FOSIPRES 10 mg Tablet

FOSIPRES 10 mg tablets
fosinopril sodium salt

Pharmacotherapeutic category
ACE inhibitors (angiotensin converting enzyme inhibitors), not associated.

THERAPEUTIC INDICATIONS
FOSIPRES is indicated for the treatment of arterial hypertension and heart failure.

Contraindications
Hypersensitivity to the active substance, to other ACE inhibitors or to any of the excipients.
Hereditary, idiopathic or ACE inhibitor-associated angioedema.
Anuria.
Second and third trimester of pregnancy (see section Special warnings).
Paediatric age (see section Precautions for use).
The concomitant use of Fosipres with medicines containing aliskiren is contraindicated in patients affected
by diabetes mellitus or renal impairment (glomerular filtration rate GFR <60
ml/min/1.73m2) (see section "Interactions").

Precautions for use
Consult your doctor or pharmacist before taking Fosipres.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists
or aliskiren increases the risk of hypotension, hyperkalaemia and reduced renal function
(including acute renal failure). Dual blockade of the RAAS through the combined use of ACE-
inhibitors, angiotensin II receptor antagonists or aliskiren is therefore not recommended (see
sections "Contraindications" and "Interactions").
If dual blockade therapy is considered absolutely necessary, this should only occur under the
supervision of a specialist and with close and frequent monitoring of renal function,
electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used
simultaneously in patients with diabetic nephropathy.
Angioedema of the neck and head
With the use of ACE inhibitors, including fosinopril, cases of angioedema have been reported,
especially after the first doses, although, rarely, they have been observed after a
prolonged period of treatment. This event requires discontinuation of therapy and replacement
of the ACE inhibitor with a different antihypertensive agent. This phenomenon affects the extremities, face, lips, mucous membranes, tongue, glottis or larynx.
Angioedema involving the tongue, glottis and/or larynx can lead to
airway obstruction and sometimes be fatal; therefore, prompt adoption of appropriate
emergency measures is required, including, among other things, subcutaneous injection of a 1:1000 solution of
adrenaline (0.3-0.5 ml).
In the case of angioedema localized to other areas, therapy should be immediately
suspended and the patient should be treated appropriately and kept under close monitoring until the
complete resolution of the clinical picture.
Intestinal angioedema: intestinal angioedema has been rarely reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or
vomiting); in some cases there was no history of facial angioedema and C-1 esterase levels were normal.
Angioedema was diagnosed by abdominal CT or ultrasound, or with surgery, and the
symptoms resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be
included in the differential diagnosis of patients treated with ACE inhibitors who present with abdominal
pain.
Anaphylactoid reactions
Anaphylactoid reactions have been observed in patients undergoing ACE inhibitor therapy during hemodialysis
with high-flux dialysis membranes and during low-density lipoprotein (LDL) apheresis
performed with dextran sulfate columns. These patients should be treated with particular attention,
especially in the case of previous similar reactions. The use of alternative membranes or
other antihypertensive drugs is recommended.
In two patients treated with hymenoptera venom (e.g., insects such as bees, wasps,
etc.) desensitization, the simultaneous administration of another ACE inhibitor, enalapril, caused
severe and sustained anaphylactoid reactions. Therefore, in this case, an antihypertensive of a different
class should be used.
Hypotension
As with other ACE inhibitors, a marked hypotensive response may occur during
treatment with FOSIPRES, especially on the first dose. Symptomatic hypotension is
rare in uncomplicated hypertension.
It is more likely in certain at-risk patient categories, such as those with salt and/or fluid depletion
of any etiology (e.g., intensive diuretic therapy) and in patients undergoing renal dialysis. In these cases, it is
necessary to restore hydro-electrolyte balance before starting treatment. In these patients
tachycardia may occur.
ACE inhibitor-induced hypotension has been reported, primarily, in patients with severe heart failure or renal insufficiency.
In subjects with congestive heart failure, both with and without renal dysfunction,
ACE inhibitors can cause excessive hypotension, sometimes associated with azotemia or oliguria,
up to a picture of acute renal failure, potentially fatal. In these subjects, therapy should be
initiated under close medical supervision, preferably in a hospital setting; patients
should be monitored especially during the first 2 weeks of treatment and on the occasion of
dose increases. In addition, consideration should be given to the possibility of suspending diuretic treatment or reducing the dose of the diuretic in subjects with normal or low blood pressure who
are undergoing intensive diuretic treatment or who show a picture of hyponatremia. These precautions
also apply to patients with ischemic heart disease or cerebrovascular disorders in whom
excessive hypotension can cause myocardial infarction or stroke.
