Bifrizide - Package Leaflet

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

Active ingredients: Zofenopril (Zofenopril calcium), Hydrochlorothiazide

Bifrizide 30mg / 12.5mg film-coated tablets

Why is Bifrizide used? What is it for?

Bifrizide contains 30 mg of zofenopril calcium and 12.5 mg of hydrochlorothiazide as active ingredients

  • Zofenopril calcium is a cardiovascular medicine that belongs to a group of blood pressure lowering medicines called angiotensin converting enzyme (ACE) inhibitors.
  • Hydrochlorothiazide is a diuretic that works by increasing the amount of urine produced.

Bifrizide is used to treat mild to moderate high blood pressure (hypertension) when it cannot be controlled by taking the drug zofenopril alone.

Contraindications When Bifrizide should not be used

Do not take Bifrizide if:

  • is beyond the third month of pregnancy (it is better to avoid taking Bifrizide even in the early stages of pregnancy - see "pregnancy" section).
  • you are allergic (hypersensitive) to zofenopril or to "hydrochlorothiazide or to any of the other ingredients contained in the medicine (see section 6:" What Bifrizide contains "and the final part of section 2:" 'Bifrizide contains lactose ").
  • you are allergic (hypersensitive) to other substances derived from sulfonamides (such as hydrochlorothiazide which is a product derived from sulphonamide).
  • have had previous allergic reactions to another ACE inhibitor such as captopril or enalapril.
  • have a history of severe swelling and itching around the face, nose and throat (angioneurotic edema) associated with previous ACE inhibitor therapy or have hereditary / idiopathic angioneurotic edema (rapid swelling of the skin, tissues, digestive tract and other organs).
  • suffer from severe liver or kidney problems.
  • suffer from narrowing of the arteries of the kidneys.
  • 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 Bifrizide

Talk to your doctor before taking Bifrizide if:

  • have liver and kidney problems.
  • have high blood pressure due to a kidney problem or narrowing of the artery leading to the kidneys (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 aldosteronism)
  • 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 areas)
  • is undergoing desensitization treatment ("allergy injections") for insect bites.
  • suffer from lupus erythematosus (a disorder of the immune system, your body's defense system)
  • tend to have low blood potassium levels and particularly if you have prolonged QT syndrome (a type of ECG abnormality) or if you take digitalis (to help pump the heart)
  • have diabetes
  • if you have angina or a disorder that affects the brain, as low blood pressure can lead to heart attack or stroke
  • 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 Bifrizide".

The hydrochlorothiazide in the drug Bifrizide may cause hypersensitivity of the skin to sunlight or artificial UV rays. Stop taking Bifrizide and tell your doctor if you develop a rash, itchy areas or sensitive skin during treatment (see also section 4).

Anti-doping test: Bifrizide can give positive results in the anti-doping test.

If your blood pressure becomes too low during treatment with Bifrizide, especially after the first dose (this is much more common if you have also taken other diuretics, are dehydrated or on a low-salt diet, or if you have a disease or diarrhea). If this happens, notify your doctor immediately and then lie down on your back (see also section 4).

If you need to have surgery, tell your anesthetist that you are taking Bifrizide before receiving anesthesia. This will help the anesthetist to check your blood pressure and heart rate during the procedure.

You should tell your doctor if you think you are (or could be) pregnant. The use of Bifrizide is not recommended in the early stages of pregnancy and should not be taken if you are beyond the third month of pregnancy, as the drug can cause serious harm to your baby if used at this stage (see "pregnancy" section). ).

Children and adolescents

The use of Bifrizide is not recommended in children and adolescents below 18 years of age as its safety has not been established.

Interactions Which drugs or foods can modify the effect of Bifrizide

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 blood potassium levels (e.g. trimethoprim, potassium supplements, potassium-sparing diuretics, such as spironolactone, triamterene, amiloride), potassium-containing salt substitutes
  • other drugs that affect the levels of chemicals in the blood (Adrenocorticotropic hormone - ACTH - used to stimulate the body's production of certain hormones, injections of amphotericin B, carboxonexolone, stimulant laxatives)
  • lithium (used to treat mood disorders)
  • anesthetics
  • narcotic medications (such as morphine)
  • antipsychotic drugs (used to treat schizophrenia and similar diseases)
  • tricyclic antidepressants, 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 adjust 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 Bifrizide" 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 break down your body's defenses)
  • drugs used for gout (e.g. probenecid, sulfinpyrazone, and allopurinol)
  • insulin and other oral antidiabetics
  • cytostatic agents (used in the treatment of cancer or in 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, hay fever and pressor amines such as adrenaline)
  • calcium salts
  • digitalis (used to help the heart pump)
  • cholestyramine and colestipol resins (used to lower cholesterol)
  • medicines used to relax muscles (e.g. tubocurarine)
  • amantidine (an antiviral drug)

Bifrizide with food, drink and alcohol

Bifrizide can be taken either with food or on an empty stomach, but always with water. To facilitate swallowing, the tablet can be divided into two parts to be swallowed one after the other.

Alcohol increases the hypotensive (blood pressure lowering) effect of Bifrizide; ask your doctor for more information on drinking alcohol while 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 Bifrizide before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Bifrizide. Taking Bifrizide is not recommended in the early stages of pregnancy. pregnancy and should not be taken when beyond the third month of pregnancy, as the drug can cause serious harm to your baby if used after the third month of pregnancy.

Feeding time

If you are breast-feeding or about to start breast-feeding ask your doctor for advice before taking this medicine. Bifrizide is not recommended for nursing mothers and your doctor may choose another medicine that is suitable for you if you wish to continue breastfeeding, particularly if you are breastfeeding a newborn or premature baby.

Driving and using machines

This drug can cause dizziness, or fatigue. If these conditions occur, do not drive vehicles or use machines.

Bifrizide 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 Bifrizide: Posology

Always take Bifrizide exactly as your doctor has told you. If in doubt, consult your doctor.

The recommended dose of Bifrizide is one tablet per day.

Bifrizide can be taken with food or on an empty stomach. It is preferable to take the tablet with water.

