Active ingredients: Perindopril (perindopril arginine)
Procaptan 2.5 mg film-coated tablets
Procaptan package inserts are available for pack sizes:- Procaptan 2.5 mg film-coated tablets
- Procaptan 5 mg film-coated tablets
- Procaptan 10 mg film-coated tablets
Why is Procaptan used? What is it for?
Procaptan is an angiotensin converting enzyme (ACE) inhibitor.ACE inhibitors work by dilating blood vessels, making it easier for the heart to pump blood through them.
Procaptan is used:
- to treat high blood pressure (hypertension),
- to treat heart failure (a condition in which the heart is unable to pump enough blood to meet the body's needs),
- to reduce the risk of cardiac events, such as a heart attack, in patients with stable coronary artery disease (a condition involving a reduction or blockage of the blood supply to the heart) and who have already had a heart attack and / or surgery to improve blood supply to the heart by widening the vessels that supply it.
Contraindications When Procaptan should not be used
Do not take Procaptan
- if you are allergic to perindopril or any of the other ingredients of this medicine (listed in section 6), or to any other ACE inhibitors,
- if you have experienced symptoms such as breathlessness, swelling of the face, tongue or throat, intense itching or severe skin rashes related to previous ACE inhibitor treatment or if you or a family member have experienced these symptoms in any other circumstance (a condition called angioedema).
- if you are more than three months pregnant (Procaptan is also better avoided in early pregnancy - see "Pregnancy" section),
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.
Precautions for use What you need to know before you take Procaptan
Talk to your doctor, pharmacist or nurse before taking Procaptan if any of the following apply to you:
- have aortic stenosis (narrowing of the main artery originating from the heart) or hypertrophic cardiomyopathy (heart muscle disease) or renal artery stenosis (narrowing of the artery that supplies blood to the kidneys),
- suffer from other heart problems,
- have liver problems,
- have kidney problems or are on dialysis
- have a collagen vascular disease (connective tissue disease) such as systemic lupus erythematosus or scleroderma,
- have diabetes,
- follows a diet that restricts the use of salt or uses salt substitutes containing potassium,
- must undergo anesthesia and / or surgery,
- if you are to undergo LDL apheresis (the removal of cholesterol from the blood by means of a machine),
- must undergo desensitization treatment to reduce the effects of an "allergy to bee or wasp stings,"
- have recently had diarrhea, vomiting, or are dehydrated,
- she was diagnosed by her doctor as having "intolerance to certain sugars,
- 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 Procaptan".
- is of black origin as it may have a higher risk of angioedema and this drug may be less effective in lowering blood pressure than non-black patients.
Angioedema
Angioedema (a severe allergic reaction with swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing) has been reported in patients treated with ACE inhibitors, including Procaptan. This can occur at any time during treatment. If you develop such symptoms, you should stop taking Procaptan and consult a doctor immediately. See also section 4.
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Procaptan 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 "Pregnancy" section).
Children and adolescents
The use of perindopril is not recommended in children and adolescents up to 18 years of age.
Interactions Which drugs or foods can modify the effect of Procaptan
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
Treatment with Procaptan can be affected by taking other medicines. Your doctor may need to adjust your dose and / or take other precautions.
These include:
- other medicines for high blood pressure, including an angiotensin II receptor antagonist (AIIRA), aliskiren (see also information under "Do not take Procaptan" and "Warnings and precautions"), or diuretics (medicines that increase the urine produced by the kidneys),
- potassium-sparing drugs (e.g. triamterene, amiloride), potassium supplements or potassium-containing salt substitutes,
- potassium-sparing drugs used to treat heart failure: eplerenone and spironolactone at doses between 12.5 mg and 50 mg per day,
- lithium for the treatment of mania or depression,
- non-steroidal anti-inflammatory medicines (e.g. ibuprofen) for pain relief or high doses of aspirin,
- medicines for diabetes (such as insulin or metformin),
- baclofen (used to treat muscle stiffness in diseases such as multiple sclerosis),
- medicines for the treatment of mental disorders such as depression, anxiety, schizophrenia, etc. (e.g. tricyclic antidepressants, antipsychotics),
- immunosuppressants (medicines capable of reducing the body's defense mechanisms) used for the treatment of autoimmune diseases or following a surgical transplant (eg cyclosporine, tacrolimus),
- trimethoprim (to treat infections),
- estramustine (used in cancer therapy),
- allopurinol (for the treatment of gout),
- procainamide (to treat irregular heartbeat),
- vasodilators including nitrates (products that dilate blood vessels),
- heparin (medicine used to thin the blood),
- medicines used to treat hypotension, shock or asthma (eg ephedrine, noradrenaline or adrenaline),
- gold salts, especially with intravenous administration (used in the treatment of symptoms of rheumatoid arthritis).
Procaptan with food and drink
Procaptan is best taken before meals.
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 become pregnant, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Your doctor will usually advise you to stop taking Procaptan before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Procaptan.
Procaptan 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 after the third month of pregnancy.