If hypotension develops, place the patient in a supine position and, if necessary, administer
physiological solution.
In patients with heart failure, a reduction in blood pressure is not in itself a condition
sufficient to interrupt treatment. This reduction, often desirable in heart failure, is usually greater at the beginning of treatment. The effect tends to stabilize
during the first two weeks and disappear thereafter with a return to pre-treatment blood pressure
values without a reduction in therapeutic efficacy.
Renovascular hypertension
In patients with renovascular hypertension, the risk of severe hypotension and renal failure is
increased by the administration of ACE inhibitors. Diuretic treatment may represent
a predisposing factor. In these patients, the initiation of therapy with ACE inhibitors and dose increase
should be carried out under close medical supervision, preferably in a hospital setting. Diuretics should be suspended and renal function monitored during the first
weeks of therapy.
Impaired renal function
In the treatment with ACE inhibitors, patients with pre-existing congestive heart failure,
renovascular hypertension (renal artery stenosis affecting one or both kidneys) and severe
fluid and/or salt depletion, have an increased risk of developing signs of renal dysfunction
(increased creatinine, azotemia and serum potassium; proteinuria; alterations in urine volume) that
however regress upon discontinuation of therapy.
Mild and transient increases in azotemia and creatinine are occasionally possible even in
patients with apparently intact renovascular function, particularly if undergoing concomitant treatment
with diuretics.
This event occurs more frequently in subjects with a previous alteration of renal
function. In subjects with severe heart failure, renal function may depend on the
renin-angiotensin-aldosterone system.
In these subjects, treatment with ACE inhibitors may induce hyperazotemia and oliguria which rarely
progress to a picture of acute renal failure, sometimes fatal.
Although this event has not been described with FOSIPRES, if such cases should occur, it is
advisable to suspend any diuretic therapy or reduce the dose or discontinue FOSIPRES.
Hepatic insufficiency
Since FOSIPRES is partially converted into the active form at the hepatic level, in subjects with
severe hepatic insufficiency, such conversion may be slowed, generating elevated plasma levels of
fosinopril. In these cases, it is advisable to observe the patient's response in relation to the
dose adopted.
In a study in patients with alcoholic or biliary cirrhosis, the total clearance of fosinopril resulted
decreased with an AUC approximately doubled.
In rare cases, ACE inhibitors have been associated with a syndrome that began with cholestatic jaundice and
progressed to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this clinical picture is not known. Patients treated with ACE inhibitors who show a marked
increase in liver enzymes or jaundice should discontinue treatment and be appropriately
followed by the doctor.
Hyperkalaemia
In the treatment with ACE inhibitors, including fosinopril, the presence of the following conditions may
determine a greater risk of hyperkalaemia: renal insufficiency, heart failure, diabetes
mellitus, concomitant use of potassium-sparing diuretics, taking potassium supplements
and/or saline substitutes containing potassium, use of other drugs that cause an increase in potassium
serum (e.g.: heparin). In these situations, regular monitoring of potassium levels is appropriate.
Anesthesia/Surgery
During surgery or during anesthesia with hypotensive agents, FOSIPRES may
increase the hypotensive response. If it is not possible to discontinue the ACE inhibitor, careful monitoring of circulatory volume is required.
Neutropenia/Agranulocytosis
Treatment with other ACE inhibitors has been, in rare cases, associated with agranulocytosis and bone marrow depression, particularly in patients with associated renal insufficiency and/or collagen disease (e.g., SLE,
scleroderma) or immunosuppressive drug treatment. The available data are not sufficient to
demonstrate that fosinopril does not cause agranulocytosis. Periodic monitoring of
white blood cells is recommended in patients with renal insufficiency and/or collagen diseases and these patients should be
warned to immediately report any indication of infection (such as sore throat,
fever) which may be a sign of neutropenia.
Aortic stenosis/hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in patients with obstruction of the left ventricular outflow tract.
Cough
A cough has been reported during treatment with ACE inhibitors, including FOSIPRES. This is typically a
non-productive, persistent cough that resolves after discontinuation of therapy. ACE-
inhibitors should be considered in the differential diagnosis of cough.
Elderly patients
In clinical studies, no difference was noted between the efficacy or safety of use of
fosinopril in elderly patients compared to that observed in younger patients.
However, it is not possible to exclude a greater antihypertensive response in some of the
older patients. Assessment of renal function and careful medical monitoring are recommended
at the start of treatment.
Use in paediatrics
The product should not be used in paediatric age, as there is currently insufficient experience in this regard.

