) apheresis with dextran sulfate have developed life-threatening anaphylactoid reactions. These reactions were avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis session.
Patients on hemodialysis
Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (eg AN 69®) and treated at the same time with an ACE inhibitor. For such patients, the use of a different type of dialysis membrane or a different class of antihypertensive agents should be considered.
Diabetic patients
In diabetic patients treated with oral antidiabetics or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5, Antidiabetic).
Cough
Cough has been reported with the use of ACE inhibitors. Cough is typically nonproductive, persistent and resolves upon discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery / Anesthesia
In patients undergoing major surgery or during anesthesia with agents that cause hypotension, enalapril blocks angiotensin II formation secondary to compensatory renin release. The hypotension that occurs in these cases can be corrected by volume expansion.
Hyperkalemia
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril. Patients at risk of developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those concomitantly using potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes; or patients taking other drugs associated with increases in serum potassium (eg, heparin). If concomitant use of the above drugs is deemed adequate, regular monitoring of serum potassium is recommended.
Lithium
The combination of lithium and enalapril is generally not recommended (see section 4.5).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that 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.
Lactose
Naprilene contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
Naprilene contains less than 200 mg of lactose per tablet.
Pediatric population
There is limited experience in terms of efficacy and safety in hypertensive children over 6 years of age, but there is no experience for the other indications. Limited pharmacokinetic data are available in children above 2 months of age (see sections 4.2, 5.2). Naprylene is not recommended in children for indications other than hypertension.
Naprylene is not recommended in neonates and pediatric patients with glomerular filtration rate
Pregnancy and breastfeeding
Pregnancy:
ACE inhibitor therapy should not be initiated during pregnancy.
For patients planning to become pregnant, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued therapy with an ACE inhibitor is considered essential. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started (see sections 4.3, 4.6).
The use of enalapril is not recommended during breastfeeding.
Ethnic differences
As with other angiotensin converting enzyme inhibitors, enalapril appears to be less effective in lowering blood pressure in blacks than in non-blacks, possibly due to a higher prevalence of a low-renin condition in the black hypertensive population. .
04.5 Interactions with other medicinal products and other forms of interaction -
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 and potassium supplements
ACE inhibitors reduce diuretic induced potassium loss. Potassium-sparing diuretics (e.g., spironolactone triamterene and amiloride), potassium supplements or potassium-containing salt substitutes may lead to significant increases in serum potassium. 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)
Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril (see section 4.4). The hypotensive effects may be reduced by discontinuing diuretics, by increasing blood volume or by taking salts or by initiating therapy with low dose enalapril.
Other antihypertensive agents
Concomitant use of these drugs may increase the hypotensive effect of enalapril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.
Lithium
Reversible increases in serum lithium concentrations and episodes of lithium toxicity have been reported during concomitant administration of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and increase the risk of lithium toxicity with ACE inhibitors. The use of enalapril with lithium is not recommended, but if the combination is necessary, it should be carefully monitor serum lithium levels (see section 4.4).
Tricyclic antidepressants / Antipsychotics / Anesthetics / Narcotics
The concomitant use of some anesthetic drugs, 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)
Co-administration with NSAIDs: When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (eg selective Cox 2 inhibitors, acetyl salicylic acid starting at 325 mg / day and non-selective NSAIDs), a " attenuation of the anti-hypertensive effect.
The concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function including possible acute renal failure and increased serum potassium levels especially in patients with pre-existing renal impairment. The combination should be administered with special caution. in the elderly. Patients should be adequately hydrated and monitoring of renal function should be considered at the initiation of concomitant therapy.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Antidiabetic
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic drugs (insulins, oral hypoglycemic drugs) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This effect appears to occur more likely during the first weeks of combined treatment and in patients with impaired renal function.
Alcohol
Alcohol increases the hypotensive effect of ACE inhibitors.
Acetylsalicylic acid, thrombolytics and beta-blockers
Enalapril can be safely administered concomitantly with acetylsalicylic acid (at cardiological dosages), thrombolytics and beta-blockers.
04.6 Pregnancy and breastfeeding -
Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 4.4).
Epidemiological evidence on 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.
For patients planning pregnancy, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued therapy with an ACE inhibitor is considered essential.
When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitors during the second and third trimesters is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in women (see sect. 5.3).
Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Neonates whose mothers have taken ACE inhibitors should be closely monitored for hypotension (see sections 4.3 4.4).
Feeding time
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 NAPRILENE 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 not enough clinical experience.
In older infants, if deemed necessary for the mother, NAPRILENE can be taken during breastfeeding, but in this case the infant must be followed for possible adverse effects.
04.7 Effects on ability to drive and use machines -
When driving or using machines it should be borne in mind that dizziness and fatigue have occasionally been reported.
04.8 Undesirable effects -
Side effects reported for enalapril include:
Very common (≥1 / 10); Common (≥1 / 100,
Disorders of the blood and lymphatic system
Uncommon: anemia (including aplastic and haemolytic anemia).
Rare: neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases.