Use in children and adolescents

The use of this medicine is not recommended in children and adolescents under the age of 18. If you are over 65 and have impaired kidney function, Bifrizide may not be the right medicine for you (see section 2 - "Warnings and precautions. ")

If you forget to take Bifrizide

If you have forgotten to take a dose of the medicine, take the next dose as soon as you remember. However, if the time for your next dose is near, skip the missed dose and take your next scheduled normal dose at the usual time. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Bifrizide

Always consult your doctor before stopping treatment with Bifrizide. If you have any further questions on the use of Bifrizide, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Bifrizide

If you accidentally take more tablets than you should, contact your doctor or nearest emergency department immediately (take any remaining tablets, the box or this leaflet with you if possible). The most frequent symptoms and signs of an overdose are low blood pressure with fainting (hypotension), very slow heart rate (bradycardia), changes in blood chemistry (electrolytes), kidney dysfunction, excessive urination resulting in dehydration, nausea and sleepiness, muscle spasms, heart rhythm disturbances (particularly if you are taking digitalis or other medicines for heart rhythm problems).

Side Effects What are the side effects of Bifrizide

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

The following undesirable effects were reported in clinical studies with Bifrizide:

Common side effects (seen in less than one in every 10 people treated):

  • dizziness
  • headache
  • cough.

Less common side effects (seen in less than 1 in every 100 people treated):

  • infections
  • bronchitis
  • sore throat
  • increase in cholesterol and / or other lipids in the blood, increase in blood glucose, potassium, uric acid, creatinine and liver enzymes
  • decrease in potassium in the blood
  • insomnia
  • drowsiness, fainting, muscle stiffness (hypertonia)
  • angina, myocardial infarction, atrial fibrillation, palpitations
  • hot flashes, low blood pressure, high blood pressure
  • nausea, indigestion, gastritis, inflammation of the gums, dry mouth, stomach pain
  • rapid onset of swelling, especially of the lips, cheeks, eyelids, tongue, palate, larynx, with possible sudden difficulty in breathing (angioneurotic edema). If you have any of these, it means you have a "severe allergy to Bifrizide. You may need urgent medical attention, or be hospitalized.
  • skin diseases characterized by pink scaly areas (psoriasis), acne, dry skin, itching, hives
  • backache
  • increased amount of urine (polyuria)
  • generalized weakness (asthenia), flu-like symptoms, peripheral swelling (usually around the ankles)
  • impotence

The following side effects have not been reported in clinical trials with Bifrizide, but have been reported for zofenopril calcium and / or other ACE inhibitors, so they can also occur with the use of Bifrizide:

  • Tiredness (fatigue). Severely low blood pressure at the start of treatment or when the dose is increased, with dizziness, change in vision, fainting; low blood pressure on standing.
  • Chest pain, muscle aches and / or cramps
  • Change in consciousness, sudden dizziness, sudden blurring of vision or weakness and / or loss of sensation to touch on one side of the body (transient ischemic attack or stroke).
  • Decreased kidney function, changes in the daily amount of urine, presence of protein in the urine (proteinuria)
  • Vomiting, diarrhea, constipation
  • Allergic skin reactions with peeling, redness, sagging and eruptions of the skin (toxic epidermal necrolysis), worsening of psoriasis, hair loss (alopecia).
  • Increased sweating
  • Changes in mood, depression, sleep disturbances
  • Altered skin sensations such as burning, tingling, tingling (paraesthesia)
  • Disturbed balance, confusion, ringing in the ears (tinnitus), changes in taste, blurred vision.
  • Difficulty breathing, narrowing of the airways in the lungs (bronchospasm), sinusitis, stuffy or runny nose (rhinitis), inflammation of the tongue (glossitis)
  • Yellowing of the skin (jaundice), inflammation of the liver or pancreas (hepatitis, pancreatitis), intestinal obstruction (ileus).
  • Changes in blood tests, counts of red blood cells, white blood cells or platelets or a reduction in the number of all blood cells (pancytopenia): contact your doctor if you notice that you develop bruising easily or have an unexplained sore throat or fever.
  • Increase in the level of bilirubin and urea in the blood.
  • Anemia due to breakdown of red blood cells (haemolytic anemia), which can occur if you have G6PD (glucose-6-phosphate dehydrogenase) deficiency.

The following side effects have not been reported in clinical trials with Bifrizide, but have been reported for hydrochlorothiazide, so they could also occur with the use of Bifrizide:

  • Change in the production of new blood cells by the bone marrow (bone marrow failure)
  • Fever, whole organism allergic reaction (anaphylactic reaction)
  • Altered levels of body fluids (dehydration) and blood chemicals (electrolytes), gout, diabetes, metabolic alkalosis.
  • Apathy, nervousness, agitation.
  • Convulsions, decreased levels of awareness, coma, paresis
  • Yellowed vision (xanthopsia), worsening of myopia, decreased lacrimation
  • Vertigo (spinning sensation)
  • Heart rhythm disturbances (arrhythmias), changes in the electrocardiogram
  • Formation of blood clots in the veins (thrombosis) and embolisms, circulatory collapse (shock)
  • Respiratory stress, inflammation of the lungs (pneumonia), formation of fibrous tissue in the lungs (interstitial lung disease), accumulation of fluid in the lungs (pulmonary edema)
  • Thirst, lack of appetite (anorexia), lack of bowel movement (paralytic ileus), excessive gas in the stomach, inflammation of the salivary glands (sialadenitis), increased blood amylase (an enzyme in the pancreas, hyperamylasemia), inflammation of the gallbladder ( gallbladder)
  • Purple spots on the skin (purpura), increased sensitivity of the skin to sunlight, rash (especially facial) and / or red patches which can cause scarring (cutaneous lupus erythematosus), inflammation of blood vessels resulting in tissue necrosis (vasculitis necrotizing)
  • Acute kidney failure (with reduced urine production and increased fluid and waste products in the body), inflammation of the connective tissue inside the kidneys (interstitial nephritis), sugar in the urine.

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 of the Italian Medicines Agency - Website: http://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 store Bifrizide above 30 ° C

Do not use Bifrizide after the expiry date ("EXP") which is stated on the outer carton and blister.

Always keep your tablets in the original package.

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.

Deadline "> Other information

What Bifrizide contains

The active ingredients are 30mg zofenopril calcium and 12.5mg hydrochlorothiazide.

