Active ingredients: Zofenopril (zofenopril calcium)
Zofenopril Mylan Generics 30 mg film-coated tablets
Why is Zofenopril used? What is it for?
Zofenopril Mylan Generics contains zofenopril, which belongs to a group of medicines known as ACE inhibitors (angiotensin converting enzyme inhibitors). Zofenopril works by widening your blood vessels.This helps lower your blood pressure, making it easier for your heart to pump blood around your body.
Zofenopril Mylan Generics can be used
- To treat high blood pressure - also called hypertension.
- After a heart attack (acute myocardial infarction) in people with or without signs and symptoms of heart failure and not undergoing treatment for the dissolution of blood clots (thrombolytic therapy).
Contraindications When Zofenopril should not be used
Do not take Zofenopril Mylan Generics:
- if you are allergic to zofenopril or any of the other ingredients of this medicine (listed in section 6)
- if you have had a previous allergic reaction to other ACE inhibitors, such as captopril or enalapril
- if you have ever had severe swelling of the face, tongue and throat (angioneurotic edema) associated with previous ACE inhibitor therapy, or if you have ever had these symptoms for no known reason (idiopathic / hereditary angioneurotic edema)
- if you are more than 3 months pregnant (it is better to avoid Zofenopril in early pregnancy - see pregnancy and breastfeeding section)
- if you suffer from narrowing of the blood vessels (arteries) of both kidneys (or only one kidney if you have only one)
- if you suffer from severe hepatic impairment
- 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 taking Zofenopril
Talk to your doctor or pharmacist before taking Zofenopril Mylan Generics if:
- have diabetes
- suffer from psoriasis
- have liver problems
- you have been told to limit the amount of salt in your diet, or have had severe diarrhea or nausea because zofenopril can cause your blood pressure to drop too low
- has low amounts of fluids and salts in the body due to a diuretic treatment
- have kidney problems, including narrowing of the blood vessels (arteries) in a kidney (renal artery stenosis) or have recently had a kidney transplant. Your doctor may find it necessary to reduce your dose.
- you are being treated to reduce the effects of an "allergy to insect bites, you are undergoing dialysis or a treatment to remove cholesterol from your blood through a machine (LDL cholesterol apheresis), as there is a risk of develop an allergic reaction to zofenopril
- take potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, as zofenopril can lead to significant increases in (potassium) salts in the blood
- suffer from low blood pressure as zofenopril can cause a further drop in blood pressure
- suffer from heart failure (a weakening of the heart muscle), have thickened heart walls resulting in obstruction of blood flow from the left side of the heart (hypertrophic cardiomyopathy) or narrowing of the heart valve (aortic and mitral valve stenosis)
- have reduced blood flow to the heart (angina) or brain, or have had a stroke or mini-stroke (also known as a transient ischemic attack (TIA)
- suffer from a collagen vascular disease, for example scleroderma, systemic lupus erythematosus (or lupus, an allergic condition that causes joint pain, rash and fever)
- have an abnormal increase in serum aldosterone levels (primary aldosteronism)
- are over 75 years of age; zofenopril should be used with caution
- he is a black patient. You may be at a higher risk for angioneurotic edema or this medicine may be less effective than non-black patients.
- 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 Zofenopril Mylan Generics".
- You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Zofenopril 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 and breast-feeding section).
During the treatment
- Tell your doctor, dentist or hospital staff that you are taking this medicine in case you need to undergo anesthesia (for a "surgery). This will help the anesthetist who will check your blood pressure and heart rate during the "intervention.
Interactions Which drugs or foods may change the effect of Zofenopril
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines:
- Medicines to increase the elimination of fluids in the urine (diuretics) such as spironolactone, triamterene or amiloride are not recommended as these can increase potassium levels in the blood. Other types of diuretics can also cause blood pressure to drop too much.
- potassium supplements, potassium-containing salt substitutes or a medicine called heparin (given by injection to thin the blood). These can increase potassium levels in the blood.
- lithium (for some types of mental illness), as zofenopril can increase the level of lithium in the blood
- medicines for severe mental illness (psychosis), barbiturates (usually used for epilepsy), anesthetics or narcotics (for example strong painkillers), because taking these medicines together with zofenopril can cause a drop in blood pressure
- other medicines to treat high blood pressure, including calcium channel blockers, beta blockers and α-blockers; when taken with zofenopril they can cause your blood pressure to drop too much
- cimetidine may increase the risk of a drop in blood pressure
- allopurinol (used to treat gout and kidney stones), procainamide (used to treat heart beat problems), corticosteroids and immunosuppressive medicines can increase the risk of low white blood cell counts
- cyclosporine (used to suppress the immune system), as there is a risk of kidney problems when taken with zofenopril
- non-steroidal anti-inflammatory drugs (NSAIDs), (for pain or inflammation) may reduce the effectiveness of zofenopril
- diabetes medicines taken by mouth, or insulin, as zofenopril can cause low blood sugar levels when taken with these medicines
- antacids (used to treat heartburn and stomach ulcers), as they reduce the effectiveness of zofenopril
- Medicines that affect the nervous system (known as sympathomimetics) may reduce the effectiveness of zofenopril. Your doctor will tell you if this applies to you.
- Glyceryl trinitrate and other nitrates (used to relieve chest pain (angina) or improve blood flow)
- cytostatic agents (used in cancer treatment)
- tricyclic antidepressants (normally used for depression)
- injections of gold salts to treat arthritis because they can lower blood pressure.
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 Zofenopril Mylan Generics" and "Warnings and precautions").
