Active ingredients: Zofenopril (Zofenopril calcium)
BIFRIL 7.5mg, 15mg, 30mg, 60mg film-coated tablets
Why is Bifril used? What is it for?
BIFRIL contains 7.5 mg, 15 mg, 30 mg, 60 mg of zofenopril calcium which belongs to a group of blood pressure lowering medicines called angiotensin converting enzyme (ACE) inhibitors.
BIFRIL is used to treat the following conditions:
- high blood pressure (hypertension);
- heart attack (acute myocardial infarction) in people who may or may not show signs and symptoms of heart failure and who have not received treatment to dissolve blood clots (thrombolytic therapy).
Contraindications When Bifril should not be used
Do not take BIFRIL if:
- you are allergic (hypersensitive) to the active substance or to any of the other ingredients of BIFRIL (see Section - "What BIFRIL contains" ").
- have had previous allergic reactions to another ACE inhibitor, such as captopril or enalapril.
- have had previous severe episodes of swelling and itching of the face, nose and throat (angioneurotic edema) associated with previous ACE inhibitor therapy or have hereditary / idiopathic angioneurotic edema (rapid swelling of the skin, , digestive tract and other organs).
- suffer from severe liver problems.
- suffer from narrowing of the arteries of the kidneys.
- is beyond the third month of pregnancy (it is better to avoid taking BIFRIL even in the early stages of pregnancy - see Section: Pregnancy).
- you are a woman of childbearing age, unless you are using effective contraceptive methods.
- 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 Bifril
Talk to your doctor before taking BIFRIL if:
- have high blood pressure and liver and kidney problems;
- have high blood pressure due to a kidney problem or narrowing of the renal artery (renovascular hypertension);
- recently underwent a kidney transplant;
- is on dialysis;
- you are on LDL apheresis (a procedure similar to kidney dialysis that clears your blood of harmful cholesterol);
- have abnormally high levels of the hormone aldosterone in the blood (primary hyperaldosteronism);
- have narrowing of the heart valve (aortic stenosis) or thickening of the heart walls (hypertrophic cardiomyopathy);
- have or have suffered from psoriasis (skin disease characterized by scaly pink patches);
- is receiving desensitization treatment ("allergy injections") for insect bites;
- 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 (for example potassium) in your blood at regular intervals.
See also information under the heading "Do not take Bifril".
When taking BIFRIL your blood pressure can drop to too low levels especially after taking the first dose (this is more likely if you are taking diuretics at the same time, if you are dehydrated, or if you are on a low-fat diet. salt content) If this happens, tell your doctor immediately and lie on your back.
If you are going to have surgery, tell your anesthetist that you are taking BIFRIL before receiving anesthesia. This will aid the anesthetist in checking his blood pressure and heart rate during the procedure.
Also, if you suffer from heart attacks (acute myocardial infarction) and if:
- have low blood pressure (<100mmHg) or are in circulatory shock (resulting from your heart problem)
- BIFRIL is not the recommended drug for you;
- is over 75 years old
- BIFRIL should be used with particular care.
You should tell your doctor if you think you are (or could be) pregnant. The use of BIFRIL in the early stages of pregnancy is not recommended and it should not be taken if you are over the third month of pregnancy, as the drug could cause serious harm to the baby if used at this stage (see "Pregnancy" section). .
Children and adolescents
Do not give this medicine to children and adolescents under 18 years of age as its safety has not been established
Interactions Which drugs or foods can modify the effect of Bifril
Tell your doctor if you are taking, have recently taken or might take any other medicines.
In particular, tell your doctor if you are taking:
- drugs that increase potassium levels in the blood (potassium-sparing diuretics, such as spironolactone, triamterene, amiloride, or potassium supplements), potassium-containing salt substitutes;
- itium (used to treat mood disorders);
- anesthetics;
- narcotic drugs (such as morphine);
- antipsychotic drugs (used to treat schizophrenia and similar diseases);
- antidepressants or tricyclics, eg. amitriptyline and clomipramine;
- other medicines for high blood pressure and vasodilators (including beta blockers, alpha blockers and diuretics such as hydrochlorothiazide, furosemide, torasemide); 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 Bifril" and "Warnings and precautions") ;
- nitroglycerin and other nitrates used for chest pain (angina);
- antacids including cimetidine (used to treat heartburn and stomach ulcers);
- cyclosporine (used after organ transplantation) and other immunosuppressive drugs (drugs that suppress the body's defenses);
- allopurinol (used to treat gout);
- insulin and other oral antidiabetic drugs;
- cytostatic agents (used to treat cancer or diseases affecting the immune system);
- corticosteroids (powerful anti-inflammatory drugs);
- procainamide (used to control irregular heartbeat);
- non-steroidal anti-inflammatory drugs (NSAIDs, such as aspirin or ibuprofen);
- sympathomimetic drugs (drugs that affect the nervous system, including some drugs used to treat asthma or hay fever and pressor amines such as adrenaline).