Interactions

• 1. Diuretics As with other ACE-Inhibitors, a marked hypotensive response, more frequent in the first hours after administration, may occur with FOSIPRES, when the patient has been pre-treated with high doses of diuretics or in case of a low-sodium diet or dialysis.
• 2. Antacids The concomitant administration of antacids (e.g. aluminum hydroxide, magnesium hydroxide, simethicone) may slightly reduce the intestinal absorption of FOSIPRES. Therefore, if associated, these should be administered 2 hours apart.
• 3. Potassium and potassium-sparing diuretics Treatment with FOSIPRES may reduce potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene and others) or the administration of potassium salts may increase the risk of hyperkalemia. Therefore, the use of such drugs, if required, must be practiced with caution and potassium levels must be checked frequently.
• 4. Lithium In patients treated concurrently with ACE-Inhibitors and lithium, increases in lithium blood levels and symptoms of lithium intoxication have been described. Therefore, the concomitant administration of the two drugs should be done with caution and lithium blood levels should be checked frequently. The concomitant administration of a diuretic may increase the toxicity of lithium.
• 5. Anesthetics ACE-Inhibitors may potentiate the hypotensive effect of some anesthetics.
• 6. Narcotics/antipsychotics The concomitant administration of ACE-Inhibitors and narcotics/antipsychotics may cause orthostatic hypotension.
• 7. Hypoglycemic agents The concomitant administration of ACE-Inhibitors and antidiabetic drugs (oral hypoglycemic agents or insulin) may cause an increase in the hypoglycemic effect of the latter, with a greater risk of hypoglycemia, especially during the first weeks of combined treatment and in patients with impaired renal function.
• 8. Prostaglandin inhibitors It has been reported that indomethacin reduces the antihypertensive efficacy of ACE-Inhibitors, especially in subjects with low-renin hypertension. Other non-steroidal anti-inflammatory compounds (e.g. acetylsalicylic acid) may have similar effects.
• 9. Sympathomimetics May reduce the antihypertensive effect of ACE-Inhibitors.
• 10. Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide Concomitant administration with ACE-Inhibitors may increase the risk of leucopenia.
• 11. Alcohol Increases the hypotensive effect.

• 12. NSAIDs When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (e.g. selective Cox 2 inhibitors, acetylsalicylic acid starting from 325 mg/day and non-selective NSAIDs), an attenuation of the antihypertensive effect may occur. The concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function including possible acute renal failure and increased serum potassium levels, especially in patients with pre-existing impaired renal function. The combination should be administered with caution especially in the elderly. Patients should be adequately hydrated and monitoring of renal function should be considered at the beginning of concomitant therapy.
• 13. Interaction with laboratory tests Fosinopril may interfere with the determination of plasma digoxin levels, resulting in values lower than actual when determined by charcoal absorption methods such as Digi-Tab. Alternatively, the Coat-A-Count method, which is based on "COATED-TUBE" antibodies, can be used. In addition, therapy with FOSIPRES should be discontinued a few days before laboratory evaluation of parathyroid function.
• 14. Others FOSIPRES and its metabolites do not cause interactions with food. Single or multiple dose pharmacokinetic interaction studies with acetylsalicylic acid, chlortalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, warfarin, have not shown modifications in the bioavailability of unbound fosinopril. The bioavailability, protein binding and anticoagulant effect of warfarin (evaluated with prothrombin time) were not altered by the concomitant administration of FOSIPRES.