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). As a rule, your doctor will advise you to stop taking zofenopril before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Zofenopril Mylan Generics. Zofenopril 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 breastfeeding or about to start breastfeeding. Zofenopril is not recommended for women who are breastfeeding and your doctor may choose another treatment if you wish to breastfeed, especially if the baby is newborn or was born. premature.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
When driving vehicles or using machines it should be borne in mind that occasionally drowsiness, dizziness or tiredness may occur.
Dose, Method and Time of Administration How to use Zofenopril: Posology
Dosage
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The tablets should be swallowed whole, or divided in half, with a glass of water. They can be taken before, during or after meals.
Your doctor or pharmacist will tell you the frequency and duration of the treatment.
Adults with high blood pressure (hypertension)
The recommended starting dose is 15 mg per day (half tablet).
Your doctor may increase the dose until the dose is suitable for you. The usually effective dose is 30 mg per day. The maximum dose is 60 mg per day to be administered as a single dose or in 2 divided doses.
Adults with high blood pressure associated with hypovolaemia or salt depletion
Excessive lowering of blood pressure may occur with the first administration of zofenopril. If this applies to you, ask your doctor or pharmacist. If you are taking diuretics, you will need to stop taking them for two to three days before you start taking zofenopril. The recommended starting dose is 15 mg per day, but your doctor may start with 7.5 mg per day if they think it is more suitable for you. Not all recommended dosages can be administered with this product.
Adults with high blood pressure and liver problems
If you have mild to moderate liver problems, your doctor will adjust the amount of zofenopril you need to take based on your liver function response.
Adults with high blood pressure and kidney problems
If you have kidney problems, your doctor will adjust your zofenopril dosage according to your kidney function response.
Senior citizens
The dose depends on your kidney function. Your doctor will prescribe the appropriate strength of Zofenopril Mylan Generics.
Adults after a heart attack
It is recommended that you start taking this medicine within 24 hours of your heart attack and continue therapy for at least 6 weeks.
The recommended starting dose is 7.5 mg twice daily (every 12 hours). On the third day, the dose can be increased to 15 mg twice a day (every 12 hours). From the fifth day, the dose can be increased to 30 mg twice a day (every 12 hours). Not all recommended dosages can be administered with this product.
Use in children and adolescents
Zofenopril Mylan Generics is not recommended for children.
If you forget to take Zofenopril Mylan Generics
If you miss a dose, don't worry. Take your next dose at the time of day you usually take it. Do not take a double dose to make up for a forgotten dose.
If you stop taking Zofenopril Mylan Generics
If you stop taking Zofenopril Mylan Generics you may have side effects. If you want to stop using this medicine consult your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Zofenopril
Contact your doctor immediately or go to the emergency room of the nearest hospital. Take the box and any remaining tablets with you. Signs and symptoms of an overdose include: sudden drop in blood pressure, shock, drowsiness, abnormal slow heart rate, changes in electrolytes and kidney failure.
Side Effects What are the side effects of Zofenopril
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any of the following side effects, contact your doctor immediately or go to the emergency room at the nearest hospital. It is important to inform your healthcare professional that you are taking this medicine:
Rare (may affect up to 1 in 1,000 people)
- Serious allergic reaction which causes swelling of the face, tongue or throat, difficulty in swallowing, hives and difficulty in breathing
Very rare (may affect up to 1 in 10,000 people)
- Swelling of the intestines, which can cause stomach pain which can become severe Not known (frequency cannot be estimated from the available data)
- Severe skin reaction, which can cause blistering of the skin, mouth, eyes and genitals or a more severe form leading to extensive skin damage (separation of the upper layer of the skin from the lower one) and flu symptoms (fever, muscle pain, joint pain and changes in blood cells, which may show up in blood tests)
- Severe reduction in blood cells which can lead to weakness, bruising or bleeding or make you more prone to infections. This can be seen in blood tests.
- Fever associated with severely compromised general health or fever with symptoms of local infection such as sore throat / mouth ulcers or difficulty urinating (agranulocytosis)
- Irregular heart rhythm or chest pain, particularly at rest, which may be a sign of a reduced blood supply to the heart (angina pectoris)
- Heart attack. You may feel sweaty, wheezy, or have severe chest pain and pain radiating to your jaw and arms. This can happen if the blood pressure is very low.
- Inflammation of the pancreas causing severe pain in the abdomen and back
- Lack of bowel movements, which can result in a swollen belly, stomach pain, feeling sick / vomiting, and no passing of gas and stool
- Stroke, which can be caused by bleeding from the brain. You may have speech disturbances, sudden weakness or numbness on one side of the face or body, vision problems or a sudden severe headache.
Other side effects that have been seen with this medicine:
Common (may affect up to 1 in 10 people)
- Unusual feeling of tiredness
- Feeling or being unwell
- Dizziness
- Headache
- Cough. This medicine can cause a persistent dry (mucus-free) cough. If this happens to you, contact your doctor as you may need an alternative medicine.
Uncommon (may affect up to 1 in 100 people)
- Rash
- Weakness, muscle cramps The following side effects have been seen with other ACE inhibitors and therefore may occur while you are taking this medicine.
Rare (may affect up to 1 in 1,000 people)
- Muscular pain
- Shortness of breath
- Swollen and inflamed sinuses causing pain, high temperature and sensitivity
- Runny and itchy nose
- Swollen and painful tongue
- Inflammation of the airways. You may have a fever, cough, and produce colored mucus
- Abdominal pain
- Diarrhea
- Constipation
- Dry mouth
- Depression
- Mood changes
- Sleep disorders
- Impotence
- Confusion
- Ringing in the ears
- Increased sweating
- Flushes
- Difficulty urinating
- Visual disturbances.