BIFRIL with food, drink and alcohol
BIFRIL can be taken either with food or on an empty stomach, but it is preferable to take the tablet with water. Alcohol increases the hypotensive effect of BIFRIL (lowering blood pressure); consult your doctor for more information on drinking alcohol while you are taking this drug.
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
If you are pregnant, think you may be pregnant or are planning to become pregnant, ask your doctor for advice before taking this medicine. Your doctor will usually advise you to stop taking BIFRIL before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of BIFRIL. BIFRIL is not recommended at the start of your pregnancy. pregnancy and should not be taken after the third month of pregnancy, as the drug can cause serious harm to the baby if taken after the third month of pregnancy.
Feeding time
If you are breast-feeding or about to start breastfeeding ask your doctor for advice before taking this medicine. BIFRIL is not recommended during breastfeeding and your doctor may choose another medicine that is suitable for you if you wish to continue breastfeeding and especially if you are breastfeeding a premature baby.
Driving and using machines
This drug can cause dizziness or tiredness. If this happens, do not drive or use machines until the symptoms go away
BIFRIL contains lactose
This product contains lactose. If you know that you have an "intolerance to some sugars, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Bifril: Posology
Always take BIFRIL exactly as your doctor has told you. If in doubt, consult your doctor. BIFRIL can be taken with food or on an empty stomach. It is preferable to take the tablet with water.
Treatment of high blood pressure (hypertension)
The normal starting dose of BIFRIL is 15mg once a day. Your doctor will gradually adjust your dose (usually at four-week intervals) to find the best dose for you. Long-term antihypertensive effects are normally achieved with a dose of 30mg of BIFRIL taken once daily. The maximum dose is 60 mg per day, which can be taken as a single dose or in two divided doses
If you are dehydrated, have a salt deficiency or are taking diuretics, it may be necessary to start treatment with BIFRIL 7.5 mg.
Liver or kidney problems
If you have mild to moderate hepatic impairment or moderate to severe renal impairment, your doctor will start treatment with half the normal therapeutic dose of BIFRIL (15 mg). If you are on dialysis you should start treatment with one quarter of the normal therapeutic dose (7.5 mg).
Heart attack (acute myocardial infarction)
Treatment with BIFRIL should start within the first 24 hours after the onset of symptoms. Take BIFRIL tablets twice a day, in the morning and in the evening as follows:
- 7.5mg twice a day, on the first and second day of treatment;
- 15mg twice a day, on the third and fourth day of treatment;
- from the fifth day onwards, the dose should be increased to 30mg twice a day;
- Your doctor may adjust the dose or maximum dose you receive based on your blood pressure measurements;
- treatment will then be continued for six weeks or more if heart failure symptoms persist.
Overdose What to do if you have taken too much Bifril
If you take more BIFRIL than you should
If you accidentally take more tablets than you should, contact your doctor or the nearest emergency department immediately (take any remaining tablets, the box or this leaflet with you if you can). The most frequent symptoms and signs of an overdose are low blood pressure with fainting (hypotension), very low heart rate (bradycardia), abnormal blood tests (electrolytes) and kidney dysfunction.
If you forget to take BIFRIL
If you forget to take a dose, take your normal dose the next day. However, if the delay is very long (eg several hours) so that the time for your next dose is very close, skip the missed dose and take the next one directly at the scheduled time. Do not take a double dose to make up for it. the forgotten tablet.
If you stop taking BIFRIL
Always consult your doctor before stopping treatment with BIFRIL, whether you are taking it for high blood pressure or following a heart attack.
If you have any further questions on the use of BIFRIL, ask your doctor or pharmacist.
Side Effects What are the side effects of Bifril
Like all medicines, BIFRIL can cause side effects, although not everyone gets them. Most of the side effects associated with ACE inhibitors are reversible and disappear after the end of treatment.
Common side effects (seen in less than 1 in 10 people treated):
- tiredness
- nausea and / or vomiting
- dizziness
- headache
- cough.
Less common side effects (seen in less than 1 in every 100 people treated):
- general weakness
- muscle cramps
- rash
Rare side effects (found in less than one person in every 1000 treated):
- rapid swelling and itching particularly of the face, mouth and throat with possible difficulty in breathing.