Feeding time
Tell your doctor if you are breast-feeding or about to start breast-feeding.
Procaptan is not recommended for women who are breastfeeding and your doctor may choose another treatment if you wish to breastfeed, especially if your baby is newborn or was born prematurely.
Driving and using machines
Procaptan does not usually affect alertness but reactions such as dizziness or tiredness related to the decrease in blood pressure may occur in some patients. If you get these symptoms, your ability to drive or use machines may be reduced.
Procaptan contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, consult your doctor before taking this medicine.
Dosage and method of use How to use Procaptan: Dosage
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Take the tablet by swallowing it with a glass of water, preferably at the same time each day in the morning, before a meal. Your doctor will decide on the right dose for you.
The recommended dose is as follows:
Hypertension: the usual starting and maintenance dose is 5 mg once daily. After one month, this dose can be increased to 10 mg once daily if required. 10 mg per day is the maximum recommended dose for the treatment of high blood pressure.
If you are over 65, the usual starting dose is 2.5 mg once a day. After one month this dose can be increased to 5 mg once a day and if needed to 10 mg once a day.
Heart failure: the usual starting dose is 2.5 mg once a day. After two weeks, this dose can be increased to 5 mg once daily, which is the maximum recommended dose for heart failure.
Stable coronary artery disease: the usual starting dose is 5 mg once daily. After two weeks, this dose can be increased to 10 mg once daily, which is the maximum recommended dose for this indication.
If you are over 65, the usual starting dose is 2.5 mg once a day. After one week this dose can be increased to 5 mg once daily and after another week to 10 mg once daily.
Use in children and adolescents
Not recommended for use in children and adolescents.
If you forget to take Procaptan
It is important to take the medicine every day as regular treatment is more effective. However, if you forget to take a dose of Procaptan, just take the next dose as usual.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Procaptan
As treatment with Procaptan is usually for life, you will need to speak to your doctor before stopping taking this medicine.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.
Overdose What to do if you have taken too much Procaptan
If you have taken too many tablets, go to the nearest emergency department or consult your doctor immediately. The most likely effect of an overdose is a drop in blood pressure which can cause dizziness or fainting. In this case, lying down with your legs elevated may help.
Side Effects What are the side effects of Procaptan
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking the medicine and tell your doctor straight away if you experience any of the following side effects which can be serious:
- swelling of the face, lips, mouth, tongue or throat, difficulty in breathing (angioedema) (see section 2 "Warnings and precautions") (uncommon - may affect up to 1 in 100 people),
- severe dizziness or fainting due to low blood pressure (common - may affect up to 1 in 10 people),
- unusually fast or irregular heartbeat, chest pain (angina) or heart attack (very rare - may affect up to 1 in 10,000 people),
- weakness in the arms or legs or trouble speaking which could be a sign of a possible stroke (very rare - may affect up to 1 in 10,000 people),
- sudden wheezing, chest pain, shortness of breath or difficulty in breathing (bronchospasm) (uncommon - may affect up to 1 in 100 people),
- inflamed pancreas which can cause severe abdominal pain and back pain accompanied by feeling very unwell (very rare - may affect up to 1 in 10,000 people),
- yellowing of the skin or eyes (jaundice) which could be a sign of hepatitis (very rare - may affect up to 1 in 10,000 people),
- rash often starting with red, itchy patches on the face, arms or legs (erythema multiforme) (very rare - may affect up to 1 in 10,000 people).
Tell your doctor if you notice any of the following side effects:
Common (may affect up to 1 in 10 patients):
- headache,
- dizziness,
- vertigo,
- tingling,
- vision disturbances,
- tinnitus (sensation of noise in the ears),
- cough,
- shortness of breath (dyspnoea),
- gastro-intestinal disturbances (nausea, vomiting, abdominal pain, taste disturbances, dyspepsia or difficulty in digestion, diarrhea, constipation),
- allergic reactions (such as rash, itching),
- muscle cramps,
- feeling tired.
Uncommon (may affect up to 1 in 100 patients):
- mood changes,
- sleep disorders,
- dry mouth,
- intense itching or severe skin rashes,
- formation of clusters of blisters on the skin,
- kidney problems,
- impotence,
- sweating,
- excess eosinophils (a type of white blood cell),
- drowsiness,
- fainting,
- palpitations,
- tachycardia,
- vasculitis (inflammation of the blood vessels),
- photosensitization reactions (increased sensitivity of the skin to the sun),
- arthralgia (joint pain),
- myalgia (muscle pain),
- chest pain,
- malaise,
- peripheral edema,
- fever,
- risk of falls,
- alteration of laboratory parameters: high level of potassium in the blood reversible on discontinuation of treatment, low level of sodium, hypoglycemia (very low blood sugar levels) in diabetic patients, increase in plasma urea and increase in creatinine plasma.
Rare (may affect up to 1 in 1,000 patients):
- changes in laboratory parameters: increased level of liver enzymes, high level of serum bilirubin.