Very rare (may affect up to 1 in 10,000 people)
- Chest pain
- Excess of fluids in the body
- Low blood sugar levels.
Not known (frequency cannot be estimated from the available data)
- Reduction in red blood cells which can make the skin pale or yellow and cause weakness or breathlessness. This occurs more frequently in people with an "other medical condition (known as glucose-6-phosphate dehydrogenase deficiency).
- Yellowing of the skin or whites of the eyes, which may be caused by blockage of the bile duct or inflammation of the liver. You may also experience dark urine, pale stools or fever.
- Severe decrease in blood pressure, which can cause dizziness, feeling faint, impaired vision or, rarely, fainting or loss of consciousness. This happens more often when you first take the medicine or when the dose is increased.
- Severe kidney problems. You may experience lower back pain, small or no urine, or urine that is cloudy or bloody.
- Tingling sensations as from pins and needles
- Problems with balance
- Taste disturbances
- Rapid heartbeat, or awareness of beating in the chest (palpitations)
- Itchy skin, hives, a psoriasis-like skin reaction or a "rash with raised, red spots similar to measles
- Hair loss
- Changes in blood cell counts and liver function tests, which may show up in blood tests.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister, carton, label or bottle after EXP. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions. Zofenopril Mylan Generics supplied in bottles should not be used more than 30 days after first opening the bottle.
Do not use this medicine if you notice that the tablets are discolored.
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 Zofenopril Mylan Generics contains
The active ingredient is zofenopril calcium. Each tablet contains 30 mg of zofenopril calcium.
The other ingredients are microcrystalline cellulose, pregelatinised starch (maize), magnesium stearate, hypromellose (E464), titanium dioxide (E171), macrogol 400 and polysorbate 80.
What Zofenopril Mylan Generics looks like and contents of the pack
Zofenopril Mylan Generics 30 mg film-coated tablets are white, film-coated, capsule-shaped, 5.5 mm x 10.0 mm in size, with "ZP / 1" on one side and "M" on the side opposite to.
The tablet can be divided into equal halves.
Zofenopril Mylan Generics is available in plastic bottles containing 500 tablets (hospital pack) or blister packs of 7, 12, 14, 28, 30, 56, 90 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
ZOFENOPRIL MYLAN GENERICS 30 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each tablet contains 30 mg of zofenopril calcium, equivalent to 28.7 mg of zofenopril.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Film-coated tablet.
White, capsule-shaped, film-coated, biconvex tablets of 5.5 mm x 10.0 mm with "ZP / 1" on one side and "M" on the other side.
The tablet can be divided into equal halves.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Hypertension
Zofenopril is indicated for the treatment of mild to moderate essential hypertension.
Acute myocardial infarction
Zofenopril is indicated for the treatment, initiated within the first 24 hours, of patients with acute myocardial infarction, with or without signs and symptoms of heart failure, who are haemodynamically stable, who have not received thrombolytic therapy.
04.2 Posology and method of administration -
NOTE! Please be aware that not all recommended dosages can be administered with this product, as the lowest achievable dose with this product is 15 mg (half tablet).
Dosage
Zofenopril can be taken before, during or after meals. Dosage is adjusted based on the patient's therapeutic response.
Hypertension
The need for dose adjustment should be determined by blood pressure measurement immediately prior to a new administration.
The dosage should be increased at four-week intervals.
Patients who are not hypovolaemic and without salt depletion
Treatment should start with 15 mg once daily, increasing the dosage until optimal blood pressure control is achieved.
The usually effective dose is 30 mg once a day.
The maximum dose is 60 mg per day to be administered as a single dose or in two divided doses.
In case of inadequate therapeutic response, other antihypertensive drugs, such as diuretics, may be added (see sections 4.3, 4.4, 4.5 and 5.1).
Patients with suspected hypovolaemia or salt depletion
With the first dose, episodes of hypotension may occur in high-risk patients (see section 4.4). Initiation of ACE inhibitor therapy requires correction of hypovolaemia and / or salt depletion, discontinuation of pre-existing diuretic therapy for two to three days prior to ACE inhibition and an initial dosage of 15 mg per day. if this is not possible, the starting dose should be 7.5 mg per day.
Patients at high risk of severe acute hypotension should be carefully monitored, preferably in hospital, after administration of the first dose, for as long as it takes to achieve maximum therapeutic effect, and each time the therapeutic dose of ACE inhibitors is increased. and / or diuretics. The foregoing should also apply to patients with angina pectoris or cerebrovascular disease for whom excessive hypotension can cause myocardial infarction or cerebrovascular accident.
Posology in patients with renal impairment and patients undergoing dialysis
In hypertensive patients with mild renal impairment (creatinine clearance> 45 ml / min) zofenopril therapy at the same dose and once-daily regimen may be used as for patients with normal renal function. Patients with moderate to severe renal impairment (creatinine clearance
The starting dose and dosing regimen of zofenopril for hypertensive patients undergoing dialysis should be one quarter of the dose indicated in patients with normal renal function.
Recent clinical observations have shown a high incidence of anaphylactic-like reactions in patients treated with ACE inhibitors during hemodialysis performed with high-flux membranes or during LDL apheresis (see section 4.4).
Posology in elderly patients
No dosage adjustments are required in elderly patients with normal creatinine clearance.
In elderly patients with reduced creatinine clearance (less than 45 ml / min), half the daily dose is recommended.