ACE-inhibitors, angiotensin II receptor antagonists or aliskiren:
Data from clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor antagonists or aliskiren, is associated with an increased frequency of adverse events such as hypotension, hyperkalemia and reduced renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see paragraphs "Contraindications" and "Precautions for use").

Special warnings
In case of ascertained sugar intolerance, contact your doctor before taking the medicine.
Pregnancy and breastfeeding

Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy.
The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see paragraph Contraindications).
Therapy with ACE inhibitors should not be started during pregnancy.
Epidemiological evidence on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not yielded conclusive results; however, a small increase in risk cannot be ruled out.
For patients who are planning a pregnancy, the doctor must be immediately informed as alternative antihypertensive treatment with a proven safety profile for use in pregnancy must be used, unless continued therapy with an ACE inhibitor is considered essential.
When pregnancy is diagnosed, the doctor must be immediately informed as treatment with ACE inhibitors must be stopped immediately and, if appropriate, alternative therapy should be started.
If exposure to an ACE inhibitor occurs from the second trimester of pregnancy, ultrasound monitoring of renal function and the skull is recommended.
Newborns whose mothers have taken ACE inhibitors should be carefully monitored for hypotension, oliguria and hyperkalemia.

Breastfeeding
Since only very limited data are available regarding the use of FOSIPRES during breastfeeding, FOSIPRES is not recommended and alternative treatments with a proven safety profile for use during breastfeeding are preferred, especially in case of breastfeeding of newborns or premature infants
Effects on ability to drive and operate machinery
Although the medicine does not affect the ability to drive and operate machinery, very rarely side effects such as dizziness and visual disturbances may occur.

Dosage, method and duration of administration
Hypertension: the daily dosage necessary to maintain stable blood pressure control is between 10-40 mg. Most patients obtain adequate blood pressure control with a single daily dose of 20 mg.
The recommended initial dose of FOSIPRES (fosinopril sodium salt) is 10 mg once a day. The daily dosage may then be modified by evaluating the patient's blood pressure response.
In some patients treated with a single daily dose, a reduction in the antihypertensive effect may occur at the end of the dose interval. In such cases, a twice-daily dose should be considered. If blood pressure is not satisfactorily controlled with FOSIPRES in monotherapy, a diuretic may be added.
The concomitant administration of FOSIPRES with potassium supplements, potassium-sparing salt substitutes or potassium-sparing diuretics may lead to increases in potassium levels.
Heart failure: the initial dose of FOSIPRES is 10 mg once a day. The start of therapy must take place under medical supervision. If the initial dose is well tolerated, it may proceed, in agreement with the clinical response, to an increase in dosage up to 40 mg once a day.
The possible occurrence of hypotension after the initial dose should not, however, preclude a dosage increase. Obviously, hypotension must be carefully assessed and treated.
Fosinopril has a dual (hepatic and renal) elimination pathway and therefore, dose reductions are usually not necessary in patients with impaired hepatic or renal function.
High-risk patients
In high-risk patients, the first administration of an ACE-Inhibitor may induce marked hypotension (see paragraph Precautions for use).
The start of therapy requires, if possible, correction of any salt and/or water depletion, suspension of diuretic treatment for 2-3 days and use of the minimum dose. If this is not possible, in high-risk patients the normal dose should be halved.
In patients with malignant hypertension or severe heart failure, the start of therapy or dosage adjustment should be carried out in a hospital setting.
On the first administration of FOSIPRES and subsequent increases in the dosage of the ACE-Inhibitor and/or diuretic, high-risk patients of severe acute hypotension (see paragraph Precautions for use) should be monitored, preferably, in a hospital setting for a period sufficient to cover at least the peak of the antihypertensive effect of fosinopril (3-6 hours).
This also applies to patients with ischemic heart or brain disease in whom severe hypotension may cause myocardial infarction or stroke.
Use in the elderly
No dosage adjustment is necessary in the elderly as neither the pharmacokinetic parameters, nor the antihypertensive response, nor the safety of use are different from those found in young subjects.
However, it is not possible to exclude a greater response in some of the older patients.
Use in renal and hepatic insufficiency
Due to its peculiar dual and compensatory elimination, FOSIPRES does not require dosage adjustments. Only in patients with severe hepatic or renal insufficiency, it is advisable to start therapy with a dosage of 10 mg, subsequently adapting the dose to the patient's blood pressure response.