Very rare (may affect up to 1 in 10,000 patients):
- confusion,
- eosinophilic pneumonia (rare type of pneumonia),
- rhinitis (congested or runny nose),
- acute renal failure,
- change in blood values such as a lowering of the number of white blood cells and red blood cells, a lowering of hemoglobin, a lowering of the number of platelets.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist or nurse. 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 / responsible. 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 carton and bottle. The expiry date refers to the last day of the month.
Keep the container tightly closed to protect the product from moisture.
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 Procaptan 2.5 mg contains
- The active ingredient is perindopril arginine. One film-coated tablet contains 1.6975 mg of perindopril (corresponding to 2.5 mg of perindopril arginine).
- The other ingredients in the tablet core are: lactose monohydrate, magnesium stearate, maltodextrin, hydrophobic colloidal silica, sodium starch glycolate (type A), and in the film coating: glycerol, hypromellose, macrogol 6000, magnesium stearate, titanium dioxide.
What PROCAPTAN 2.5 mg looks like and contents of the pack
Procaptan 2.5 mg tablets are white, round, convex film-coated tablets.
The tablets are available in boxes of 5, 10, 14, 20, 30, 50, 60 (60 or 2 containers of 30), 90 (90 or 3 containers of 30) 100 (100 or 2 containers of 50), 120 ( 120 or 4 containers of 30) or 500 tablets (500 or 10 containers of 50).
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.
01.0 NAME OF THE MEDICINAL PRODUCT -
PROCAPTAN 2.5 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Perindopril arginine.
One film-coated tablet contains 1.6975 mg perindopril equivalent to 2.5 mg perindopril arginine.
Excipient with known effect: 36.29 mg of lactose monohydrate.
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM -
Film-coated tablets.
White, round, convex film-coated tablets.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Hypertension
Treatment of hypertension.
Heart failure
Treatment of congestive heart failure.
Stable coronary artery disease
Reduction of the risk of cardiac events in patients with a history of myocardial infarction and / or revascularisation.
04.2 Posology and method of administration -
Dosage
The posology should be individualized based on the patient profile (see section 4.4) and blood pressure response.
- Hypertension
Procaptan can be used alone or in combination with other classes of antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).
The recommended starting dose is 5 mg to be taken in a single daily administration in the morning.
In patients with a strongly activated renin-angiotensin-aldosterone system (particularly renovascular hypertension, salt and water depletion, heart failure or severe hypertension), an excessive decrease in blood pressure may occur following intake of the starting dose. In these patients it is recommended to initiate treatment with a dose of 2.5 mg and under close medical supervision.
After one month of treatment the dose can be increased up to 10 mg in a single daily administration.
Symptomatic hypotension may occur following initiation of Procaptan therapy and is more likely to occur in patients who are currently being treated with diuretics. Therefore, caution is recommended as these patients may be salt and water depleted.
Whenever possible, the diuretic should be discontinued 2 to 3 days before starting treatment with Procaptan (see section 4.4).
In hypertensive patients in whom the diuretic cannot be discontinued, treatment with Procaptan should be initiated with a dose of 2.5 mg. Renal function and serum potassium levels should be monitored.
Procaptan dosage should subsequently be adjusted according to the blood pressure response. Where required, diuretic treatment can be reintroduced.
In elderly patients, treatment should be initiated with a dose of 2.5 mg which, if necessary, can be progressively increased to 5 mg after one month of treatment and then to 10 mg based on renal function (see table below).
- Congestive heart failure
It is recommended that treatment with Procaptan, generally in combination with a non-potassium-sparing diuretic and / or digoxin and / or a beta-blocker, is instituted under close medical supervision with a recommended starting dose of 2.5 mg taken daily. morning.
This dose may be increased, if tolerated, to 5 mg in a single daily intake after 2 weeks. Dosage adjustments should be made based on the patient's individual clinical response.
In patients with severe heart failure and in other patients considered to be at high risk (patients with impaired renal function and electrolyte disturbance, patients treated concomitantly with diuretics and / or vasodilators), treatment should be initiated under careful medical supervision ( see section 4.4).
In patients at high risk of symptomatic hypotension, e.g. salt-depleted patients with or without hyponatremia, hypovolaemic patients or patients receiving high dose diuretics, correction of these factors should be made where possible before initiating therapy with Procaptan.
Blood pressure, renal function and plasma potassium concentrations should be carefully monitored both before and during treatment with Procaptan (see section 4.4).
- Stable coronary artery disease
Procaptan treatment should be started with a dose of 5 mg in a single "daily intake for 2 weeks, to be increased to 10 mg, in a single daily intake, depending on renal function and provided that the 5 mg dose is well tolerated.
Elderly patients should start treatment with 2.5 mg to be taken as a single daily dose for one week, to be increased to 5 mg once daily for the following week, before increasing the dose to 10 mg, in one week. "Once daily administration, based on renal function (see Table" Dosage Adjustment in "Renal Insufficiency"). Dosage should only be increased if the previous lower dose has been well tolerated.