In addition to the side effects reported for BIFRIL, the following effects have generally been reported for ACE inhibitors:
- severe drop in blood pressure at the start of treatment or with increasing dose with dizziness, blurred vision, fainting (syncope);
- increased or irregular heart rate, palpitations and chest pain (heart attack or angina pectoris);
- loss of consciousness, sudden dizziness, sudden blurring of vision, weakness and / or loss of sensation of touch on one side of the body (transient ischemic attack or stroke);
- peripheral edema (swollen limbs from fluid accumulation), low blood pressure on standing, chest pain, muscle aches and / or cramps;
- impaired kidney function, changes in the amount of urine per day, presence of protein in the urine (proteinuria), impotence;
- abdominal pain, diarrhea, constipation, dry mouth;
- allergic actions such as rash, hives, itching, peeling of the skin, redness, sagging and blistering of the skin (toxic epidermal necrolysis), worsening of psoriasis (a skin disease characterized by scaly pink areas), hair loss ( alopecia);
- increased sweating and hot flashes;
- mood changes, depression, sleep disturbances, altered skin sensations such as burning, pricking, or tingling (paraesthesia), balance disturbances, confusion, ringing in the ears (tinnitus), taste disturbances, blurred vision;
- breathing difficulties, narrowing of the airways of the lung (bronchospasm), sinusitis, stuffy nose (rhinitis), inflammation of the tongue (glossitis), bronchitis;
- yellowing of the skin (jaundice), inflammation of the liver or pancreas (hepatitis, pancreatitis), obstruction of the small intestine (ileus);
- changes in blood tests such as counts of red blood cells, white blood cells or platelets or a reduction in all blood cells (pancytopenia).
Contact your doctor if you notice that you bruise easily or if you develop an unexplained sore throat or fever;
- increased blood levels of liver enzymes (transaminases) and bilirubin, increased blood urea and creatinine levels;
- anemia due to the breakdown of red blood cells (haemolytic anemia) which can occur if you suffer from G6PD (glucose-6phosphate dehydrogenase) deficiency;
- Hypoglycemia.
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 "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
This medicinal product does not require any special storage conditions.
Do not take BIFRIL beyond the expiry date which is stated on the carton and blister after "EXP."
Do not throw any medicines down the drain. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What BIFRIL contains
The active ingredient is zofenopril calcium 7.5mg, 15mg, 30mg, 60mg.
The other ingredients are: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal anhydrous silica, hypromellose, titanium dioxide (E 171), macrogol 400 and macrogol 6000 (see section "BIFRIL contains lactose").
What BIFRIL looks like and contents of the pack
BIFRIL 7.5 is available as round white film-coated tablets with convex faces in packs of 12, 14, 15, 28, 30, 48, 50, 56, 90 or 100 and in packs of 50 and 56 in perforated blister. per unit dose.
BIFRIL 15 is available as oblong white film-coated tablets in packs of 12, 14, 15, 28, 30, 50, 56, 90 or 100 and in packs of 50 and 56 in perforated unit dose blisters.
BIFRIL 30 is available as oblong white film-coated tablets in packs of 7, 14, 15, 28, 30, 50, 56, 90 or 100 and in packs of 50 and 56 in perforated unit dose blisters.
BIFRIL 60 is available as oblong white film-coated tablets in packs of 14, 15, 28, 30, 50, 56, 90 or 100 and in packs of 50 and 56 in perforated unit dose blisters.
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
BIFRIL TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each BIFRIL 7.5 mg film-coated tablet contains 7.5 mg of zofenopril calcium equivalent to 7.2 mg of zofenopril.
Each BIFRIL 15 mg film-coated tablet contains 15 mg of zofenopril calcium equivalent to 14.3 mg of zofenopril.
Each BIFRIL 30 mg film-coated tablet contains 30 mg of zofenopril calcium equivalent to 28.7 mg of zofenopril.
Each BIFRIL 60 mg film-coated tablet contains 60 mg of zofenopril calcium equivalent to 57.3 mg of zofenopril calcium.
Excipients with known effects:
Each BIFRIL 7.5 mg film-coated tablet contains 17.35 mg of lactose monohydrate.
Each BIFRIL 15 mg film-coated tablet contains 34.7 mg of lactose monohydrate.
Each BIFRIL 30 mg film-coated tablet contains 69.4 mg of lactose monohydrate.
Each BIFRIL 60 mg film-coated tablet contains 138.8 mg of lactose monohydrate
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Film-coated tablets.
BIFRIL 7.5 mg:
White round film-coated tablets with convex faces.
BIFRIL 15 mg, 30 mg and 60 mg:
White, oblong film-coated tablets with score line.
The tablet can be divided into equal halves.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Hypertension
BIFRIL is indicated for the treatment of mild to moderate essential arterial hypertension.
Acute myocardial infarction
BIFRIL is indicated in 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
BIFRIL can be taken before, during or after meals. The dose should be titrated based on the patient's therapeutic response.
Hypertension:
The need for therapeutic dose adjustment is determined by blood pressure measurement immediately prior to a new administration. The dose 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 dose until optimal blood pressure control is achieved.
The effective dose is usually 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:
Hypotension episodes may occur with the first administration of the product in high-risk patients (see section 4.4 "Special warnings and precautions for use").