The other ingredients are:

  • Tablet core: microcrystalline cellulose, lactose monohydrate, maize starch, hypromellose, colloidal anhydrous silica, magnesium stearate.
  • Coating: Opadry Pink 02B24436 (hypromellose, titanium dioxide (E 171), macrogol 400, red iron oxide (E172), macrogol 6000 (see paragraph 2 "Bifrizide contains lactose")

What Bifrizide looks like and contents of the pack

Bifrizide 30mg / 12.5mg tablets are pastel red, round, slightly biconvex film-coated tablets with a score line on one side. The score line on the tablet is to facilitate breaking for easier swallowing and not to divide into equal doses. The tablets are available in packs of 14, 28, 30, 50, 56, 90 or 100 tablets.

Not all pack sizes may be marketed.

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

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

01.0 NAME OF THE MEDICINAL PRODUCT -

BIFRIZIDE TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each film-coated tablet contains 28.7 mg of zofenopril (equivalent to 30 mg of zofenopril calcium) and 12.5 mg of hydrochlorothiazide.

Excipients with known effects:

Each film-coated tablet contains 56.20 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Pastel red, round, slightly biconvex film-coated tablets with a score line on one side.

The score line on the tablet is intended to facilitate breaking for easier swallowing and not to divide into equal doses.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Treatment of mild to moderate essential hypertension.

This fixed dose combination is indicated in those patients whose blood pressure is not adequately controlled with Zofenopril alone.

04.2 Posology and method of administration -

General

BIFRIZIDE should be taken once daily, with or without food.

Dose titration with the individual components (ie Zofenopril and Hydrochlorothiazide) is recommended before switching to the fixed dose combination.

When clinically appropriate, a direct switch from monotherapy to fixed dose combination can be considered.

To facilitate swallowing, the tablets can be divided into two parts to be swallowed one after the other, at the time of administration.

Adults (18 to 65 years old)

Patients who are not hypovolaemic or without salt depletion:

The usually effective dose is one tablet once a day.

Patients with suspected hypovolaemia or salt depletion

The use of BIFRIZIDE is not recommended

Elderly (over 65 years of age)

Dosage adjustments are not required in the elderly with normal creatinine clearance.

In the elderly with reduced creatinine clearance (less than 45ml / min) the use of BIFRIZIDE is not recommended. Creatinine clearance can be estimated from serum creatinine levels using the Cockroft-Gault formula:

Creatinine Clearance (ml / min) = (140-age) xx weight (Kg) 72 x Serum Creatinine (mg / dL)

This formula provides the creatinine clearance in men. In women, the value obtained must be multiplied by 0.85.

Pediatric population (under 18 years of age)

The safety and efficacy of BIFRIZIDE in children and adolescents have not been established. Therefore, its use is not recommended in children and adolescents.

Patients with renal impairment and on dialysis

In hypertensive patients with mild renal dysfunction (creatine clearance> 45ml / min.) BIFRIZIDE can be used with the same dosage and regimen (once daily) as patients with normal renal function.

In patients with moderate to severe dysfunction (creatine clearance

In patients with severe renal dysfunction (creatinine clearance

In hypertensive patients undergoing dialysis the use of BIFRIZIDE is not recommended.

Patients with impaired hepatic function

In hypertensive patients with mild to moderate hepatic dysfunction in whom the monotherapy dose of 30 mg of Zofenopril is achieved, the same dosage regimen as in patients with normal hepatic function can be used. BIFRIZIDE is contraindicated in hypertensive patients with severe hepatic dysfunction.

04.3 Contraindications -

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

• Hypersensitivity to Zofenopril or any other ACE inhibitor.

• Hypersensitivity to hydrochlorothiazide or other sulfonamide-derived substances.

• Hypersensitivity to any of the excipients.

• History of angioneurotic edema associated with previous ACE inhibitor therapy.

• Hereditary / idiopathic angioneurotic edema.

• Severe impairment of liver function.

• Severe impairment of renal function (creatinine clearance

• Bilateral stenosis of the renal arteries or unilateral stenosis in the case of a single kidney.

• The concomitant use of Bifrizide with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR

04.4 Special warnings and appropriate precautions for use -

ZOFENOPRIL

Hypotension:

Like other ACE inhibitors and diuretics, BIFRIZIDE can cause a substantial decrease in blood pressure, especially after the first dose, although symptomatic hypotension has rarely been reported in uncomplicated hypertensive patients. & EGRAVE; this is more likely to occur in patients with hypovolaemia and electrolyte depletion caused by diuretic therapy, 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. & EGRAVE; this condition is more likely to occur in patients with a more severe degree of heart failure, treated with high doses of loop diuretics, with hyponatraemia or impaired renal function.

In patients with a high risk of symptomatic hypotension, treatment should begin under close medical supervision, preferably in the hospital, with a low dose and careful dose titration.

If possible, treatment with diuretics should be temporarily discontinued upon initiation of Zofenopril therapy.

These considerations are also applicable to patients with angina pectoris or with cerebrovascular disease in whom an excessive reduction in blood pressure could cause a myocardial infarction or cerebrovascular events.

In case of hypotension, the patient should be reclined in the supine position. Volumetric repletion may be required by intravenous administration of saline. The onset of hypotension following the administration of the first dose does not preclude the possibility of careful titration of the dose of the drug components once the event has completely resolved.

Patients with renovascular hypertension:

Hypertensive patients with bilateral stenosis of the renal arteries or stenosis of the afferent artery to a solitary kidney when treated with ACE inhibitors are at increased risk of developing severe hypotension and renal failure. Diuretics therapy may be a contributing cause. Loss of renal function. it can also occur with only slight alterations in serum creatinine levels even in patients with unilateral renal artery stenosis.

In these patients, therapy should be initiated under close medical supervision, with low doses, careful titration and monitoring of renal function.

Patients with renal insufficiency:

During therapy, renal function should be closely monitored as deemed appropriate. Cases of renal failure associated with the administration of ACE inhibitors have been reported, mainly in patients with severe heart failure with renal disease including renal artery stenosis. Some patients with no apparent pre-existing renal disease have developed elevations in blood urea and blood creatinine, particularly when given concomitant administration of a diuretic. It may therefore be necessary to reduce the dosage of the individual components. Close monitoring of renal function is recommended during the first few weeks of therapy.

Patients on dialysis:

Dialysis patients using high flux polyacrylonitrile membranes (eg AN 69) and treated with ACE inhibitors may develop anaphylactoid reactions such as facial swelling, flushing, hypotension and dyspnoea within minutes of starting hemodialysis. The use of alternative membranes or alternative antihypertensive drugs is recommended.