Special populations:
Patients with renal insufficiency:
In patients with renal insufficiency the posology should be adjusted based on creatinine clearance as outlined in Table I below:
table I: dosage adjustment in renal insufficiency
* The dialysis clearance of perindoprilat is 70 ml / min. In hemodialysis patients, the dose should be administered after dialysis.
Patients with hepatic insufficiency
No dosage adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2).
Pediatric population:
The safety and efficacy of perindopril in children and adolescents below 18 years of age have not been established.
Currently available data are described in section 5.1 but no recommendation on a posology can be made.
Therefore, use is not recommended in children and adolescents.
Method of administration
For oral use.
It is recommended to take Procaptan in a single daily dose in the morning before a meal.
04.3 Contraindications -
- Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to any other ACE inhibitor;
- History of angioedema related to previous ACE inhibitor therapy;
- Hereditary or idiopathic angioedema;
- Second and third trimester of pregnancy (see sections 4.4 and 4.6);
- Concomitant use of Procaptan with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR
04.4 Special warnings and appropriate precautions for use -
Stable coronary artery disease
If an episode of unstable angina pectoris (major or not) occurs during the first month of treatment with perindopril, a careful risk / benefit assessment should be made before continuing treatment.
Hypotension
ACE inhibitors can cause a drop in blood pressure.
Symptomatic hypotension has rarely been observed in patients with uncomplicated hypertension, and this event is more likely to occur in hypovolaemic patients, for example following diuretic treatment, a salt-reduced diet, dialysis, diarrhea. o vomiting, or in patients with severe renin-dependent hypertension (see sections 4.5 and 4.8). Symptomatic hypotension has been observed in patients with congestive heart failure, with or without associated renal failure. This is more likely to occur in patients with more severe heart failure, as reflected by the administration of high doses of loop diuretics, hyponatremia or impaired renal function. Treatment initiation and adaptations. Dosages should be carefully monitored in patients at high risk of symptomatic hypotension (see sections 4.2 and 4.8).
Similar considerations should be made for patients with ischemic heart disease or cerebrovascular disorders in whom an excessive drop in blood pressure can lead to myocardial infarction or a cerebrovascular event.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of sodium chloride 9 mg / ml (0.9%) solution. The appearance of transient hypotension does not represent a contraindication to the administration of further doses, which generally can occur without difficulty after an increase in blood pressure due to volume expansion.
In some patients with congestive heart failure and normal or low blood pressure, a "further decrease in systemic blood pressure may occur following the administration of Procaptan. This effect is expected and generally does not constitute a reason for discontinuation of treatment." hypotension becomes symptomatic, dose reduction or discontinuation of Procaptan may be necessary.
Stenosis of the aortic and mitral valves / hypertrophic cardiomyopathy
Like other ACE inhibitors, Procaptan should be administered with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction such as aortic stenosis or hypertrophic cardiomyopathy.
Kidney failure
In cases of renal insufficiency (creatinine clearance
Regular monitoring of potassium and creatinine in these patients should be part of current medical practice (see section 4.8).
In patients with congestive heart failure, hypotension following initiation of ACE inhibitor therapy may result in further impairment of renal function. Generally reversible acute renal failure has been reported in this situation.
In some patients with bilateral renal artery stenosis or single kidney artery stenosis treated with ACE inhibitors, an increase in blood urea nitrogen and creatinine has been observed and is generally reversible upon stopping treatment. This is most likely to occur in patients with renal insufficiency. The simultaneous presence of renovascular hypertension increases the risk of severe hypotension and renal insufficiency.
In these patients, treatment should be initiated under strict medical supervision with reduced and carefully titrated dosages. Since treatment with diuretics may contribute to the above, their administration should be discontinued and renal function monitored during the first weeks of Procaptan therapy.
In some hypertensive patients with no apparent prior renovascular disease, a generally mild and transient increase in blood urea nitrogen and plasma creatinine has been observed, especially when Procaptan was administered concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment A dose reduction and / or discontinuation of the diuretic and / or Procaptan may be necessary.
Patients on hemodialysis
Anaphylactoid reactions have been reported in patients on hemodialysis with high-flux membranes and treated with ACE inhibitors. The use of a different type of dialysis membrane or a different class of antihypertensive agents should be considered for these patients.
Kidney transplant
There is no experience with the administration of Procaptan in patients undergoing a recent kidney transplant.
Hypersensitivity / angioedema
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx has been rarely reported in patients treated with ACE inhibitors, including Procaptan (see section 4.8). This can occur at any time during therapy. In such cases Procaptan should be discontinued immediately and the patient observed until complete resolution of symptoms. In the case of edema limited to the face and lips, the reaction resolved without the need for treatment, although antihistamines were useful in relieving symptoms.
Angioedema associated with laryngeal edema can be fatal. If there is involvement of the tongue, glottis or larynx that could cause airway obstruction, emergency therapy should be instituted quickly. adrenaline and / or the maintenance of a patent airway.