Creatinine clearance can be calculated from serum creatinine using the following formula:
This formula provides creatinine clearance in male subjects. In women, the value obtained must be multiplied by 0.85.
Posology in patients with hepatic impairment
In hypertensive patients with mild to moderate hepatic impairment, the starting dose of zofenopril is half that expected in patients with normal hepatic function.
Zofenopril is contraindicated in hypertensive patients with severe hepatic impairment.
Acute myocardial infarction
Treatment with zofenopril should be started within 24 hours after the onset of acute myocardial infarction symptoms and continued for six weeks.
The dosage is as follows:
1st and 2nd day: 7.5 mg every 12 hours
3rd and 4th day: 15 mg every 12 hours
from the 5th day onwards: 30 mg every 12 hours.
In case of low systolic blood pressure (≤120 mmHg) at the start of treatment or during the first three days following myocardial infarction, the daily dose should not be increased.
In case of hypotension (≤100 mmHg) the treatment can be continued with the last tolerated dose. In case of severe hypotension (values lower than 90 mmHg detected in two consecutive measurements at least one hour from each other ), treatment with zofenopril should be discontinued.
After 6 weeks of treatment, patients should be re-evaluated and treatment discontinued if there are no more signs of left ventricular dysfunction or heart failure. In the presence of such symptoms, treatment can be continued over the long term.
Patients should also be given standard therapies, such as nitrates, aspirin, or beta-blockers, as appropriate.
Dosage in elderly patients
In patients with myocardial infarction over the age of 75, zofenopril should be used with caution.
Posology in patients with renal impairment and dialysis patients
The efficacy and safety of zofenopril have not been established in myocardial infarction patients with renal impairment or undergoing dialysis. Therefore, zofenopril should not be used in such patients.
Posology in patients with hepatic impairment
The efficacy and safety of zofenopril have not been established in myocardial infarction patients with hepatic impairment. Therefore, it should not be used in such patients.
All indications
Pediatric population
The efficacy and safety of zofenopril in children and adolescents under the age of 18. Therefore, it should not be used in children.
Method of administration
For oral use.
04.3 Contraindications -
Hypersensitivity to the active substance, to any other ACE inhibitor or to any of the excipients listed in section 6.1.
History of angioneurotic edema associated with previous ACE inhibitor therapy.
Hereditary / idiopathic angioneurotic edema.
Severe hepatic insufficiency.
Second and third trimester of pregnancy (see sections 4.4 and 4.6).
Bilateral or unilateral renal artery stenosis in patients with single kidney.
The concomitant use of zofenopril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR
04.4 Special warnings and appropriate precautions for use -
Hypotension:
Like other ACE inhibitors, zofenopril may cause excessive lowering of blood pressure, especially after administration of the first dose, although cases of symptomatic hypotension in uncomplicated hypertensive patients are rare.
It is more likely to occur in patients with fluid and electrolyte depletion due to treatment with diuretics, a low-sodium diet, dialysis, diarrhea or vomiting or with severe renin-dependent hypertension (see sections 4.5 and 4.8).
In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is more likely to occur in patients with severe heart failure treated with high doses of loop diuretics or in patients with hyponatremia or with impaired renal function. In patients most at risk of symptomatic hypotension, treatment should begin under close medical supervision. , preferably in the hospital, with low doses and careful adjustment of the dosage.
If possible, diuretics should be temporarily discontinued when initiating therapy with zofenopril. These considerations also apply to those patients with angina pectoris or cerebrovascular disease in whom excessive hypotension could cause a myocardial infarction or cerebrovascular accident. .
If hypotension occurs, place the patient in the supine position. If necessary, restore volume by intravenous infusion of normal saline.
The onset of hypotension, after the initial dose, does not exclude the possibility of a subsequent accurate adjustment of the drug dosage.
In some heart failure patients with normal or low blood pressure, further lowering of systemic blood pressure may occur with zofenopril. This effect is expected and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, a dose reduction or discontinuation of treatment with zofenopril may be necessary.
Pregnancy:
ACE inhibitors should not be initiated during pregnancy. Alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used for patients planning to become pregnant, unless considered essential. the continuation of therapy with ACE inhibitors. 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).
Hypotension in acute myocardial infarction:
Treatment with zofenopril should not be initiated in patients with acute myocardial infarction if there is a risk of further severe haemodynamic depression following treatment with a vasodilator. These are patients with a cardiogenic shock systolic pressure. In patients with acute myocardial infarction, treatment with zofenopril can cause severe hypotension. If hypotension persists (systolic pressure
Myocardial infarction in patients with impaired hepatic function:
The efficacy and safety of zofenopril have not been established in myocardial infarction patients with hepatic impairment. Therefore it should not be used in these patients.
Senior citizens:
In patients with myocardial infarction aged ≥75 years zofenopril should be used with caution.
Patients with renovascular hypertension:
In patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or single kidney afferent artery stenosis, the risk of severe hypotension and renal failure increases when treated with ACE inhibitors. A contributing cause may be treatment with diuretics. Loss of renal function may occur even with only slight changes in serum creatinine even in patients with unilateral renal artery stenosis. If deemed absolutely necessary, treatment with zofenopril should be initiated in the hospital, under close medical supervision, at low doses. and with careful dosage adjustment Temporarily discontinue treatment with diuretics upon initiation of zofenopril therapy and closely monitor renal function during the first weeks of therapy.