The efficacy and safety of Zofenopril in patients with myocardial infarction undergoing hemodialysis have not been established, therefore the drug should not be used in these patients.

Patients in LDL apheresis:

Patients treated with an ACE inhibitor undergoing LDL apheresis with dextran sulfate may develop anaphylactic reactions similar to those seen in patients undergoing hemodialysis with high flux membranes (see above). It is recommended that an antihypertensive drug belonging to a different class be used in these patients.

Anaphylactic reactions during desensitizing therapy or in case of insect bites:

Rarely, patients taking ACE inhibitors during desensitizing therapy (e.g. hymenoptera venom) or after insect bites have experienced life-threatening anaphylactic reactions. In the same patients, these reactions were avoided by temporarily withholding ACE inhibitor therapy, but they reappeared following inadvertent re-administration of the 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 BIFRIZIDE to patients who have recently undergone kidney transplantation. Therefore use in transplant recipients is not recommended.

Primary aldosteronism:

Patients with primary aldosteronism generally do not respond to antihypertensive drugs which act by inhibiting the renin-angiotensin system. Therefore, the use of Zofenopril is not recommended in such cases.

Angioedema:

Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx may occur in patients treated with ACE inhibitors, especially during the first weeks of treatment. However, in rare cases, severe angioedema may develop after long-term treatment with angiotensin converting enzyme inhibitors. Treatment with ACE inhibitors should be stopped immediately and replaced with an agent belonging to another class of antihypertensive drugs.

Angioedema of the tongue, glottis, or larynx can be fatal. In these cases, emergency therapy should be given that includes, but is not necessarily limited to, immediate subcutaneous injection of a 1: 1000 (0) adrenaline solution. , 3 to 0.5 ml) or a slow intravenous infusion of adrenaline 1 mg / ml (which should be diluted as directed) under careful monitoring of the electrocardiogram and blood pressure. The patient should be hospitalized and kept under observation for at least 12-24 hours and discharged only after complete resolution of symptoms.

Even in cases where there is only swelling of the tongue, without respiratory changes, the patient must be observed, as treatment with antihistamines and corticosteroids may not be sufficient.

Angiotensin converting enzyme inhibitors can cause angioedema more frequently in black patients.

Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of angioedema when treated with ACE inhibitors (see section 4.3 Contraindications).

Cough:

During treatment with ACE inhibitors, a dry non-productive cough may arise which disappears when therapy is discontinued. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Liver failure:

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 experiencing jaundice or marked elevation of liver enzymes, should discontinue ACE inhibitor therapy and undergo appropriate medical follow-up.

Hyperkalemia:

Hyperkalaemia may occur during treatment with ACE inhibitors. This effect is generally attenuated by the potassium loss induced by thiazide diuretics. Patients at risk for hyperkalaemia include individuals with renal insufficiency, diabetes mellitus, or those concomitantly using potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or patients taking concomitantly other active substances associated with "increase in serum potassium levels (eg heparin). If concomitant use of the above mentioned agents is deemed appropriate, frequent monitoring of serum potassium is recommended (see section 4.5).

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

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

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

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

Surgery / anesthesia:

ACE inhibitors can cause hypotension or even hypotensive shock in patients undergoing major surgery or anesthesia, due to blocking the formation of angiotensin II in response to compensatory renin release. If ACE administration cannot be stopped. -inhibitor, carefully monitor the blood volume.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy:

ACE inhibitors should be used with caution in patients with mitral valve stenosis and left ventricular outflow obstruction and avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

Neutropenia / agranulocytosis:

Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. The risk of neutropenia appears to be related to dosage and type of drug and is dependent on the patient's clinical status. It rarely occurs in patients without complications, but can occur in patients with renal impairment of varying degrees, particularly when associated with collagenopathies eg. systemic lupus erythematosus, scleroderma, immunosuppressive drug therapy, allopurinol or procainamide or when there is 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, a white blood cell count and a white blood cell count should be done before starting therapy, at two-week intervals during the first three months of zofenopril therapy and periodically thereafter. During treatment, patients should be instructed to report any signs of infection (e.g. sore throat, fever) when performing a white blood cell count. Zofenopril and other concomitant medications (see section 4.5) should be discontinued in case of neutropenia (neutrophils below 1000 / mm³) or if this condition is suspected. The condition is reversible after discontinuation of the ACE inhibitor.

Psoriasis:

ACE inhibitors should be used with caution in patients with psoriasis.

Proteinuria:

Proteinuria may occur particularly in patients with pre-existing renal impairment or who are taking a relatively high dose of ACE inhibitors. In patients with a history of kidney disease, a check for proteinuria (test strip on an early morning urine sample) should be performed prior to treatment and periodically thereafter.

Diabetic patients:

In diabetic patients already being treated with oral antidiabetics or insulin, blood glucose levels should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).

Lithium:

The concomitant use of lithium and BIFRIZIDE is generally not recommended (see section 4.5).

Ethnicity:

As with other angiotensin converting enzyme inhibitors, zofenopril may be less effective in lowering blood pressure in black patients. Angiotensin converting enzyme inhibitors may also cause angioedema more frequently in black patients.

Pregnancy:

ACE inhibitor treatment should not be undertaken during pregnancy. Patients planning pregnancy should undergo alternative antihypertensive treatment for which a pregnancy safety profile has been established, unless continued ACE inhibitor therapy is deemed essential. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if deemed appropriate, alternative therapy should be started (see Sections 4.3 and 4.6).

HYDROCHLOROTHIAZIDE

Renal impairment:

In patients with renal disease, thiazide diuretics may increase azotemia. In patients with impaired renal function, cumulative effects of this active substance may occur. If there is progression of renal impairment, indicated by an increase in non-protein nitrogen, it is necessary to proceed to a "careful re-evaluation of the therapy, also taking into consideration the suspension of the diuretic.

Hepatic impairment:

Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, as slight alterations in the hydroelectric balance can lead to hepatic coma.

Metabolic and endocrine effects:

Therapy with thiazide diuretics can impair glucose tolerance. Dosage adjustments of insulin and oral hypoglycaemics may be required (see section 4.5). Latent diabetes mellitus may become clinically manifest during therapy with thiazide diuretics. Increases in triglyceride and cholesterol levels have been associated with thiazide diuretic therapy. Therapy with thiazide diuretics can lead to hyperuricaemia and / or gout in some patients.