The patient should be closely monitored until the symptoms disappear completely and for a long time.
Patients with a history of angioedema unrelated to ACE inhibitor treatment may be at increased risk of angioedema when treated with an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no previous history of facial angioedema and C-1 esterase levels were normal. Angioedema was diagnosed with procedures that included abdominal CT scan or ultrasound or with surgery and symptoms resolved after the ACE inhibitor was discontinued. Intestinal angioedema should be included in the differential diagnosis of patients treated with ACE inhibitors who present with abdominal pain.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rarely, cases of life-threatening anaphylactoid reactions have been reported in patients treated with ACE inhibitors undergoing low density lipoprotein (LDL) apheresis with dextran sulfate. These reactions were avoided by temporarily withholding ACE inhibitor treatment prior to each apheresis.
Anaphylactic reactions during desensitization treatment
Cases of anaphylactoid reactions have been reported in patients treated with ACE inhibitors undergoing desensitizing treatment (e.g. hymenoptera venom). In the same patients, these reactions were prevented by temporarily withholding treatment with ACE inhibitors, but they reappeared upon accidental re-exposure of the patient.
Hepatic insufficiency
Rarely, ACE inhibitor treatment has been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is unknown. Patients treated with ACE inhibitors who experience jaundice or a significant increase in liver enzymes should discontinue the ACE inhibitor and be under close medical supervision (see section 4.8).
Neutropenia / agranulocytosis / thrombocytopenia / anemia
Cases of neutropenia / agranulocytosis / thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. In patients with normal renal function and in the absence of other complicating factors, neutropenia rarely occurs. Perindopril should be administered with extreme caution to patients with collagen disease, treated with immunosuppressive agents, with allopurinol or procainamide, or with a combination of these complicating factors, especially in the presence of prior renal impairment. Some of these patients developed severe infections, which in a few cases did not respond to intensive antibiotic therapy. If these patients are treated with perindopril, it is recommended that their white blood cell counts be checked periodically and asked to report any episodes of infection (e.g. sore throat, fever).
Ethnicity
ACE inhibitors can cause angioedema more frequently in black patients than in non-black patients.
Like other ACE inhibitors, perindopril may be less effective in lowering blood pressure in black patients than in non-ethnic patients, possibly due to a higher prevalence of low-renin concentrations in the black hypertensive population.
Cough
Cough has been reported following administration of ACE inhibitors. This characteristic cough is dry, persistent and resolves upon discontinuation of treatment. ACE inhibitor-induced cough should be considered when making the differential diagnosis of cough.
Surgery / anesthesia
In patients undergoing major surgery or undergoing anesthesia with agents that cause hypotension, Procaptan may block angiotensin II formation secondary to compensatory renin release. Treatment should be stopped one day before surgery. If hypotension occurs and is believed to be related to the above mechanism, it should be corrected by volume expansion.
Hyperkalemia
Increased serum potassium concentrations have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the onset of hyperkalaemia include renal failure, impaired renal function, age (> 70 years), diabetes mellitus, concomitant events, particularly dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics. (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; patients taking other drugs associated with an increase in serum potassium (e.g. heparin) are also at higher risk.
The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, can lead to a significant increase in serum potassium. Hyperkalaemia can cause serious and sometimes fatal arrhythmias. If concomitant use of the above mentioned agents is deemed appropriate, they should be used with caution and frequent monitoring of serum potassium should be performed (see section 4.5).
Diabetic patients
In diabetic patients treated with oral antidiabetic agents or insulin, blood glucose should be carefully monitored during the first month of therapy with an ACE inhibitor (see section 4.5).
Lithium
The combination of lithium and perindopril is generally not recommended (see section 4.5).
Potassium-sparing drugs, potassium supplements, or potassium-containing salt substitutes
The combination of perindopril and potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes 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.
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 and 4.6).
Excipients
Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction -
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).
Drugs that induce hyperkalemia
Some drugs or therapeutic classes may increase the onset of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressive agents such as cyclosporine or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.
Concomitant use contraindicated (see section 4.3)
Aliskiren:
In diabetic patients or patients with renal insufficiency, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and increased mortality.
Concomitant use not recommended (see section 4.4)
Aliskiren:
In patients who are not diabetic or do not have renal insufficiency, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and increased mortality.
Concomitant therapy with ACE inhibitor and angiotensin receptor blocker:
It has been reported in the literature that in patients with overt atherosclerotic disease, heart failure or in diabetics with end organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker is associated with a higher frequency of hypotension, syncope , hyperkalaemia and worsening of renal function (including acute renal failure) when compared with the use of a single agent active on the renin-angiotensin-aldosterone system. Dual blockade (eg by combining an ACE inhibitor with an antagonist angiotensin receptor II) should be limited to individually evaluated cases with close monitoring of renal function, potassium levels and blood pressure.
Estramustine:
Risk of increased side effects such as angioneurotic edema (angioedema).