Patients with renal insufficiency:
Zofenopril should be used with caution in patients with renal insufficiency as they require dose reduction. Close monitoring of renal function should be performed during therapy, as appropriate. Renal failure has been reported in association with the administration of ACE inhibitors mainly in patients with severe heart failure or with renal disease, including renal artery stenosis. In some patients with no apparent pre-existing renal disease, elevations in urea have been observed blood and serum creatinine concentrations, particularly when undergoing concomitant diuretic treatment. In these cases, a reduction in the dose of ACE inhibitors and / or interruption of the administration of diuretics may be necessary. Close monitoring of renal function is recommended during the first weeks of therapy.
The efficacy and safety of zofenopril in myocardial infarction patients with renal impairment has not been established. Therefore, in the presence of renal impairment (serum creatinine ≥2.1 mg / dl and proteinuria 500 mg / day) and myocardial infarction, zofenopril it must not be used.
Patients undergoing dialysis:
Dialysis patients treated with ACE inhibitors, using high-flux polyacrylonitrile membranes (eg AN 69), may experience anaphylactoid reactions such as: facial edema, redness, hypotension and dyspnoea within minutes of starting hemodialysis. It is recommended to use alternative membranes or to use another type of antihypertensive medicine.
The efficacy and safety of zofenopril in myocardial infarction patients undergoing hemodialysis has not been established. Therefore, it should not be used in these patients.
Patients undergoing LDL apheresis:
Anaphylactoid reactions similar to those seen in patients undergoing hemodialysis with high flux membranes may occur in patients treated with an ACE inhibitor undergoing LDL apheresis with dextran sulfate (see above). It is recommended that a medicine belonging to another class of antihypertensive agents be used in these patients.
Anaphylactic reactions during desensitization or in case of insect bites:
Rarely, patients receiving ACE inhibitors have reported life-threatening anaphylactoid reactions during desensitization therapy (eg hymenoptera venom) or after insect bites. In the same patients, these reactions were avoided by temporarily withholding ACE inhibitor therapy but reappeared after inadvertent re-administration of the drug. Therefore, caution is recommended in patients treated with ACE inhibitors undergoing such desensitization procedures.
Kidney transplant:
There is no experience with the administration of zofenopril in patients who have recently undergone kidney transplantation.
Primary aldosteronism:
Patients with primary aldosteronism generally do not respond to antihypertensive medicinal products which act through "inhibition of the renin-angiotensin system. The use of this product is therefore not recommended."
Angioedema:
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx has occurred in patients treated with ACE inhibitors, especially during the first weeks of treatment. In rare cases, however, the onset of severe angioedema may occur after long-term treatment with an angiotensin converting enzyme inhibitor. other class.
Angioedema affecting the tongue, glottis or larynx can be fatal. Immediately implement emergency therapy including, but not necessarily limited to, immediate subcutaneous administration of a 1: 1000 (0.3) adrenaline solution. -0.5 ml) or slow intravenous administration of adrenaline 1 mg / ml (to be diluted as indicated), with close monitoring of electrocardiography and blood pressure. The patient must be hospitalized and placed under observation for at least 12-24 hours and discharged only after complete remission of the symptoms presented.
Even in cases where edema is confined to the tongue alone, without respiratory distress, patients may require observation as treatment with antihistamines and corticosteroids may not be sufficient.
Black patients receiving angiotensin converting enzyme 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 section 4.3).
Cough:
A dry, non-productive cough may occur during treatment with zofenopril which disappears when zofenopril is discontinued.
ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Hepatic insufficiency:
Rarely, ACE inhibitors have 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 not known. Patients receiving ACE inhibitors who develop jaundice or a significant increase in liver enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Hyperkalemia:
Hyperkalaemia can occur during treatment with an ACE inhibitor.
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; o patients taking other medicines associated with increases in serum potassium (e.g. heparin). If concomitant use of the above medicinal products is deemed appropriate, frequent monitoring of serum potassium is recommended (see section 4.5).
Surgery / anesthesia:
In patients undergoing major surgery or during anesthesia, the use of ACE inhibitors can cause hypotension or even hypotensive shock as these drugs can block angiotensin II formation secondary to compensatory renin release.
If it is not possible to stop treatment with ACE inhibitors, carefully monitor plasma and intravascular volumes.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy:
ACE inhibitors should be used with extreme caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction.
Neutropenia / agranulocytosis:
Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. The risk of neutropenia appears to be type- and dose-related and also dependent on the patient's clinical status. It is rarely observed in uncomplicated patients but can occur in patients with any degree of renal impairment especially in association with vascular collagenopathies eg. systemic lupus erythematosus, scleroderma and immunosuppressive drug therapy, treatment with allopurinol or procainamide or a combination of these complications. Some of these patients developed serious infections which in some cases did not respond to intensive antibiotic therapy.
If zofenopril is used in these patients, monitoring of white blood cell counts and differential blood counts is recommended prior to initiation of therapy, every 2 weeks during the first three months of treatment with zofenopril and periodically thereafter. Treatment All patients should be instructed to report any signs of infection (eg sore throat, fever), in which case a WBC differential check should be performed.
Zofenopril and other concomitant treatments (see section 4.5) should be discontinued in case of known or suspected neutropenia (neutrophils less than 1000 / mm³).
It is reversible after discontinuation of the ACE inhibitor.
Psoriasis:
ACE inhibitors should be used with caution in patients with psoriasis.
Proteinuria:
Proteinuria may occur especially in patients with pre-existing renal impairment or following relatively high doses of ACE inhibitors. Patients with previous kidney disease should have a urinary protein check (dip stick on first morning urine) before treatment and periodically thereafter.
Diabetic patients:
Glucose levels should be carefully monitored in diabetic patients previously treated with oral antidiabetic agents or insulin during the first month of treatment with an ACE inhibitor (see section 4.5).