Electrolyte imbalance:

As with any patient undergoing diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazide diuretics, including hydrochlorothiazide, can cause hydroelectric imbalance (hypokalaemia, hyponatremia, and hypochloraemic alkalosis). Signs of an electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, agitation, muscle aches and cramps, muscle weakness, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Although the use of thiazide diuretics may lead to hypokalaemia, concomitant therapy with zofenopril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with cirrhosis of the liver, in patients with profuse diuresis, in patients with inadequate oral electrolyte intake and in patients on concomitant treatment with corticosteroids or ACTH (see section 4.5).

In hot weather, dilution hyponatremia may occur in oedematous patients. Chloride deficiency is usually mild and usually does not require treatment.

Thiazide diuretics may decrease urine calcium excretion and may cause urine and may cause mild and intermittent rise in serum calcium in the absence of known disturbances of calcium metabolism. Marked hypercalcemia may be an expression of latent hyperparathyroidism. Thiazide diuretics should be discontinued before testing for parathyroid function.

Thiazide diuretics have been shown to increase urinary excretion of magnesium with possible consequent hypomagnesaemia.

Lupus erythematosus:

Exacerbation or activation of systemic lupus erythematosus has been reported in conjunction with the use of thiazide diuretics.

Anti-doping test:

The hydrochlorothiazide contained in this drug can lead to a positive result in the doping test.

Other:

Sensitization reactions can occur in patients with or without a history of allergy or bronchial asthma.

Cases of photosensitivity have been reported with thiazide diuretics (see section 4.8). If photosensitivity episodes occur during treatment, discontinuation of therapy is recommended. If re-administration of diuretics is deemed necessary, it is recommended that areas exposed to sunlight or artificial UVA be protected

COMBINATION ZOFENOPRIL / HYDROCHLOROTHIAZIDE

In addition to the warnings relating to single components, the following must be borne in mind:

Pregnancy:

The use of BIFRIZIDE is not recommended during the first trimester of pregnancy (see section 4.6).

Patients with renal insufficiency:

In view of the effects of zofenopril and hydrochlorothiazide in patients with impaired renal function, BIFRIZIDE should not be administered to patients with moderate to severe renal impairment (creatinine clearance

Risk of hypokalaemia:

The combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Therefore, regular monitoring of serum potassium levels should be performed.

Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption:

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.

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

ZOFENOPRIL

Concomitant use not recommended

Potassium-sparing diuretics or potassium supplements:

ACE inhibitors reduce diuretic induced potassium loss. Potassium-sparing diuretics eg. spirolactone, triamterene or amiloride, potassium supplements, or potassium-containing substitute salts can lead to significant increases in serum potassium levels. If concomitant use is indicated due to a documented condition of hypokalaemia they should be used with caution and with frequent monitoring of serum potassium and electrocardiogram levels (see section 4.4).

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 (thiazide diuretics 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). Hypotensive effects may be reduced by discontinuation of the diuretic by increasing fluid intake. and go up or starting therapy with a low dose of Zofenopril.

Anesthetic pharmaceutical products:

ACE inhibitors may potentiate the hypotensive effects of some anesthetics.

Narcotics / tricyclic antidepressants / antipsychotics / barbiturates:

Postural hypotension may occur.

Other antihypertensive substances (e.g. beta blockers, alpha blockers, calcium channel blockers):

Additive or potentiating hypotensive effects may occur. Use nitroglycerin and other nitrates or other vasodilators with caution.

Cimetidine:

It may increase the risk of hypotensive effects.

Ciclosporin:

Concomitant use of ACE inhibitors increases the risk of renal dysfunction.

Allopurinol, procainamide, cytostatic or immunosuppressive agents:

Concomitant use of ACE inhibitors increases the risk of hypersensitivity reactions. Data from other ACE inhibitors indicate an increased risk of leukopenia with concomitant use.

Antidiabetics:

In rare cases, ACE inhibitors may potentiate the hypoglycemic effects of insulin and oral antidiabetics, such as sulphonylureas, 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 with concomitant administration of ACE inhibitors.

Sympathomimetics:

They can reduce the antihypertensive effects of ACE inhibitors; patients should be monitored to verify that the desired antihypertensive effects are being achieved.

Antacids:

They reduce the bioavailability of ACE inhibitors.

Food:

It may reduce the rate but not the amount of zofenopril absorption.

Gold:

Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension which can be very severe) following the injection of gold products (eg sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitors.

Additional information

CYP enzymes: No direct clinical data on the interaction of Zofenopril with other active substances metabolised by CYP enzymes are available. However, in vitro metabolic studies with Zofenopril did not demonstrate potential interactions with active substances metabolised by CYP enzymes.

HYDROCHLOROTHIAZIDE

Concomitant use requiring caution

Cholestyramine and colestipol resins:

The absorption of hydrochlorothiazide is compromised by the presence of ion exchange resins. Single doses of cholestyramine or colestipol resins bind with hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by 85% and 43%, respectively Sulfonamide diuretics should be taken at least one hour before or four to six hours after taking these medicines.

Corticosteroids, ACTH, amphotericin B (parenteral), carbenoxolone, stimulant laxatives:

They may intensify electrolyte depletion, particularly hypokalaemia in cases of concomitant use of hydrochlorothiazide.

Calcium salts:

An increase in serum calcium levels, as a consequence of decreased excretion, may occur following concomitant administration with thiazide diuretics.

Cardiac glycosides:

Hypokalaemia or hypomagnesaemia induced by thiazide diuretics favor the onset of digitalis-induced cardiac arrhythmias.

Drugs associated with torsades de pointes:

Due to the risk of hypokalaemia, caution should be exercised in co-administration of hydrochlorothiazide and drugs associated with torsades de pointes, such as some antiarrhythmics, some antipsychotics, or other drugs with a known risk of induction of torsades de pointes.

Pressor amines (e.g. adrenaline):

Possible reduction of the response to pressor amines, but not sufficient to preclude their administration with hydrochlorothiazide.

Musculoskeletal relaxants, non-depolarizing (e.g. tubocurarine):

Possible enhancement of responsiveness to the muscle relaxant when used with hydrochlorothiazide.

Amantadina:

Thiazide diuretics may increase the risk of side effects caused by amantadine.

Drugs used in the treatment of gout (probenecid, sulfinpyrazone, allopurinol):

Dosage adjustment of the uricosuric drug may be necessary as hydrochlorothiazide may increase serum uric acid levels.