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 dose of 15 mg per day. day. If the above is not possible, the dose should be 7.5 mg per day.
Patients at high risk of acute severe hypotension should be carefully monitored, preferably in hospital, after the first dose, for as long as it takes to achieve the maximum therapeutic effect, and whenever the therapeutic dose of ACE inhibitors is increased. and / or diuretics. The foregoing should also apply to patients with angina pectoris or cerebrovascular diseases for whom excessive hypotension could cause myocardial infarction or cerebrovascular accidents.
Posology in patients with renal insufficiency and patients undergoing dialysis:
In hypertensive patients with mild renal impairment (creatinine clearance> 45 mL / min) BIFRIL can be used at the same dose and once-daily dosing regimen as for patients with normal renal function. Patients with moderate to severe renal impairment (creatinine clearance
The starting dose and dosage regimen of BIFRIL for hypertensive patients undergoing dialysis should be one quarter of that indicated in patients with normal renal function.
Recent clinical observations have shown a "high incidence of anaphylactoid-like reactions in patients treated with ACE inhibitors during hemodialysis performed with high-flux membranes or during LDL apheresis (see section 4.4" Warnings and special precautions for use ").
Elderly people (over the age of 65):
No dosage adjustments are required in elderly people with normal creatinine clearance.
In elderly people 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 the creatinine clearance in men. In women the value obtained must be multiplied by 0.85.
Posology in patients with hepatic insufficiency:
In hypertensive patients with mild to moderate hepatic impairment, the starting dose of BIFRIL is half that expected in patients with normal hepatic function.
BIFRIL is contraindicated in hypertensive patients with severe hepatic insufficiency.
Pediatric population (under 18 years of age):
The efficacy and safety of BIFRIL in children have not been established. The use of the drug is therefore not recommended.
Acute myocardial infarction
Treatment with BIFRIL 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 BIFRIL should be discontinued.
After 6 weeks of treatment, patients should be re-evaluated and treatment discontinued if there are no longer any 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 the elderly:
In patients with myocardial infarction over 75 years of age BIFRIL should be used with caution.
Posology in patients with renal insufficiency and dialysis:
The efficacy and safety of BIFRIL have not been established in patients with myocardial infarction suffering from renal insufficiency or undergoing dialysis. Therefore BIFRIL should not be used in such patients.
Posology in patients with hepatic insufficiency
The efficacy and safety of BIFRIL have not been established in patients with myocardial infarction with hepatic insufficiency. Therefore it should not be used in these patients.
04.3 Contraindications
• Hypersensitivity to zofenopril calcium, to any other ACE inhibitor or to any excipient constituting the drug.
• 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).
• In women of childbearing age unless protected by effective contraception.
• Bilateral or unilateral renal artery stenosis in patients with single kidney.
• The concomitant use of Bifril with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).
04.4 Special warnings and appropriate precautions for use
Hypotension:
Like other ACE inhibitors, BIFRIL can cause excessive lowering of blood pressure, especially after administration of the first dose, however, cases of symptomatic hypotension in uncomplicated hypertensive patients are rare.
It is more likely to occur in patients with hypovolaemia and electrolyte depletion caused by treatment with diuretics, a low-sodium diet, dialysis, diarrhea or vomiting, or in patients 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 condition is more likely to occur in patients with a more severe degree of heart failure as a result of the use of high doses of loop diuretics, in patients with hyponatremia or impaired renal function. In these patients with a high risk of symptomatic hypotension, treatment should begin under close medical supervision, preferably in hospital, at low doses and with careful dosage adjustment.
If possible, diuretics should be temporarily stopped when initiating therapy with BIFRIL. These considerations also apply to those patients with angina pectoris or cerebrovascular disease in whom an excessive drop in blood pressure could cause a myocardial infarction or a 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 who have normal or low blood pressure, further lowering of systemic blood pressure may occur with the administration of BIFRIL. This is an expected effect and does not normally represent a reason to discontinue treatment. If hypotension becomes symptomatic, the dose may need to be reduced or treatment with BIFRIL may need to be stopped.
Hypotension in acute myocardial infarction:
Treatment with BIFRIL should not be initiated in patients with acute myocardial infarction if there is a risk of additional major haemodynamic depression following treatment with a vasodilator. These are patients with a cardiogenic shock systolic pressure. In patients with acute myocardial infarction, treatment with BIFRIL can cause severe hypotension. If hypotension persists (systolic pressure
Myocardial infarction in patients with hepatic insufficiency:
The efficacy and safety of BIFRIL have not been established in patients with myocardial infarction with hepatic insufficiency. Therefore it should not be used in such patients.
Older people
In patients with myocardial infarction aged> 75 years BIFRIL should be used with caution.