Duration of treatment
According to medical prescription.

Overdosage
No overdose syndromes from fosinopril have been described in humans.
The symptoms of ACE-Inhibitor overdose are: hypotension, shock, loss of consciousness, bradycardia, electrolyte disorders and renal failure.
In case of overdose, the patient should be kept under strict medical supervision, preferably in an intensive care unit, with frequent monitoring of serum electrolytes and creatinine levels. The suggested treatment includes inducing vomiting if ingestion is recent and/or gastric lavage or the administration of adsorbents or sodium sulfate within 30 minutes of ingestion.
If hypotension occurs, the patient should be kept in a supine position and rapidly administered liquid and saline supplements; if necessary, angiotensin II, atropine administration or pacemaker application should be considered.
FOSIPRES is poorly dialyzable. The clearance of fosinoprilate by hemodialysis and peritoneal dialysis is 2% and 7% of urea clearance, respectively.

UNDESIRABLE EFFECTS
The incidence of undesirable effects was the same in young and elderly patients (≥65 years).
The undesirable effects reported more frequently during controlled clinical studies with FOSIPRES
in hypertension(treatment duration from 2 to 3 months) are reported below:

Treatment discontinuation due to adverse event or alteration of laboratory parameters was 3% in the fosinopril group and 1.2% in the placebo group.
Other disorders reported with fosinopril and other ACE-Inhibitors are listed below

Adverse events possibly or probably related, or with uncertain correlation, to therapy
occurring in at least 1% of patients treated with fosinopril in controlled clinical studies versus placebo
in heart failureare: dizziness, cough, hypotension, nausea/vomiting, diarrhea, non-cardiac chest pain, orthostatic hypotension, palpitations, rash, weakness, angina pectoris.
Other adverse events possibly or probably related, or with uncertain correlation, to therapy
occurring in 0.4-1.0% of patients treated (exceptions in parentheses) with fosinopril in controlled clinical studies
versus placebo in heart failure are:

The following undesirable effects have been associated with ACE-Inhibitor therapy: anaphylactoid reactions
(see Precautions for use), agranulocytosis, pancytopenia, cholestatic or hepatocellular jaundice, erythema
multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia, paralytic ileus and a
syndrome including arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash, or other dermatological manifestations,
positivity for antinuclear antibodies, elevated ESR, eosinophilia and leukocytosis.
It is important to inform your doctor or pharmacist of the appearance of any undesirable effect

EXPIRY AND STORAGE
Expiry: see the expiry date reported on the packaging
The expiry date indicated refers to the product in intact packaging, correctly
stored.

Warning: do not use the medicine after the expiry date indicated on the packaging.
Special precautions for storage:store at room temperature protected from humidity.

Keep the medicine out of the reach and sight of children
Composition
Each tablet contains: active ingredient: fosinopril sodium salt 10 mg, excipients: anhydrous lactose,
microcrystalline cellulose, crospovidone, povidone, sodium stearyl fumarate.

Pharmaceutical form and content
Tablets for oral use.
FOSIPRES 10 mg tablets – 28 tablets

Marketing authorization holder:

• A. Menarini Industrie Farmaceutiche Riunite s.r.l., Via Sette Santi, 3 - Florence

Manufacturer responsible for batch release:
Bristol-Myers Squibb s.r.l., Località Contrada Fontana del Ceraso - Anagni (FR)

• A. Menarini Manufacturing Logistics and Services s.r.l., Loc. Campo di Pile - L'Aquila

February 2015.