The dosage of probenecid or sulfinpyrazone may need to be increased. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Additional information

Interactions with laboratory tests:

Due to the effects on calcium metabolism, thiazide diuretics may interfere with parathyroid function tests.

COMBINATION ZOFENOPRIL / HYDROCHLOROTHIAZIDE

In addition to the interactions related to the monocomponents, the following must also be taken into account:

Concomitant use not recommended

Lithium: Concomitant use of thiazide diuretics may increase the risk of lithium toxicity by further increasing the risk of lithium toxicity due to the concomitant use of ACE inhibitors. Therefore, the use of BIFRIZIDE in combination with lithium is not recommended and careful monitoring of serum lithium levels should be performed if concomitant administration is necessary.

Laboratory Tests: Thiazide diuretics may decrease plasma protein bound iodine (PBI) values ​​in the absence of signs of thyroid dysfunction.

Concomitant use requiring caution

Non-steroidal anti-inflammatory drugs (including acetylsalicylic acid ≥ 3g / day): Administration of non-steroidal anti-inflammatory drugs may reduce the antihypertensive effect of ACE inhibitors and diuretics. In addition, NSAIDs and ACE inhibitors have been reported to exert an effect. additive on the increase of serum potassium, while renal function may decrease.

These effects are in principle reversible and occur especially in patients with impaired renal function. Acute renal failure may occur rarely, particularly in patients with impaired renal function, such as elderly or dehydrated patients.

Alcohol: Potentiates the hypotensive effect of ACE inhibitors and hydrochlorothiazide.

Trimethoprim: Concomitant administration of ACE inhibitors and thiazide diuretics with trimethoprim increases the risk of hyperkalaemia.

04.6 Pregnancy and breastfeeding -

Use in pregnancy

Zofenopril and HCTZ

Given the effects of the individual components of this combination during pregnancy, the use of BIFRIZIDE is not recommended during the first trimester of pregnancy (see section 4.4). The use of BIFRIZIDE is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Zofenopril

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is deemed necessary, patients planning pregnancy should undergo alternative antihypertensive treatment for which a safety profile has been established for use in pregnancy. diagnosed pregnancy, 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 may induce fetotoxicity in humans (decreased renal function, oligohydramnios, retarded "cranial ossification) and neonatal toxicity (renal impairment, hypotension, hyperkalaemia) (see section 5.3). In case of exposure to ACE inhibitors from the second trimester of during pregnancy, an ultrasound check of renal function and skull is recommended Infants whose mothers have taken ACE inhibitors should be closely monitored for the risk of hypotension (see Sections 4.3 and 4.4).

Hydrochlorothiazide

Experience with the use of hydrochlorothiazide in pregnancy, especially during the first trimester, is limited. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can compromise fetal-placental perfusion and can cause fetal and neonatal effects such as jaundice, alterations of the " electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be administered in the case of gestational edema, gestational hypertension or pre-eclampsia due to the risk of placental hypovolaemia and hypoperfusion without benefit on the course of the disease.

Hydrochlorothiazide should not be used in the case of essential hypertension in pregnant women except in rare cases in which there are no therapeutic alternatives.

Feeding time:

Since no information is available regarding the use of BIFRIZIDE during lactation, the use of the drug is not recommended and it is preferable to resort to alternative treatments, for which the safety profile during lactation has been evaluated, especially if breastfeeding a newborn or premature baby.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in breast milk in small quantities. Thiazides in high doses, cause intense diuresis, and can inhibit milk production. The use of Bifrizide during breastfeeding is not recommended. If Bifrizide is used during breastfeeding. breastfeeding, doses should be kept as low as possible.

04.7 Effects on ability to drive and use machines -

No studies on the effects of the drug on the ability to drive and use machines have been performed. Remember that drowsiness, dizziness or fatigue may occasionally occur when driving vehicles or when operating machinery.

04.8 Undesirable effects -

In controlled clinical trials involving 597 patients randomized to receive zofenopril plus hydrochlorothiazide, no specific adverse reactions were observed for this.

Association.

Adverse reactions were limited to those previously reported with zofenopril calcium or hydrochlorothiazide.

The incidence of undesirable effects showed no correlation with the gender or age of the patients. The table below shows all adverse reactions that have been reported during clinical trials as at least probably-possibly related to treatment with zofenopril / hydrochlorothiazide 30 / 12.5. They are listed by organ-system class and classified with indication of frequency using the following convention: very common (≥1 / 10); common (≥1 / 100,

Infections and Infestations Uncommon: Infection, bronchitis, pharyngitis. Metabolism and nutrition disorders Uncommon: Hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalaemia, hyperkalaemia, hyperuricemia. Psychiatric disorders Uncommon: Insomnia Nervous system disorders Common: Vertigo, headache Uncommon: Somnolence, syncope, hypertonia. Cardiac pathologies Uncommon: Angina pectoris, atrial fibrillation, myocardial infarction, palpitations Vascular pathologies Uncommon: Hot flashes, hypotension, hypertension Respiratory, thoracic and mediastinal disorders Common: Cough Uncommon: Dyspnea Gastrointestinal disorders Uncommon: Nausea, dyspepsia, gastritis, gingivitis, dry mouth, abdominal pain. Skin and subcutaneous tissue disorders Uncommon: Angioedema, psoriasis, acne, dry skin, itching, hives. Musculoskeletal and connective tissue disorders Uncommon: Backache Renal and urinary disorders Uncommon: Polyuria General disorders and administration site conditions Uncommon: Asthenia, flu-like syndrome, peripheral edema Diseases of the reproductive system and breast Uncommon: Erectile dysfunction Diagnostic tests Uncommon: Increased creatinine, abnormal liver function tests.

Further information on the individual components:

Adverse reactions that are known for each component administered as monotherapy may occur during treatment with BIFRIZIDE:

Zofenopril

The most common side effects typical of ACE inhibitors that occurred in clinical trials in patients treated with zofenopril are the following:

Nervous system disorders Common Vertigo, 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 spasms General disorders and administration site conditions Common Fatigue Uncommon Asthenia

The following adverse reactions have been observed in association with ACE inhibitor therapy.

Disorders of the blood and lymphatic system

Agranulocytosis and pancytopenia can occur in a small number of patients.

Cases of haemolytic anemia have been reported in patients with glucose-6-phosphate dehydrogenase deficiency.