Patients with renovascular hypertension:
In patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the afferent artery to solitary kidney there is an increased risk of severe hypotension and renal failure when treated with ACE inhibitors. Treatment with diuretics may be a contributing cause. Loss of renal function can occur even with only slight changes in serum creatinine even in patients with unilateral renal artery stenosis. If deemed absolutely necessary, treatment with BIFRIL should be initiated in the hospital, under close medical supervision, at low doses and with careful adjustment of the dosage. Temporarily discontinue treatment with diuretics upon initiation of BIFRIL therapy and closely monitor renal function during the first weeks of therapy.
Patients with renal insufficiency:
Use BIFRIL 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 connection with the administration of ACE inhibitors mainly in patients with severe heart failure or with renal disease, including renal artery stenosis. blood creatinine, 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 advised during the first few weeks of therapy.
The efficacy and safety of BIFRIL in myocardial infarction patients with renal insufficiency have not been established. Therefore, in the presence of renal insufficiency (serum creatinine ≥2.1 mg / dl and proteinuria ≥500 mg / day) and heart attack myocardial, BIFRIL should 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, flushing, hypotension and dyspnoea within minutes of "onset of" hemodialysis. It is recommended to use alternative membranes or to use another type of antihypertensive drug.
The efficacy and safety of BIFRIL in patients with myocardial infarction undergoing hemodialysis have not been established. Therefore, it should not be used in such 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 drug 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 treatment (e.g. hymenoptera venom) or after insect bites. In the same patients, these reactions were avoided by temporarily withholding ACE inhibitors, but they reappeared following inadvertent re-administration of the same drug. Therefore, particular caution should be exercised in patients treated with ACE inhibitors undergoing desensitization procedures.
Kidney transplant
There is no experience with the administration of BIFRIL in patients who have recently undergone kidney transplantation.
Primary aldosteronism
Patients with primary aldosteronism generally do not respond to antihypertensive drugs which act through an "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. In these cases, immediately discontinue treatment with ACE inhibitors and replace treatment with drugs belonging to a " other class.
Angioedema affecting the tongue, glottis or larynx can be fatal. Immediately initiate emergency therapy that includes, but is not necessarily limited to: 1: 1000 (0.3-) subcutaneous adrenaline solution infusion. 0.5 ml) or slow intravenous adrenaline infusion 1 mg / ml (to be diluted as indicated), with close monitoring of electrocardiography and blood pressure. The patient must be hospitalized and observed for at least 12-24 hours and discharged only after complete remission of the symptoms presented.
Even in cases where only swelling of the tongue is present, without respiratory distress, observation of the patient is necessary, as treatment with antihistamines and corticosteroids may not be sufficient.
Angiotensin converting enzyme inhibitors cause more angioedema in black patients than in non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitor treatment may be at increased risk of angioedema if they receive an ACE inhibitor (see section 4.3. Contraindications).
Cough
During treatment with BIFRIL the onset of a dry and non-productive cough may occur which disappears when the medicinal product 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 initially presents with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not known. If jaundice or liver enzyme elevations occur in patients receiving ACE inhibitors, treatment should be discontinued and appropriate medical follow-up performed.
Hyperkalemia
Hyperkalaemia may occur during treatment with ACE inhibitors.
Patients at risk for developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, or patients on concomitant treatment with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or patients using other active substances associated with increased serum potassium levels (e.g. heparin). If concomitant use of the aforementioned drugs is deemed appropriate, frequent monitoring of serum potassium (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.
Surgery / anesthesia
In patients undergoing major surgery or during anesthesia, the use of ACE inhibitors can cause hypotension or even hypotensive shock, because the formation of angiotensin II is blocked in response to the compensatory increase in renin. If this is not possible. stop treatment with ACE inhibitors, carefully monitor the blood volume.
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 obstruction.
Neutropenia / agranulocytosis
Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. The risk of neutropenia appears to be type- and dose-related and also dependent on the patient's clinical status. Rarely observed in uncomplicated patients but may occur in patients with any degree of renal impairment especially in association with vascular collagen disease (e.g. systemic lupus erythematosus, scleroderma) and immunosuppressive drug therapy, Treatment with allopurinol, procainamide or when it exists a combination of these factors. Some of these patients developed severe infections which in some cases did not respond to intensive antibiotic therapy.
If BIFRIL is used in these patients, a white blood cell count and differential count should be performed before starting therapy, at 2-week intervals during the first three months of zofenopril therapy, and periodically thereafter. During treatment instruct patients to report any signs of infection, (e.g. sore throat, fever) when differential counts are to be performed. In case of diagnosed (neutrophils less than 1,000 / mm3) or suspected neutropenia, stop taking zofenopril and other concomitant medications (see section 4.5).
it is reversible on withdrawal 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. In patients with a history of kidney disease, perform an assessment of proteinuria (test strip on a sample of the first morning urine) before starting treatment, and periodically thereafter.