SUMMARY OF PRODUCT CHARACTERISTICS

• 1. MEDICINE NAME: FOSIPRES 20 mg tablets

• 2. QUALITATIVE AND QUANTITATIVE COMPOSITION: each tablet contains. Active ingredient: fosinopril sodium salt 20 mg. For excipients see paragraph 6.1
• 3. PHARMACEUTICAL FORM: tablets for oral use, white in colour.
• 4. CLINICAL INFORMATION
• 4.1 Therapeutic indications FOSIPRES is indicated for the treatment of arterial hypertension and heart failure.
• 4.2 Dosage and method of administration Hypertension: the daily dosage necessary to maintain stable blood pressure control is between 10-40 mg. Most patients achieve adequate blood pressure control with a single daily dose of 20 mg. The recommended initial dose of FOSIPRES (fosinopril sodium salt) is 10 mg once a day. The daily dosage can then be modified by evaluating the patient's blood pressure response. In some patients treated with a single daily dose, a reduction in the antihypertensive effect may occur at the end of the dose interval. In such cases, a twice-daily dose should be considered. If blood pressure is not satisfactorily controlled with FOSIPRES in monotherapy, a diuretic may be added. The concomitant administration of FOSIPRES with potassium supplements, potassium-sparing salt substitutes or potassium-sparing diuretics may lead to increases in potassium levels. Heart failure: the initial dose of FOSIPRES is 10 mg once a day. The start of therapy must occur under medical supervision. If the initial dose is well tolerated, it may be proceeded, in accordance with the clinical response, to an increase in dosage up to 40 mg once a day. The possible occurrence of hypotension after the initial dose should not, however, preclude an increase in dosage. Obviously, hypotension should be carefully evaluated and treated. Fosinopril has a dual elimination pathway (hepatic and renal) and therefore, dose reductions are usually not necessary in patients with impaired hepatic or renal function. High-risk patients In high-risk patients, the first administration of an ACE-Inhibitor may induce marked hypotension (see paragraph 4.4). The start of therapy requires, if possible, correction of any saline and/or fluid depletion, suspension of diuretic treatment for 2-3 days and use of the minimum dose. If this is not possible, in high-risk patients the normal dose should be halved. In patients with malignant hypertension or severe heart failure, the start of therapy or dosage adjustment should be carried out in a hospital setting. On the first administration of FOSIPRES and subsequent increases in the dose of the ACE-Inhibitor and/or diuretic, high-risk patients for severe acute hypotension (see paragraph 4.4) should be monitored, preferably, in a hospital setting for a sufficient period to cover at least

the peak of the antihypertensive effect of fosinopril (3-6 hours).
This also applies to patients with ischemic or cerebral heart disease in which
severe hypotension can cause myocardial infarction or
cerebrovascular accident.
Use in elderly patients
No dosage adjustment is necessary in elderly subjects as neither
pharmacokinetic parameters, nor the antihypertensive response, nor the safety of use
are different from those found in younger subjects.
However, it is not possible to exclude a greater response in some of the
older patients.
Use in renal and hepatic insufficiency
Due to its peculiar dual and compensatory elimination, FOSIPRES does not require
dosage adjustments. Only in carriers of severe hepatic or renal insufficiency, it is advisable to start therapy with a dosage of 10 mg, subsequently adapting
the dose in function of the patient's blood pressure response.

• 4.3 Contraindications Hypersensitivity to the active ingredient, to other ACE-inhibitors or to any of the excipients. Hereditary, idiopathic or associated angioedema with previous administrations of ACE-Inhibitors. Anuria. Second and third trimester of pregnancy (see paragraphs 4.4 and 4.6). Pediatric age (see paragraph 4.6). The concomitant use of Fosipres with medicines containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR <60 ml/min/1.73m2) (see paragraphs
• 4.5 and 5.1).
• 4.4 Special warnings and precautions for use Angioedema of the neck and head Cases of angioedema have been reported with the use of ACE-Inhibitors, including fosinopril, especially after the first administrations, although, rarely, they have been observed after a prolonged period of treatment. This event requires discontinuation of therapy and replacement of the ACE-Inhibitor with a different antihypertensive. This phenomenon affects the extremities, face, lips, mucous membranes, tongue, glottis or larynx. Angioedema involving the tongue, glottis and/or larynx can lead to airway obstruction and sometimes be fatal; therefore, prompt adoption of appropriate emergency measures is required, including, among other things, subcutaneous injection of a 1:1000 solution of adrenaline (0.3-0.5 ml). In the case of angioedema localized to the remaining districts, therapy must be immediately suspended and the patient must be treated appropriately and kept under strict control until the clinical picture is completely resolved. Intestinal angioedema: intestinal angioedema has been rarely reported in patients treated with ACE-Inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no history of facial angioedema and C-1 esterase levels were normal. Angioedema was diagnosed by abdominal CT or ultrasound, or with surgery, and symptoms resolved after