Endocrine pathologies

Not known, inappropriate antidiuretic hormone secretion

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

Single cases of tachycardia, palpitations, arrhythmia, angina pectoris, myocardial infarction have been reported with the administration of ACE inhibitors in conditions of hypotension.

Vascular pathologies

Cases of severe hypotension have occurred with initiation or escalation of therapy. This is particularly the case in certain risk groups (see Special warnings and precautions for use). Symptoms such as dizziness, a feeling of weakness, impaired vision and rarely loss of consciousness (syncope) may occur in association with hypotension.

Flushing may rarely occur.

Respiratory, thoracic and mediastinal disorders

Symptoms such as dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have been reported rarely. In a minimal subset of patients, ACE inhibitors have been associated with the onset of angioneurotic edema affecting the face and oropharyngeal tissues. In isolated cases angioneurotic edema affecting the upper respiratory tract responsible for the fatal obstruction of the respiratory tract.

Gastrointestinal disorders

Occasionally, abdominal pain, diarrhea, constipation, and dry mouth may occur.

Single cases of pancreatitis and ileus have been described in association with the intake of ACE inhibitors.

Very rare cases of angioedema of the small intestine.

Hepatobiliary disorders

Single cases of cholestatic jaundice and hepatitis have been described in association with the intake of ACE inhibitors.

Skin and subcutaneous tissue disorders

Occasionally allergic and hypersensitivity reactions such as itching, urticaria, erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like efflorescence, alopecia may occur.

These symptoms may be accompanied by fever, myalgia, arthralgia, eosinophilia, and / or increased ANA titers.

Hyperhidrosis can rarely occur.

Musculoskeletal and connective tissue disorders

Occasionally, myalgia can occur

Renal and urinary disorders

Kidney failure may occur or the condition may be intensified. Cases of acute renal failure have been reported (see Special warnings and precautions for use).

Urination disturbances may occur rarely.

Diseases of the reproductive system and breast

In rare cases, erectile dysfunction can occur.

General disorders and administration site conditions

In very rare cases peripheral edema and chest pain.

Diagnostic tests

Increases in blood urea and creatinine may occur, particularly in the presence of renal insufficiency, severe heart failure, and reno-vascular hypertension, which are reversible on discontinuation of the drug. "hematocrit, platelet count, and white blood cell count. Increases in serum liver enzyme and bilirubin levels have also been reported.

Hydrochlorothiazide

Adverse reactions reported with the use of hydrochlorothiazide monotherapy include the following:

Disorders of the blood and lymphatic system

Leukopenia, neutropenia / agranulocytosis, thrombocytopenia, aplastic anemia, haemolytic anemia, bone marrow depression

Disorders of the immune system

Anaphylactic reactions

Metabolism and nutrition disorders

Anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperukemia, electrolyte imbalance (including hyponatremia, hypokalaemia, hypomagnesaemia, hypochloraemia, hypercalcaemia), hyperglycemia, hyperamylasemia.

Psychiatric disorders

Apathy, confusion, depression, nervousness, agitation, sleep disturbances.

Nervous system disorders

Convulsions, decreased level of consciousness, coma, headache, dizziness, paraesthesia, paresis.

Eye disorders

Xanthopsia, blurred vision, myopia (aggravated), decreased lacrimation.

Ear and labyrinth disorders

Dizziness.

Cardiac pathologies

Cardiac arrhythmia, palpitations.

Vascular pathologies

Orthostatic hypotension, thrombosis, embolism, shock.

Respiratory, thoracic and mediastinal disorders

Pneumonia, interstitial lung disease, pulmonary edema.

Gastrointestinal disorders

Dry mouth, nausea, vomiting, stomach upset, diarrhea, constipation, abdominal pain, paralytic ileus, flatulence, sialoadenitis, pancreatitis.

Hepatobiliary disorders

Cholestatic jaundice, colicystitis.

Skin and subcutaneous tissue disorders

Pruritus, purpura, urticaria, photosensitivity reactions, rash, cutaneous lupus erythematosus, necrotizing vasculitis, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

muscle spasms, myalgia.

Renal and urinary disorders

renal dysfunction, acute renal failure, interstitial nephritis, glycosuria.

Diseases of the reproductive system and breast

Erectile dysfunction.

General disorders and administration site conditions

Asthenia, fever, fatigue, thirst.

Diagnostic tests

Changes in the electrocardiogram, increased cholesterol and increased triglyceridemia.

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. "Italian Medicines Agency.

Website: http://www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

Typical symptoms of overdose are severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure.

Treatment is symptomatic and supportive.

In case of excessive intake, the patient should be kept under close observation, preferably in an intensive care unit.

Serum electrolytes and creatinine should be checked frequently.

Therapeutic measures depend on the nature and severity of the symptoms.

If ingestion has occurred recently, measures to prevent absorption may be implemented, such as gastric lavage and administration of adsorbing agents and sodium sulphate.

If hypotension occurs, the patient should be placed in a safe position and it must be considered whether it is appropriate to use plasma expanders with caution and / or administer angiotensin II.

Bradycardia or severe vagal reactions should be treated by administering atropine.

The application of a pacemaker may be considered.

ACE inhibitors can be eliminated from the bloodstream by hemodialysis.

The use of high flux polyacrylonitrile membranes should be avoided. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis.

The most common signs and symptoms of overdose are nausea and sleepiness.

Hypokalaemia can cause muscle spasms and / or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: ACE inhibitors and diuretics

ATC code: C09B A 15

Zofenopril and hydrochlorothiazide tablets in combination

BIFRIZIDE is a fixed-dose combination containing zofenopril, an angiotensin converting enzyme (ACE) inhibitor and hydrochlorothiazide, a thiazide diuretic.

The two components have complementary modes of action and exert an additive antihypertensive effect.

Zofenopril is a sulfhydryl ACE inhibitor that works by blocking the enzyme that catalyzes the conversion of angiotensin I to the vasoconstrictor peptide angiotensin II, and thus leads to a lowering of vasopressor activity and a reduction in aldosterone secretion.

This latter decrease can result in an increase in serum potassium concentration, along with sodium and fluid loss.

The reduction of angiotensin II negative feedback on renin secretion leads to an increase in plasma renin activity. The mechanism by which Zofenopril reduces blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system.

The angiotensin converting enzyme (ACE) is identical to kininase II, an enzyme that degrades bradykinin, a potent vasodilator peptide that appears to play a role in the therapeutic effect of ACE inhibitors.