Diabetic patients
During the first month of treatment with an ACE inhibitor, closely monitor blood glucose levels in diabetic patients on oral antidiabetic or insulin therapy (see section 4.5).
Lithium
The combination of lithium and BIFRIL is generally not recommended (see section 4.5).
Race
Zofenopril, like other angiotensin converting enzyme inhibitors, may have reduced antihypertensive efficacy in black patients compared to non-black patients. Angiotensin converting enzyme inhibitors may also cause a higher rate of angioedema in black patients than in non-black patients.
Pregnancy
Do not initiate ACE inhibitor therapy during pregnancy. For patients planning pregnancy, resort to an alternative antihypertensive treatment with a proven safety profile for use in pregnancy, unless continued ACE inhibitor therapy is deemed essential. Immediately discontinue treatment with an ACE inhibitor. ACE inhibitors when pregnancy is diagnosed and, if appropriate, initiate alternative therapy (see sections 4.3 and 4.6).
Other
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug.
04.5 Interactions with other medicinal products and other forms of interaction
Concomitant use 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 may cause significant increases in potassium. Use with caution and with frequent monitoring of potassium and ECG (see section 4.4) in case they are indicated due to established hypokalaemia.
ACE inhibitors, angiotensin II receptor antagonists or aliskiren:
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).
Concomitant use requiring caution
Diuretics (thiazides or loop diuretics)
Previous treatment with high-dose diuretics may cause volume loss and the risk of hypotension upon initiation of Zofenopril therapy (see section 4.4). "taking salts or starting therapy with a low dose of zofenopril.
Lithium
Reversible increases in blood concentrations and lithium toxicity have been reported in conjunction with the use of ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and increase the already elevated risk of lithium toxicity with ACE. -inhibitors therefore the use of BIFRIL in combination with lithium is not recommended and if concomitant use is deemed necessary, careful monitoring of blood lithium levels is carried out.
Gold
Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension which can be very severe) after injection of gold products (e.g. sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitors.
Anesthetics
ACE inhibitors may potentiate the hypotensive effects of some anesthetics.
Narcotics / Tricyclic antidepressants / Antipsychotics / Barbiturates
Orthostatic hypotension may occur.
Other antihypertensives (e.g. beta-blockers, alpha-blockers, calcium channel blockers)
An increase or enhancement of the hypotensive effects is possible. Use nitroglycerin and other nitrates or other vasodilators with caution.
Cimetidine
It may increase the risk of hypotensive effects.
Cyclosporine
Concomitant use of ACE inhibitors increases the risk of renal dysfunction.
Allopurinol, procainamide, cytostatics or immunosuppressants
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.
Antidiabetics
Rarely, ACE inhibitors may potentiate the blood glucose lowering effects of insulin and other oral antidiabetic agents such as sulphonylurea in diabetic patients. In such 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.
Cytostatics or immunosuppressive drugs, systemic corticosteroids or procainamide
Concomitant use of ACE inhibitors may lead to an increased risk of leukopenia
Factors to be considered in case of concomitant use
Non-steroidal anti-inflammatory drugs (including ASA ≥3 g / day)
Administration of non-steroidal anti-inflammatory agents 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 while 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 for desired effects.
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 drugs metabolised by CYP enzymes are available. However, in vitro studies with zofenopril have shown no interactions with drugs metabolised by CYP enzymes.
04.6 Pregnancy and lactation
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 regarding the risk of teratogenesis 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 is considered necessary. based on ACE inhibitors, patients planning pregnancy should undergo alternative antihypertensive treatment for which a safety profile has been established for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if deemed appropriate, alternative therapy should be started. It is known that exposure to ACE inhibitor therapy during the second and third trimester of pregnancy can induce fetotoxicity in humans (decreased renal function, oligohydroamnios, delayed cranial ossification) and neonatal toxicity (renal failure, hypotension , hyperkalaemia) (see section 5.3). In case of exposure to ACE inhibitors from the second trimester of pregnancy, ultrasound check of renal function and cranial bones is recommended. Neonates whose mothers have taken ACE inhibitors they should be carefully monitored for hypotension (see sections 4.3 and 4.4).
Feeding time :
Since no information is available on the use of BIFRIL during breastfeeding, the use of the drug is not recommended and it is preferable to resort to alternative treatments for which a good safety profile during breastfeeding is demonstrated, particularly when breastfeeding a baby. newborn or premature baby.
04.7 Effects on ability to drive and use machines
There are no studies on the effect of BIFRIL on the ability to drive. It is good to remember, while driving or using machines, that the drug can induce drowsiness, dizziness or tiredness.