Lithium:
The combination of lithium and zofenopril is generally not recommended (see section 4.5).
Race:
As with other ACE inhibitors, zofenopril may be less effective in lowering blood pressure in black patients than in non-black patients. Angiotensin converting enzyme inhibitors cause a higher incidence of angioedema in black patients than in non-black patients.
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.
04.5 Interactions with other medicinal products and other forms of interaction -
Combinations not recommended
Potassium-sparing diuretics or potassium supplements: ACE inhibitors reduce diuretic induced potassium loss. Potassium-sparing diuretics such as eg. spironolactone, triamterene or amiloride, potassium supplements, or potassium-based salt substitutes can cause significant increases in potassium. If concomitant use is indicated, they should be used with caution and with frequent monitoring of potassium and potassium. "ECG due to established hypokalaemia (see section 4.4).
Concomitant use requiring caution
Diuretics (thiazide or loop diuretics). Prior treatment with high doses of diuretics may lead to fluid depletion and the risk of hypotension upon initiation of zofenopril therapy (see section 4.4). intake of fluids or salts or starting therapy with a low dose of zofenopril.
Lithium. Reversible increases in serum concentrations and lithium toxicity have been reported with concomitant administration of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and potentiate the already increased risk of lithium toxicity with ACE inhibitors.
It is not recommended to use zofenopril with lithium, but if this combination is necessary, careful monitoring of serum lithium levels is required.
Salt of gold. Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension, which can take a very severe form) following the administration of injectable gold salts (eg sodium aurothiomalate) have been reported more frequently in patients undergoing therapy. with ACE inhibitors.
Anesthetics. ACE inhibitors may potentiate the hypotensive effects of some anesthetics.
Narcotics / Tricyclic antidepressants / Antipsychotics / Barbiturates. Postural hypotension may occur.
Other antihypertensives (e.g. beta-blockers, alpha-blockers, calcium channel blockers). Concomitant use of these medicinal products may cause additive or potentiating hypotensive effects. Treatment with glyceryl trinitrate and other nitrates, or other vasodilators, should be conducted with caution.
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).
Cimetidine. It can potentiate the hypotensive risk.
Cyclosporine. Increased risk of renal dysfunction in cases of concomitant use of ACE inhibitors.
Allopurinol, procainamide, cytostatic or immunosuppressive agents. Increased risk of hypersensitivity reactions in cases of concomitant use of ACE inhibitors. Data from other ACE inhibitors indicate an increased risk of leukopenia when used in combination.
Antidiabetic: Rarely, ACE inhibitors may potentiate the blood glucose lowering effects of insulin and oral antidiabetic agents such as sulphonylurea in diabetic patients. In these cases it may be necessary to reduce the dose of the antidiabetic during concomitant treatment with ACE inhibitors.
Hemodialysis with high-flux dialysis membranes. Increased risk of anaphylactoid reactions in cases of concomitant use of ACE inhibitors.
Systemic corticosteroids. Concomitant use of ACE inhibitors may increase the risk of leukopenia.
To be taken into consideration in case of concomitant use
Non-steroidal anti-inflammatory drugs (including ASA 3g / day). Administration of non-steroidal anti-inflammatory drugs may reduce the antihypertensive effect of an ACE inhibitor. In addition, NSAIDs and ACE inhibitors have been reported to exert an additive effect on increased potassium and renal function may decrease. These effects are in principle reversible and occur in particular in patients with impaired renal function. Rarely, acute renal failure may occur, particularly in patients with impaired renal function such as the elderly or dehydrated patients.
Antacids. They reduce the bioavailability of ACE inhibitors.
Sympathomimetics. They can reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm the achievement of the desired antihypertensive effect.
Food. It may reduce the rate but not the amount of zofenopril calcium absorption.
Additional information
No clinical data on the interaction of zofenopril with other medicinal products that are metabolised by CYP enzymes are available. However, metabolic studies in vitro with zofenopril, there is no evidence of interactions with medicinal products that are metabolised by CYP enzymes.
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. For patients planning to become pregnant, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued ACE inhibitor therapy 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) (see section 5.3). . Should exposure to an 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 carefully observed for hypotension ( see sections 4.3 and 4.4).
Feeding time
As no data are available regarding the use of zofenopril during breastfeeding, Zofenopril Mylan Generics is not recommended, therefore alternative treatments with a proven safety profile are preferred during breastfeeding, especially when breastfeeding newborns and preterm births.
04.7 Effects on ability to drive and use machines -
There are no studies on the effect of zofenopril on the ability to drive. It should be remembered, while driving or using machines, that the medicine may occasionally make you sleepy, dizzy or tired.
04.8 Undesirable effects -
The following table lists all adverse reactions that have been reported during clinical practice in patients treated with zofenopril. They are listed by system organ and classified by frequency using the following convention: very common (≥ 1/10), common (≥ 1/100,
The following adverse reactions associated with ACE inhibitor therapy have been observed:
Disorders of the blood and lymphatic system
Agranulocytosis and pancytopenia may occur in some patients.
There have been reports of haemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
Metabolism and nutrition disorders
Very rare: hypoglycaemia.
Psychiatric disorders
Rarely, depression, mood changes, sleep disturbances, confusional state.
Nervous system disorders
Occasionally paraesthesia, dysgeusia, balance disturbances.
Eye disorders
Rarely, blurred vision.
Ear and labyrinth disorders
Rarely, tinnitus.
Cardiac pathologies
Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction have been reported for ACE inhibitors in association with hypotension.