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts :
Hyperkalaemia (life-threatening), especially together with renal insufficiency (additive hyperkalaemic effect. The combination of perindopril with the above mentioned drugs is not recommended (see section 4.4). If nevertheless concomitant use of the above mentioned drugs is deemed appropriate, they they should be used with caution and with frequent monitoring of potassium.
For the use of spironolactone in heart failure see below.
Lithium
Reversible increases in plasma concentrations and lithium toxicity have been observed following concomitant administration of lithium and ACE inhibitors.
Administration of perindopril during lithium treatment is not recommended, however careful monitoring of lithium plasma levels should be performed if deemed necessary (see section 4.4).
Concomitant use requiring special attention :
Antidiabetic agents (insulins, oral hypoglycemic agents):
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic drugs (insulins, oral hypoglycemic agents) may cause an increase in the hypoglycemic effect with the risk of hypoglycaemia. The occurrence of this phenomenon appears to be more likely during the first weeks of combined treatment. and in patients with renal insufficiency.
Baclofen:
Increased antihypertensive effect. Check blood pressure and, if necessary, adjust antihypertensive dosage.
Non-potassium-sparing diuretics:
Patients being treated with diuretics, and especially those with volume and / or salt depletion, may experience an excessive decrease in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be decreased by discontinuing the diuretic. expanding blood volume or increasing salt intake before starting perindopril therapy, at low and progressive doses.
In "arterial hypertension, in the event that previous therapy with a diuretic has caused volume and / or salt depletion, the diuretic must be discontinued before starting treatment with the ACE inhibitor, in which case a non-potassium-sparing diuretic may be reintroduced, or it is necessary to start treatment with the low dose ACE inhibitor and gradually increase it.
In congestive heart failure treated with diuretics, treatment with the ACE inhibitor should be started at a very low dose, possibly after reducing the dose of the associated non-potassium-sparing diuretic.
In all cases, renal function (creatinine levels) should be monitored during the first weeks of treatment with the ACE inhibitor.
Potassium-sparing diuretics (eplerenone, spironolactone):
With eplerenone or spironolactone at doses between 12.5 mg and 50 mg per day and with low doses of ACE inhibitors:
In the treatment of NYHA class II-IV heart failure with an ejection fraction
Before starting the combination, check for the absence of hyperkalaemia and renal insufficiency.
Close monitoring of kalaemia and creatinemia is recommended in the first month of treatment, initially once a week and then monthly.
Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin at doses ≥ 3g per day
When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (eg acetylsalicylic acid at the anti-inflammatory dosage, COX-2 inhibitors, non-selective NSAIDs), a decrease in the antihypertensive effect may occur.
Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure and an increase in serum potassium, especially in patients with poor pre-existing renal function.
The combination should be administered with caution, especially in the elderly.
Patients should be adequately hydrated and importance should be given to monitoring renal function after initiation of concomitant therapy and periodically during therapy.
Concomitant use requiring attention :
Antihypertensive agents and vasodilators
Concomitant administration of these drugs may increase the hypotensive effect of perindopril. Concomitant administration of nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin):
Increased risk of angioedema due to decreased dipeptidyl peptidase IV (DPP IV) activity due to gliptin in patients co-treated with an ACE inhibitor.
Tricyclic antidepressants / antipsychotics / anesthetics
Concomitant administration of ACE inhibitors and certain anesthetics, tricyclic antidepressants and antipsychotics may result in a further decrease in blood pressure (see section 4.4).
Sympathomimetics
Sympathomimetic agents may reduce the antihypertensive efficacy of ACE inhibitors.
Gold
Nitritoid reactions (symptoms include facial hyperaemia, nausea, vomiting and hypotension) have been reported rarely in patients receiving injectable gold salts (sodium aurothiomalate) and concomitant therapy with ACE inhibitors, including perindopril.
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 and 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. Unless continued therapy with an ACE inhibitor is considered essential, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used for patients planning pregnancy. 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 section 5.3 ).
Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Neonates whose mothers have taken ACE inhibitors should be closely monitored for hypotension (see sections 4.3 and 4.4).
Feeding time
As no data are available regarding the use of Procaptan during breastfeeding, Procaptan is not recommended and alternative treatments with a proven safety profile are preferred for use during breastfeeding, especially in the case of breastfeeding. breastfeeding with breast milk of newborns or premature babies.
Fertility
There was no effect on reproductive performance or fertility.
04.7 Effects on ability to drive and use machines -
Procaptan does not directly affect the ability to drive or use machines, however, individual reactions related to a drop in blood pressure may occur in some patients, especially at initiation of treatment or when combining with another antihypertensive drug.
As a result, the ability to drive or use machines may be impaired.