04.8 Undesirable effects
The following table shows all adverse reactions that have been reported during clinical practice in patients treated with BIFRIL. These are listed according to the classification for systems and organs and divided on the basis of the frequency of onset, according to the following convention: very common (> 1/10); common (> 1/100, 1/1000, 1 / 10,000,
Nervous system disorders
Common:
Dizziness, headache
Respiratory, thoracic and mediastinal disorders
Common:
cough
Gastrointestinal disorders
Common:
nausea / vomiting
Skin and subcutaneous tissue disorders
Uncommon:
rash
Rare:
angioedema
Musculoskeletal and connective tissue disorders
Uncommon:
muscle cramps
General disorders and administration site conditions
Common:
fatigue
Uncommon:
asthenia
The following adverse reactions associated with ACE inhibitor therapy have been observed.
Disorders of the blood and lymphatic system
Agranulocytosis and pancytopenia can occur in a small number of patients.
There have been reports of haemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
Metabolism and nutrition disorders
Very rare: hypoglycemia
Psychiatric disorders
In rare cases: 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
During treatment with ACE inhibitors, sporadic cases of tachycardia, palpitations, arrhythmia, angina pectoris, myocardial infarction have been reported in case of hypotension.
Vascular pathologies
Cases of severe hypotension have occurred with initiation or increase in posology. This occurs particularly in certain risk groups (see Special warnings and precautions for use). In association with hypotension, symptoms such as dizziness, feelings of weakness, impaired vision and rarely loss of consciousness (syncope) may occur.
Rarely, hot flashes.
Respiratory, thoracic and mediastinal disorders
Symptoms such as dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have been rarely reported. Cases of angioneurotic edema involving the face and oropharyngeal tissues have been reported in a small subgroup of patients receiving ACE inhibitors. In isolated cases, angioneurotic edema affecting the upper respiratory tract has resulted in fatal obstruction of the respiratory tract.
Gastrointestinal disorders
Occasionally abdominal pain, diarrhea, constipation and dry mouth.
During treatment with ACE inhibitors. sporadic cases of pancreatitis and paralytic ileus have been described. Very rare cases of angioedema of the small intestine.
Hepatobiliary disorders
Sporadic cases of cholestatic jaundice and hepatitis have been reported in association with the intake of ACE inhibitors.
Skin and subcutaneous tissue disorders
Occasionally, allergic and hypersensitivity reactions such as pruritus, urticaria, erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis, psoriatic-like skin lesions, alopecia.
These symptoms may be accompanied by fever, myalgia, arthralgia, eosinophilia, and / or increased ANA titer.
Rarely, hyperhidrosis.
Musculoskeletal and connective tissue disorders
Occasionally, myalgia can occur
Renal and urinary disorders
Onset or worsening of renal failure. Cases of acute renal failure have been reported (see Special warnings and precautions for use).
Rarely, urination disturbances.
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
Possible increase in blood urea nitrogen and creatinine, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension, reversible upon discontinuation of the drug. Reductions in hemoglobin, hematocrit, platelets, and blood count have been reported in some patients. In addition, increased liver enzymes and bilirubin levels have been reported.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Symptoms of overdose are: severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and kidney failure.
In case of 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 ingestion has occurred recently, measures to prevent absorption such as gastric lavage and administration of adsorbing agents and sodium sulphate may be undertaken. If hypotension occurs, the patient should be placed in the shock position and the use of plasma expanders and / or treatment with angiotensin II should be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The application of a pacemaker may also be considered. 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: ACE inhibitor - ATC code: C09AA15.
The beneficial effects of BIFRIL in the treatment of hypertension and acute myocardial infarction are manifested primarily in the suppression of the plasma renin-angiotensin-aldosterone system. Inhibition of ACE (Ki 0.4 nM in rabbit lung due to the arginine salt of zofenoprilat), by decreasing plasma angiotensin II, causes a "lowering of" vasopressor activity and a reduction in aldosterone secretion. "last and small decrease, 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.
After 24 hours following oral administration of a single dose of 30 mg and 60 mg of zofenopril calcium, plasma ACE activity is suppressed by 53.4% and 74.4%, respectively.
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.
In patients with hypertension, administration of BIFRIL 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 BIFRIL.
In some patients, several weeks of therapy are required to achieve an optimal reduction in blood pressure. The antihypertensive effects persist with 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 BIFRIL 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 of zofenopril given early after 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 quod vitam prognosis of the heart attacked patient) and the increase in concentrations plasma and tissue of vasodilating substances (quinine-prostaglandin system).
A randomized, placebo-controlled clinical trial 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.
Additional information:
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 concurrently 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 hydrolysis of the thioester.