Vascular pathologies
Severe hypotension has been observed after initiation of therapy or dose escalation. This occurs mainly in certain risk groups (see section 4.4). In association with hypotension, symptoms such as dizziness, feeling of weakness, visual disturbances, rarely with loss of consciousness (syncope).
Redness rarely occurs.
Respiratory, thoracic and mediastinal disorders
Dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have rarely been reported. ACE inhibitors have been associated with the onset of angioneurotic edema in a small subset of patients involving the face and oropharyngeal tissues. In isolated cases, angioneurotic edema has caused fatal respiratory obstruction affecting the upper respiratory tract.
Gastrointestinal disorders
Occasionally, abdominal pain, diarrhea, constipation, and dry mouth may occur.
Individual cases of pancreatitis and ileus have been described in association with ACE inhibitors.
Very rare angioedema of the small intestine.
Hepatobiliary disorders
Individual cases of cholestatic jaundice and hepatitis have been described in association with ACE inhibitors.
Skin and subcutaneous tissue disorders
Occasionally allergic and hypersensitivity reactions such as itching, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriatic-like efflorescence, alopecia may occur.
This may be accompanied by fever, myalgia, arthralgia, eosinophilia and / or an increase in ANA-titers.
Hyperhidrosis rarely occurs.
Musculoskeletal and connective tissue disorders
Occasionally, myalgia can occur.
Renal and urinary disorders
Renal failure may occur or intensify. Acute renal failure has been reported (see section 4.4).
Disorders of urination occur rarely.
Diseases of the reproductive system and breast
Rarely, erectile dysfunction.
General disorders and administration site conditions
Very rarely peripheral edema and chest pain.
Diagnostic tests
Increases in blood urea and creatinine, reversible on discontinuation, may occur, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension.
Decreases in hemoglobin, hematocrit, platelets and white blood cell counts have been reported in some patients.
Increases in serum levels of liver enzymes and bilirubin have also been reported.
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 -
Symptoms of overdose are: severe hypotension, shock, drowsiness, bradycardia, electrolyte disturbances and renal failure.
In the event of an overdose, the patient should be kept under close clinical observation, preferably in an intensive care unit. Creatinine and serum electrolytes should be checked frequently. The therapeutic measures to be adopted depend on the nature and severity of the symptoms. If taken recently, measures to prevent absorption such as gastric lavage and administration of adsorbing agents and sodium sulphate can be implemented. If hypotension occurs, patients should be placed in a safe position and consideration should be given to careful restoration of blood volume and / or treatment with angiotensin II. Bradycardia or extensive vagal reactions should be treated by administering atropine. Also consider fitting a pacemaker.
ACE inhibitors can be cleared from the circulation by hemodialysis. Avoid the use of high flux polyacrylonitrile membranes.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, ACE inhibitors.
ATC code: C09AA15.
Mechanism of action
The beneficial effects of zofenopril in the treatment of hypertension and acute myocardial infarction are manifested primarily in the suppression of the plasma renin-angiotensin-aldosterone system. arginine of zofenoprilat), by decreasing plasma angiotensin II, causes a lowering of vasopressor activity and a reduction in aldosterone secretion. Although this latter decrease is mild, small increases in serum potassium concentrations may occur, along with sodium and fluid losses. The cessation of angiotensin II negative feedback on renin secretion leads to an increase in plasma renin activity. Plasma ACE activity is inhibited by 53.4% and 74.4% 24 hours after single oral administration of 30 and 60 mg zofenopril calcium, respectively.
The inhibition of ACE leads to an increase in the circulating and local activity of the kallikrein - kinin system, which contributes to peripheral vasodilation by activating the prostaglandin system. It is possible that this mechanism is involved in the hypotensive effect of zofenopril calcium and is responsible for some of the side effects.
Clinical efficacy and safety
In patients with hypertension, administration of zofenopril results in a similar reduction in blood pressure in both standing and supine positions, with no compensatory increase in heart rate. Mean systemic vascular resistances tend to decrease after administration of zofenopril.
In some patients, several weeks of therapy are required to achieve an optimal reduction in blood pressure. The antihypertensive effects persist in long-term therapy.
Sudden discontinuation of therapy has not been associated with a rapid rise in blood pressure. There are currently no data on the effects of zofenopril on morbidity and mortality in hypertensive patients.
Although antihypertensive effects were seen in all populations studied, black patients with hypertension (usually a low-renin hypertension population) respond less on average to ACE inhibitor monotherapy than non-black patients. This difference disappears with the addition of a diuretic to therapy.
The clinical efficacy following the initial use of zofenopril following myocardial infarction is related to many factors, such as the reduction in plasma angiotensin II levels (limiting the ventricular remodeling process which may reduce the quoad vitam prognosis of the heart attacked patient) and "increase in plasma and tissue concentrations of vasodilating substances (quinine-prostaglandin system).
A randomized, placebo-controlled clinical study with zofenopril was performed in 1,556 patients with anterior myocardial infarction who had not undergone thrombolytic therapy. Treatment was started within 24 hours and continued for 6 weeks. The incidence of the combined primary endpoint (severe heart failure and / or death at week 6) was reduced in patients treated with zofenopril (zofenopril 7.1%, placebo 10.6%). At one year, the survival rate of the zofenopril group of patients was increased.
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 -
Zofenopril calcium is a prodrug, as the active inhibitor is the free sulfhydryl compound, zofenoprilat, resulting from the hydrolysis of the thioester.