04.8 Undesirable effects -
to. Summary of the safety profile
The safety profile of perindopril is consistent with the safety profile of ACE inhibitors:
the most frequent adverse events reported in clinical trials and observed with perindopril are: dizziness, headache, paraesthesia, dizziness, visual disturbances, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhea, dysgeusia, dyspepsia, nausea, vomiting, pruritus , rash, muscle cramps and asthenia.
b. Summary table of adverse reactions
During clinical trials and / or during treatment The following undesirable effects have been reported with perindopril and classified under the following frequency:
very common (≥1 / 10); common (≥1 / 100,
* frequency calculated from clinical studies for adverse events reported following spontaneous reporting
Clinical Studies
During the randomization period of the EUROPA study, only serious adverse events were collected. Few patients reported serious adverse events: 16 of 6122 patients (0.3%) treated with perindopril and 12 of 6107 patients (0.2%) treated with placebo. In patients treated with perindopril, hypotension was observed in 6 patients, angioedema in 3 and sudden cardiac arrest in 1 patient. More patients discontinued treatment for cough, hypotension or other intolerance in the perindopril arm than in placebo-treated subjects, 6.0% (n = 366) versus 2.1% (n = 129) respectively.
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 -
Limited clinical data are available regarding overdose in humans.
Symptoms associated with ACE inhibitor overdose may include hypotension, circulatory shock, electrolyte disturbance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.
In the event of an overdose, treatment with an intravenous infusion of sodium chloride 9 mg / ml (0.9%) solution is recommended. If hypotension occurs, the patient should be positioned as in shock. Treatment with an intravenous infusion of angiotensin II and / or catecholamines may also be considered where available.
Perindopril can be removed from the general circulation by hemodialysis (see section 4.4). The use of a pacemaker is indicated in the case of therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: ACE inhibitors, not associated.
ATC code: C09AA04.
Mechanism of action
Perindopril is an angiotensin I to angiotensin II converting enzyme (ACE) inhibitor. The converting enzyme, or kinase, is an exopeptidase that allows the conversion of angiotensin I to angiotensin II, a vasoconstrictor agent, and the degradation of bradykinin, a vasodilating agent, into an inactive heptapeptide. of angiotensin II in plasma which results in an increase in plasma renin activity (by inhibition of the negative feedback mechanism of renin release) and a reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also determines an increase in the activity of the kallikrein-kinin system at the circulatory and local level (and therefore also an activation of prostaglandins). It is likely that this mechanism contributes to the reduction of blood pressure by ACE inhibitors and that it is partially responsible for some side effects (for example cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites do not show in vitro inhibition of ACE activity.
Clinical efficacy and safety
Hypertension
Perindopril is active in all stages of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressure has been observed in both supine and standing positions.
Perindopril reduces peripheral vascular resistance causing a reduction in blood pressure. As a result, there is an increase in peripheral blood flow, with no effect on heart rate.
Renal blood flow usually increases, while the glomerular filtration rate (GFR) generally remains unchanged.
The peak of the antihypertensive effect occurs 4-6 hours after single administration and the antihypertensive efficacy is maintained for at least 24 hours: the intermediate efficacy is between 87 and 100% of the peak effect.
The reduction in blood pressure occurs rapidly. In patients who respond to treatment, blood pressure normalization is reached after one month of treatment and is maintained without the occurrence of tachyphylaxis.
The stopping of the treatment is not accompanied by phenomena of rebound.
Perindopril reduces left ventricular hypertrophy.
It has been clinically demonstrated in humans that perindopril has vasodilating properties. It improves the elasticity of large arterial trunks and reduces the media / lumen ratio of small arteries.
The addition of a thiazide diuretic results in additive synergy. The combination of an ACE inhibitor and a thiazide also reduces the risk of hypokalaemia induced by treatment with a diuretic.
Heart failure
Perindopril reduces the work of the heart by reducing the pre-load and after-load.
Studies conducted in patients with heart failure have shown:
- a reduction in the filling pressure of the left and right ventricles,
- a decrease in total peripheral vascular resistance,
- an increase in cardiac output and an improvement in the cardiac index.
In comparative studies, the first administration of 2.5 mg perindopril arginine to patients with mild to moderate heart failure did not result in any significant reduction in blood pressure compared to placebo.
Patients with stable coronary artery disease
The EUROPA study is a multicentre, international, randomized, double-blind vs placebo clinical study, which lasted for 4 years.
Twelve thousand two hundred and eighteen (12,218) patients over 18 years of age were randomized to receive 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) (n = 6,110) or placebo (n = 6,108).
Enrolled patients had documented coronary artery disease with no evidence of clinical signs of heart failure.
Overall, 90% of patients had had a previous myocardial infarction and / or a previous coronary revascularization.
Most patients took study drug in addition to conventional therapy, which included antiplatelet, lipid-lowering, and beta-blocker drugs.
The main efficacy criterion was a combination of cardiovascular mortality, non-fatal myocardial infarction and / or cardiac arrest with successful resuscitation. Treatment with perindopril tert-butylamine 8 mg (equivalent to perindopril arginine 10 mg), once daily, demonstrated a significant absolute reduction of the primary end-point of 1.9% (20% risk reduction relative, 95% CI [9.4; 28.6] - p
In patients with a history of myocardial infarction and / or revascularisation, an absolute reduction in the primary endpoint was observed compared to placebo of 2.2% corresponding to a RRR of 22.4% (95% CI [12.0 ; 31.6] - p
Pediatric use:
The safety and efficacy of perindopril in children and adolescents below 18 years of age have not been established.