Metabolism and nutrition disorders
Uncommon: hypoglycaemia (see section 4.4).
Psychiatric disorders and pathologies of the nervous system
Common: headache, depression.
Uncommon: mental confusion, somnolence, insomnia, nervousness, paraesthesia, dizziness.
Rare: changes in dream activity, sleep disturbances.
Eye disorders
Very common: blurred vision.
Cardiac and vascular disorders
Very common: dizziness.
Common: hypotension (including orthostatic hypotension), syncope, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients (see section 4.4), chest pain, dysrhythmias, angina pectoris, tachycardia.
Uncommon: orthostatic hypotension, palpitations.
Rare: Raynaud's phenomenon.
Respiratory, thoracic and mediastinal disorders
Very common: cough.
Common: dyspnoea.
Uncommon: rhinorrhea, laryngodynia and hoarseness, bronchospasm / asthma.
Rare: pulmonary infiltrates, rhinitis, allergic alveolitis / eosinophilic pneumonia.
Gastrointestinal disorders
Very common: nausea.
Common: diarrhea, abdominal pain, dysgeusia.
Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcer.
Rare: stomatitis / aphthous ulcers, glossitis.
Very rare: intestinal angioedema.
Hepatobiliary disorders
Rare: hepatic failure, hepatitis - hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice).
Skin and subcutaneous tissue disorders
Common: rash, hypersensitivity / angioneurotic edema: 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, antinuclear antibody positivity, elevated ESR, eosinophilia and leukocytosis. Rash, photosensitivity, or other dermatological manifestations may occur.
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: fatigue.
Uncommon: muscle cramps, flushing, tinnitus, malaise, fever.
Diagnostic tests
Common: hyperkalaemia, increases in serum creatinine.
Uncommon: increased uremia, hyponatremia.
Rare: increases in liver enzymes, increases in bilirubin.
Reporting of side effects
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 http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
Limited data are available on overdose in humans. The most prominent manifestations are marked hypotension, which begins 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 300 mg and 440 mg of enalapril, serum levels of enalaprilat were reported to be 100 and 200 times higher, respectively, than those typically observed after therapeutic doses.
The recommended treatment of overdose is intravenous infusion of saline. In case of hypotension the patient should be placed in the supine position. If available, treatment with angiotensin II and / or catecholamines may be considered. ingestion is recent, take measures to eliminate enalapril maleate (eg: emesis, gastric lavage, administration of adsorbents and sodium sulphate). Enalaprilat can be removed from the general circulation by hemodialysis (see section 4.4, Patients on hemodialysis). For therapy-refractory bradycardia, pacemaker treatment is indicated. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors, ATC code: C09A A02
Naprilene (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 peptidyldipeptidase 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, which leads to an increase in plasma renin activity (due to removal of negative feedback exerted on renin release) and a decrease in aldosterone secretion.
ACE is identical to kininase II. Therefore, Naprylene can also block the degradation of bradykinin, a potent vasodilator peptide. The role of this action on the therapeutic effects of Naprylene, however, has yet to be clarified.
The mechanism by which naprylene lowers blood pressure appears to be primarily the suppression of the renin-angiotensin-aldosterone system. On the other hand, Naprylene is also effective in patients with low-renin hypertension.
Administration of Naprylene to hypertensive patients leads to a reduction in blood pressure both in lying and standing position, without a significant increase in heart rate.
Symptomatic postural hypotension is infrequent. In some patients it may take several weeks of therapy to achieve an optimal reduction in blood pressure. Abrupt discontinuation of naprylene therapy has not been associated with a rapid rise in blood pressure.
Effective inhibition of converting enzyme activity usually begins 2 to 4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive activity is usually seen after one hour and maximal activity is achieved. within 4 - 6 hours of administration. The duration of the effect is dose-dependent. However, at the recommended dosage the haemodynamic and antihypertensive effects are shown to continue for at least 24 hours.
In haemodynamic studies performed in patients with essential hypertension, the reduction in blood pressure was associated with a reduction in peripheral arterial resistance with an increase in cardiac output and no or minimal change in heart rate. After administration of Naprylene there was an increase in renal blood flow; the glomerular filtration rate appeared unchanged. There were no signs of water or sodium retention. However, in patients with low glomerular filtration rate prior to treatment, this usually showed an increase.
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.
When a thiazide diuretic is co-administered with Naprylene, the effect on lowering blood pressure is at least additive. Naprylene may reduce or prevent the development of thiazide-induced hypokalaemia.
In patients with heart failure receiving digitalis and diuretics, treatment with enalapril tablets or injectable has been associated with decreases in peripheral resistance and blood pressure. Cardiac output increased while heart rate decreased (usually elevated in patients with heart failure). Pulmonary capillary wedge pressure also decreased. Exercise tolerance and heart failure severity, measured according to the New York Heart Association criteria, have improved. These actions persisted during chronic therapy.
In patients with mild or moderate heart failure, enalapril slowed the progression of heart dilation / enlargement and heart failure, as evidenced by the reduction in left ventricular systolic and end-diastolic volumes and improved ejection fraction.