Absorption
Zofenopril calcium is rapidly and completely absorbed orally and undergoes nearly complete conversion to zofenoprilat, reaching peak blood levels 1.5 hours after taking an oral dose of zofenopril. Single dose kinetics are linear on a dose range is 10 to 80 mg of zofenopril calcium and no accumulation occurs after administration of 15 to 60 mg of zofenopril calcium for 3 weeks. Presence of food in the gastrointestinal tract reduces the rate but not the amount of absorption and the AUCs of zofenoprilat are nearly identical in both fasted and non-fasted conditions.
Distribution
An ex vivo measured radio-labeled dose of zofenopril calcium is approximately 88% bound to plasma proteins, while the steady-state volume of distribution is 96 liters.
Biotransformation
Eight metabolites, responsible for 76% of urinary radioactivity, have been identified in human urine after taking a radiolabelled dose of zofenopril calcium. The major metabolite is zofenoprilat (22%), which is then metabolized by various pathways, including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), cysteine conjugation (9%) and thiol group S-methylation. (8%). The half-life of zofenoprilat is 5.5 hours and its bodywide clearance is 1300 ml / min after oral zofenopril calcium.
Elimination
Intravenously administered radiolabelled zofenoprilat is eliminated in the urine (76%) and faeces (16%), while after administration of an oral dose of radiolabelled zofenopril calcium 69% and 26% of the radioactivity is recovered in the urine and faeces, respectively. , indicating a double route of elimination (kidney and liver).
Other special populations
Pharmacokinetics in the elderly:
No dose adjustments are required in the elderly with normal renal function.
Pharmacokinetics in renal dysfunction:
Based on the comparison of the main pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabelled calcium zofenoprilat, patients with mild renal impairment (creatinine clearance> 45 and 90 ml / min).
In patients with moderate and severe renal impairment (7-44 mL / min), the elimination rate is reduced to approximately 50% of normal. This indicates that half of the usual starting dose of zofenopril should be administered in these patients.
In patients with end-stage renal disease and undergoing hemodialysis or peritoneal dialysis, the elimination rate is reduced to 25% of normal. This indicates that these patients should be given a quarter of the usual starting dose of zofenopril.
Pharmacokinetics in hepatic dysfunction:
The Cmax and Tmax values for zofenoprilat in patients with mild to moderate hepatic dysfunction after single doses of radiolabelled calcium zofenopril are the same as in healthy subjects. However, AUC values in cirrhotic patients are twice those obtained for healthy subjects, therefore the starting dose of zofenopril for patients with mild to moderate hepatic dysfunction should be half that given to patients with normal hepatic function.
There are no pharmacokinetic data for zofenopril and zofenoprilat in patients with severe hepatic dysfunction, therefore zofenopril is contraindicated in these patients.
05.3 Preclinical safety data -
In repeated dose toxicity studies conducted in three mammalian species and with oral administration, most treatment-related effects were those generally reported for ACE inhibitors. The observed effects included a decrease in erythrocyte parameters, an increase in serum urea nitrogen, a decrease in cardiac weight and hyperplasia of juxta-glomerular cells which occurred at doses much higher than the maximum recommended doses in humans. In a repeat dose oral toxicity study in dogs, species-specific immunologically mediated blood dyscrasia occurred at high doses.
No significant changes in cytochrome P450 activities were observed in a one-year oral repeated toxicity study in monkeys.
In reproductive toxicity studies, zofenopril at high doses of 90 and 270 mg / kg in the F1 generation caused a dose-related reduction in the growth rate of the offspring as well as nephrotoxicity and reduced postnatal survival. Treatment with zofenopril during pregnancy caused fetal and developmental toxicity in rats and embryo and fetal toxicity in rabbits, but only at maternally toxic dosages.
Genotoxicity studies have shown that zofenopril is neither mutagenic nor clastogenic.
In the carcinogenicity studies in rats and mice, no carcinogenicity was shown.
In the carcinogenesis study conducted in mice, an increased incidence of testicular atrophy was observed; the clinical relevance of this phenomenon is unknown.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Core of the tablet
Microcrystalline cellulose
Pregelatinised starch (maize)
Magnesium stearate
Coating film
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400
Polysorbate 80
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years
After first opening (HDPE bottle with polypropylene cap only): 30 days.
06.4 Special precautions for storage -
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package -
HDPE bottle with polypropylene cap containing 500 tablets (hospital pack).
PVC / Aclar / Aluminum blisters in packs of 7, 12, 14, 28, 30, 56, 90 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No particular precautions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Mylan S.p.A., Via Vittor Pisani 20, 20124 Milan
08.0 MARKETING AUTHORIZATION NUMBER -
040724015 - "30 MG TABLETS COATED WITH FILM" 7 TABLETS IN PVC / ACLAR / AL BLISTER
040724027 - "30 MG TABLETS COATED WITH FILM" 12 TABLETS IN PVC / ACLAR / AL BLISTER
040724039 - "30 MG TABLETS COATED WITH FILM" 14 TABLETS IN PVC / ACLAR / AL BLISTER
040724041 - "30 MG TABLETS COATED WITH FILM" 28 TABLETS IN PVC / ACLAR / AL BLISTER
040724054 - "30 MG TABLETS COATED WITH FILM" 30 TABLETS IN PVC / ACLAR / AL BLISTER
040724066 - "30 MG FILM COATED TABLETS" 56 TABLETS IN PVC / ACLAR / AL BLISTER
040724078 - "30 MG FILM COATED TABLETS" 90 TABLETS IN PVC / ACLAR / AL BLISTER
040724080 - "30 MG TABLETS COATED WITH FILM" 500 TABLETS IN HDPE BOTTLE
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
May 2011
10.0 DATE OF REVISION OF THE TEXT -
November 2016
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