Hydrochlorothiazide is a diuretic and antihypertensive agent.

It acts on the mechanism of electrolyte reabsorption at the level of the distal renal tubule.

Hydrochlorothiazide increases the excretion of sodium and chloride in approximately equivalent amounts.

Natriuresis can be accompanied by the loss of potassium and bicarbonate.

Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of Zofenopril tends to offset the potassium loss associated with these diuretics.

With hydrochlorothiazide, diuresis begins within 2 hours, peaks in approximately 4 hours and lasts for approximately 6-12 hours.

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 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 -

Concomitant administration of zofenopril and hydrochlorothiazide has little or no effect on the bioavailability of both active substances.

The combination tablet is bioequivalent to the simultaneous administration of the two single components separately.

ZOFENOPRIL

Zofenopril is a prodrug, as the active inhibitor is zofenoprilat, ie the molecule with the free sulfhydryl group, resulting from the hydrolysis of the thio-ester bond.

Absorption

Zofenopril 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 over the dose range of 10 to 80 mg of zofenopril and no accumulation occurs after administration of 15 to 60 mg of zofenopril for 3 weeks.

The 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 radiolabelled dose of zofenopril is approximately 88% bound to plasma proteins and the steady-state volume of distribution is 96 liters.

Biotransformation

Eight metabolites, responsible for 76% of urinary radioactivity, have been identified in human urine following a radiolabelled dose of zofenopril. The major metabolite is zofenoprilat (22%), which is metabolised by various pathways, including glucurono-conjugation (17%), cyclization and glucurono-conjugation (13%), conjugation with cysteine ​​(9%) and S -methylation of the thiol group (8%).

Elimination

Intravenously administered radiolabelled zofenoprilat is eliminated in urine (76%) and faeces (16%), while after administration of an oral dose of radiolabelled zofenopril 69% and 26% of the radioactivity is found in urine and faeces, respectively. indicating a double route of elimination (kidney and liver). The half-life of zofenoprilat is 5.5 hours and the total clearance is 1300 ml / min after oral administration of zofenopril.

Pharmacokinetics in the elderly

Dosage adjustments are not required in elderly people with normal renal function.

Pharmacokinetics in renal insufficiency

Based on the comparison of the main pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabelled zofenopril, patients with mild renal impairment (creatinine clearance> 45 and 90 ml / min). In patients with moderate to severe renal impairment (7-44 mL / min), the elimination rate is reduced by approximately 50% of normal. In patients with end-stage renal disease and undergoing hemodialysis or peritoneal dialysis, the elimination rate is reduced to 25% of normal.

Pharmacokinetics in hepatic insufficiency

The Cmax and Tmax values ​​for zofenoprilat in patients with mild to moderate hepatic dysfunction after single dose of radiolabelled zofenopril are the same as in normal subjects.

However, AUC values ​​in cirrhotic patients are approximately double those obtained for normal subjects, indicating that the starting dose of zofenopril for patients with mild to moderate hepatic dysfunction should be half that given for patients with functional normal liver. There are no pharmacokinetic data for zofenopril and zofenoprilat in patients with severe hepatic dysfunction, therefore zofenopril is contraindicated in these patients.

HYDROCHLOROTHIAZIDE

Absorption

Hydrochlorothiazide after oral administration is well absorbed (65-75%).

Plasma concentrations are linearly related to the administered dose.

The absorption of hydrochlorothiazide depends on the intestinal transit time, it increases when the intestinal transit time is slow, for example when administered with food.

By monitoring plasma levels for at least 24 hours, the plasma half-life was observed to range from 5.6 to 14.8 hours and peak plasma levels were observed within 1-5 hours after administration.

Distribution

Thiazide diuretics are widely distributed in body fluids and bind extensively (92%) to plasma proteins, particularly albumin, and in this the substituted thiazide diuretics prove to be the most highly bound.

This results in a lower renal clearance than the first compounds and a longer duration of action. No relationship has been demonstrated between plasma levels of hydrochlorothiazide and the degree of reduction in blood pressure.

Elimination

Hydrochlorothiazide is eliminated primarily by the kidney.

Most of the thiazide diuretic is excreted unchanged in the urine and more than 95% of hydrochlorothiazide is recovered unchanged in the urine within 3-6 hours of the oral dose.

In patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged.

Hydrochlorothiazide crosses the placental but not the blood brain barrier.

05.3 Preclinical safety data -

The fixed combination zofenopril / hydrochlorothiazide demonstrated no special hazard for human use based on acute toxicity, repeated dose toxicity and genotoxicity studies.

The reproductive toxicity of the combination was studied in rats and rabbits, and zofenopril and hydrochlorothiazide were not shown to be teratogenic.

However, the combination markedly increased maternal toxicity induced by zofenopril alone in pregnant rats and rabbits. Carcinogenicity studies have not been conducted with the zofenopril / hydrochlorothiazide combination. Carcinogenicity studies conducted in mice and rats with zofenopril alone showed no evidence of carcinogenicity.

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

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Tablet core:

Microcrystalline cellulose

Lactose monohydrate

Cornstarch

Hypromellose

Anhydrous colloidal silica

Magnesium stearate

Coating:

Opadry Pink 02B24436:

Hypromellose

Titanium dioxide (E 171)

Macrogol 400

Red iron oxide (E 172)

Macrogol 6000

06.2 Incompatibility "-

Not relevant

06.3 Period of validity "-

3 years

06.4 Special precautions for storage -

Do not store at temperatures above 30 ° C

06.5 Nature of the immediate packaging and contents of the package -

PVC / Aluminum blisters coated with PVDC

Packs of 14, 28, 30, 56, 50, 90 or 100 film-coated tablets

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

No special instructions

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Luso Farmaco Institute of Italy SpA - Milanofiori - Street 6 - Building L - Rozzano (MI)

08.0 MARKETING AUTHORIZATION NUMBER -

14 film-coated tablets - AIC n. 036823019

28 film-coated tablets - AIC n. 036823021

30 film-coated tablets - AIC n. 036823033

50 film-coated tablets - AIC n. 036823045

56 film-coated tablets - AIC n. 036823058

90 film-coated tablets - AIC n. 036823072

100 film-coated tablets - AIC n. 036823060

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 12 April 2006

Date of most recent renewal: March 3, 2009

10.0 DATE OF REVISION OF THE TEXT -

April 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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