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 was 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 was 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 simultaneously in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was 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.
A multicentre, randomized, double-blind, placebo-controlled study (SOLVD Prevention Study) examined a population with left ventricular dysfunction (LVEF
A multicentre, randomized, double-blind, placebo-controlled study (SOLVD Treatment Study) examined a population with congestive heart failure due to systolic dysfunction (ejection fraction myocardial infarction 23% (95% CI, 11 - 34%; 20% unstable pangina pectoris (95% CI, 9 - 29%; p
There is limited experience of use in pediatric hypertensive patients over 6 years of age. In a clinical study of 110 pediatric hypertensive patients aged 6 to 16 years with body weight ≥20 kg and a glomerular filtration rate> 30 ml / min / 1.73 m², for patients with body weight
05.2 "Pharmacokinetic properties -
Absorption
Oral enalapril is rapidly absorbed; peak serum concentrations of enalapril are achieved within one hour of administration. Based on the amount excreted in the urine, the rate of absorption of enalapril from Naprylene tablets is approximately 60%. Oral absorption of Naprylene is not affected by the presence of food in the gastrointestinal tract.
Following absorption, oral enalapril is rapidly and largely 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. The effective accumulation half-life of enalaprilat after multiple doses of enalapril is 11 hours. In individuals with normal renal function, steady-state serum enalaprilat concentrations were achieved after 4 days of treatment.
Distribution
Within a range of therapeutically relevant concentrations, enalaprilat binding to human plasma proteins does not exceed 60%.
Biotransformation
Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.
Elimination
Enalaprilat is eliminated essentially by the kidney. The main compounds in the urine are enalaprilat, which accounts for 40% of the dose, and unchanged enalapril (approximately 20%).
Impaired renal function
Enalapril and enaprilat exposure was increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml / min), the steady-stage AUC of enalaprilat was twice as high. compared to patients with normal renal function after administration of 5 mg once daily. The effective half-life of enalaprilat after multiple doses of enalapril maleate is prolonged at this stage of renal failure and the time to steady state is longer (see 4.2 Posology and method of administration). Enalaprilat can be removed from the general circulation by hemodialysis. Dialysis clearance is 62 mL / min.
Pediatric population
A multiple dose pharmacokinetic study was conducted in 40 male and female hypertensive pediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg / kg enalapril maleate. There were no major differences in the pharmacokinetics of enalaprilat in children compared with historical data in adults. The data indicate an increase in AUC (normalized to dose for body weight) with increasing age, however no increase in AUC is observed when the data are normalized by body surface area. At steady state, the mean effective accumulation half-life of enalaprilat was 14 hours.
Feeding time
After a single 20 mg oral dose in 5 postpartum women, the mean peak enalapril milk value was 1.7mcg / L (range 0.54 to 5.9mcg / L) 4-6 hours post dose. . The mean peak enalaprilat value was 1.7 mcg / L (range 1.2 to 2.3 mcgL); the peaks occurred at different times over the 24-hour period. Using the peak milk level data, the maximum estimated amount ingested by an exclusively breastfed infant would be approximately 0.16% of the maternal weight-adjusted dose. A woman who had taken an oral dose of 10 mg per day of enalapril for 11 months had peak enalapril milk levels of 2 mcg / L 4 hours post dose and peak enalaprilat levels of approximately 0.75 mcg / L. 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk over the 24 hour period was 1.44 mcg / L and 0.63 mcg / L, respectively. The levels of enalaprilat in milk were undetectable (
05.3 Preclinical safety data -
Non-clinical safety data highlight 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 effect on fertility and reproductive performance in the rat and is not teratogenic. In a study in which the drug was administered to female rats prior to mating until gestation, there was an increase in the rate of deaths in lactating offspring. The compound has been shown to cross the placental barrier and is excreted in breast milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to be foetotoxic (causing fetal harm and / or death) when administered during the second or third trimester.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Each 5 mg tablet contains the following ingredients: sodium bicarbonate, lactose monohydrate, maize starch, pregelatinised starch, magnesium stearate.
Each 20 mg tablet contains the following ingredients: sodium bicarbonate, lactose monohydrate, maize starch, pregelatinised starch, red iron oxide, yellow iron oxide, magnesium stearate.
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
In intact packaging: 30 months.
06.4 Special precautions for storage -
There are no special storage precautions.
06.5 Nature of the immediate packaging and contents of the package -
The tablets are fully protected by aluminum foil. To remove the tablet from its socket, press on the unprinted aluminum: the tablet will come out of its socket on the opposite side.
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A.
Viale Shakespeare, 47
00144 Rome
08.0 MARKETING AUTHORIZATION NUMBER -
NAPRILENE 5 mg tablets: 28 divisible tablets of 5 mg 025725045
NAPRILENE 20 mg tablets: 14 divisible tablets of 20 mg 025725021
NAPRILENE 20 mg tablets: 28 divisible tablets of 20 mg 025725072
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 21 June 1985
Date of most recent renewal: April 2009
10.0 DATE OF REVISION OF THE TEXT -
March 2016