Absorption
Zofenopril calcium is rapidly and completely absorbed orally and undergoes almost complete conversion to zofenoprilat, reaching peak blood levels 1.5 hours after taking an oral dose of BIFRIL. The kinetics of a single dose are linear in 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 AUC of zofenoprilat are nearly identical in both fasted and fed 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
The eight metabolites, responsible for 76% of urinary radioactivity, were identified in human urine following a radiolabelled dose of zofenopril calcium. The major metabolite is zofenoprilat (22%), which is then metabolized by various pathways, including glucuronidation (17%), cyclization and glucuronidation (13%), conjugation to cysteine (9%) and S-methylation of the thiol group ( 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).
Pharmacokinetics in the elderly
Dosage adjustments are not required in elderly people 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 insufficiency (7-44 mL / min), the elimination rate is reduced to approximately 50% of normal. This indicates that half of the usual starting dose of BIFRIL 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 BIFRIL.
Pharmacokinetics in hepatic dysfunction
The Cmax and Tmax values for zofenoprilat in patients with mild or moderate hepatic dysfunction following a single dose 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 BIFRIL for patients with mild or 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 heart 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 immune-mediated blood dyscrasia was found at high doses.
No significant changes in cytochrome P450 activities were observed in monkeys in a one-year repeated oral toxicity study.
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 gestation caused fetal and developmental toxicity in rats and embryo and fetotoxicity in rabbits, but only at maternally toxic doses.
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 carcinogenicity study conducted in mice, an increased incidence of testicular atrophy was observed; the clinical relevance of this phenomenon is not known.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, anhydrous colloidal silica.
Coating: hypromellose, titanium dioxide (E 171), macrogol 400, macrogol 6000.
06.2 Incompatibility
Not relevant
06.3 Period of validity
3 years.
06.4 Special precautions for storage
No special storage precautions.
06.5 Nature of the immediate packaging and contents of the package
PVDC / PVC / aluminum or Aclar / aluminum blisters, packs of:
BIFRIL 7.5 mg - 12, 14, 15, 28, 30, 48, 50, 56, 90 or 100 film-coated tablets; 50 and 56 film-coated tablets in perforated unit dose blisters
BIFRIL 15 mg - 12, 14, 15, 28, 30, 50, 56, 90 or 100 film-coated tablets; 50 and 56 film-coated tablets in perforated unit dose blisters
BIFRIL 30 mg - 7, 14, 15, 28, 30, 50, 56, 90 or 100 film-coated tablets; 50 and 56 film-coated tablets in perforated unit dose blisters
BIFRIL 60 mg - 14, 15, 28, 30, 50, 56, 90 or 100 film-coated tablets; 50 and 56 film-coated tablets in perforated unit dose blisters
Not all pack sizes may be marketed
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Luso Farmaco Institute of Italy S.p.A. - Milanofiori - Road 6 - Building L - Rozzano (Mi)
08.0 MARKETING AUTHORIZATION NUMBER
BIFRIL 7.5 mg: 12 blister tablets PVDC / PVC / aluminum AIC n. 034408017
14 blister tablets PVDC / PVC / aluminum AIC n. 034408029
28 tablets blister PVDC / PVC / aluminum AIC n. 034408031
48 tablets blister PVDC / PVC / aluminum AIC n. 034408043
12 tablets blister Aclar / aluminum AIC n. 034408144
14 Aclar / aluminum AIC blister tablets n. 034408157
28 tablets blister Aclar / aluminum AIC n. 034408169
48 tablets Aclar / aluminum AIC blister n. 034408171
BIFRIL 15 mg: 12 blister tablets PVDC / PVC / aluminum AIC n. 034408056
14 blister tablets PVDC / PVC / aluminum AIC n. 034408068
28 tablets blister PVDC / PVC / aluminum AIC n. 034408070
12 tablets blister Aclar / aluminum AIC n. 034408183
14 Aclar / aluminum AIC blister tablets n. 034408195
28 tablets Aclar / aluminum AIC blister n. 034408207
BIFRIL 30 mg: 14 blister tablets PVDC / PVC / aluminum AIC n. 034408082
28 tablets blister PVDC / PVC / aluminum AIC n. 034408094
56 tablets blister PVDC / PVC / aluminum AIC n. 034408106
14 Aclar / aluminum AIC blister tablets n. 034408219
28 tablets Aclar / aluminum AIC blister n. 034408221
56 tablets Aclar / aluminum AIC blister n. 034408233
BIFRIL 60 mg: 14 blister tablets PVDC / PVC / aluminum AIC n. 034408118
28 tablets blister PVDC / PVC / aluminum AIC n. 034408120
56 tablets blister PVDC / PVC / aluminum AIC n. 034408132
14 Aclar / aluminum AIC blister tablets n. 034408245
28 tablets blister Aclar / aluminum AIC n. 034408258
56 tablets Aclar / aluminum AIC blister n. 034408260
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 30 July 1998
Renewal date: July 30, 2008
10.0 DATE OF REVISION OF THE TEXT
February 2015