In an open, non-comparative clinical study in 62 hypertensive children aged 2 to 15 years with a glomerular filtration rate> 30 ml / min / 1.73 m², patients were given an average dose of perindopril equal to at 0.07 mg / kg. The dose was individualized based on the patient profile and blood pressure response, up to a maximum dose of 0.135 mg / kg / day.
59 patients completed the three-month study period, and 36 patients completed the study extension period, i.e. they were followed up for at least 24 months (mean study duration: 44 months).
In patients previously undergoing other antihypertensive treatments, systolic and diastolic blood pressure remained stable from "inclusion to" last evaluation, and decreased in naive patients.
More than 75% of the children had systolic and diastolic blood pressure below the 95th percentile at their last assessment.
The safety was found to be satisfactory and consistent with the already known safety profile of perindopril.
Clinical trial data on dual blockade of the renin-angiotensin-aldosterone system (RAAS):
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.
05.2 "Pharmacokinetic properties -
Absorption
After oral administration, the absorption of perindopril is rapid and the peak concentration is reached within one hour. The plasma half-life of perindopril is one hour.
Perindopril is a prodrug. 27% of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril produces 5 metabolites, all of which are inactive. The peak plasma concentration of perindoprilat is reached in 3-4 hours.
Since food intake reduces conversion to perindoprilat, and hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.
a linear correlation has been demonstrated between the dose of perindopril taken and the relative plasma concentration.
Distribution
The volume of distribution of free perindoprilat is approximately 0.2 l / kg.
The binding of perindoprilat to plasma proteins, mainly to the angiotensin converting enzyme, is 20%, but is concentration-dependent.
Elimination
Perindoprilat is eliminated in the urine and the final half-life of the free fraction is approximately 17 hours, with steady state being reached within 4 days.
Special populations
Elimination of perindoprilat is reduced in the elderly, as well as in patients with heart or renal insufficiency. In renal insufficiency, dosage adjustment is desirable according to the patient's degree of impairment (creatinine clearance).
The dialysis clearance of perindoprilat is 70ml / min.
In the cirrhotic patient, the kinetics of perindopril are modified: the hepatic clearance of the parent molecule is reduced by half. However, the amount of perindoprilat formed is not reduced and therefore no dosage adjustment is necessary (see sections 4.2 and 4.4).
05.3 Preclinical safety data -
In chronic toxicity studies with oral administration of the drug (conducted in rats and monkeys) the target organ is the kidney, with reversible damage.
No mutagenicity was observed in the studies performed in vitro or in vivo.
In reproductive toxicity studies (rats, mice, rabbits and monkeys) no signs of embryotoxicity or teratogenicity were shown. However, the class of angiotensin converting enzyme inhibitors has been shown to cause undesirable effects on late fetal development, leading to fetal death and birth defects in rodents and rabbits: kidney injury and increased peri- and postnatal mortality. Fertility was not impaired in rats, either male or female.
Carcinogenicity was not observed in long-term studies in rats and mice.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Nucleus
Lactose monohydrate
Magnesium stearate
Maltodextrin
Hydrophobic colloidal silica
Maize starch glycolate (type A)
Film coating
Glycerol
Hypromellose
Macrogol 6000
Magnesium stearate
Titanium dioxide
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
Keep the container tightly closed to protect it from moisture.
06.5 Nature of the immediate packaging and contents of the package -
White polypropylene tablet container equipped with a polyethylene flow reducer and with an opaque white cap containing a desiccant gel.
Box of 5, 10, 14, 20, 30, 50, 60 (60 or 2 containers of 30), 90 (90 or 3 containers of 30), 100 (100 or 2 containers of 50), 120 (120 or 4 containers of 30) or 500 tablets (500 or 10 containers of 50)
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
I.F.B. STRODER S.r.l.
Via Luca Passi, 85
00166 Rome
08.0 MARKETING AUTHORIZATION NUMBER -
AIC n ° 027469067 2.5 mg - 5 film-coated tablets
AIC n ° 027469079 2.5 mg - 10 film-coated tablets
AIC n ° 027469081 2.5 mg - 14 film-coated tablets
AIC n ° 027469093 2.5 mg - 20 film-coated tablets
AIC n ° 027469105 2.5 mg - 30 film-coated tablets
AIC n ° 027469117 2.5 mg - 50 film-coated tablets
AIC n ° 027469129 2.5 mg - 60 film-coated tablets
AIC n ° 027469131 2.5 mg - 90 film-coated tablets
AIC n ° 027469384 2.5 mg - 100 film-coated tablets
AIC n ° 027469143 2.5 mg - 120 film-coated tablets
AIC n ° 027469156 2.5 mg - 500 film-coated tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of most recent renewal: 3 April 2012
10.0 DATE OF REVISION OF THE TEXT -
07/2015
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