suspension of the ACE-Inhibitor. Intestinal angioedema should be included in the
differential diagnosis of patients treated with ACE-Inhibitors who present with abdominal pain.
Anaphylactoid reactions
Anaphylactoid reactions have been observed in patients undergoing ACE-Inhibitor therapy
during hemodialysis with high-flux dialysis membranes and during low-density lipoprotein (LDL)
apheresis performed with dextran sulfate columns. These
patients should be treated with particular attention, especially in the case of
previous similar reactions. The use of alternative membranes or other
antihypertensive drugs is recommended.
In two patients treated with desensitizing therapy to hymenoptera venom (e.g., insects
such as bees, wasps, etc.), the simultaneous administration of another ACE-
Inhibitor, enalapril, caused severe and sustained anaphylactoid reactions. Therefore in
this case it is necessary to use an antihypertensive of a different class.
Hypotension
As with other ACE-Inhibitors, a marked hypotensive response may occur in
treatment with FOSIPRES, especially on the first dose.
Symptomatic hypotension is rare in uncomplicated hypertension.
It is more likely in some categories of patients at risk, such as those with saline and/or fluid depletion of any etiology (e.g. intensive diuretic therapy) and in subjects
undergoing renal dialysis. In these cases it is necessary to restore the hydro-
electrolyte balance before starting treatment. In these patients, tachycardia may occur.
Hypotension from ACE-Inhibitors has been reported, mainly, in patients with
severe heart failure or renal insufficiency.
In subjects with congestive heart failure, both in the presence and in the absence of
renal dysfunction, ACE-Inhibitors can cause excessive hypotension, sometimes
associated with hyperazotemia or oliguria, up to a picture of acute renal
failure, potentially fatal. In these subjects, therapy should be initiated under close
medical supervision, preferably in a hospital setting; patients should be
followed especially during the first 2 weeks of treatment and on the occasion
of dosage increases. In addition, the possibility of
suspending diuretic treatment or reducing the dosage of the diuretic in subjects with
normal or low blood pressure who are undergoing intensive treatment with diuretics
or who show a picture of hyponatremia. These precautions also apply to
patients with ischemic heart disease or cerebrovascular disorders in which
excessive hypotension can cause myocardial infarction or a
cerebrovascular accident.
In case of hypotension, place the patient in a supine position and, if necessary,
administer physiological solution.
In patients with heart failure, a decrease in blood pressure is not
a condition in itself sufficient to interrupt treatment. This
reduction is often desirable in heart failure, is usually greater
at the beginning of treatment. The effect tends to stabilize in the first two weeks and to
disappear later with the return to pre-treatment blood pressure values without
finding a reduction in therapeutic efficacy.
Renovascular hypertension
In patients with renovascular hypertension, the risk of severe hypotension and
renal insufficiency is increased by the administration of ACE-Inhibitors. The
treatment with diuretics may be a favoring factor. In these patients
the start of therapy with ACE-Inhibitors and the dosage increase should be
carried out under strict medical control, preferably in a hospital setting. The
diuretics should be suspended and renal function monitored during the
first weeks of therapy.
Impaired renal function
In treatment with ACE-Inhibitors, patients with pre-existing congestive heart failure,
renovascular hypertension (stenosis of the renal artery on one or
both kidneys) and intense saline and/or fluid depletion, have an increased risk of
developing signs of renal dysfunction (increased creatinine, azotemia and serum potassium
proteinuria; alterations in urine volume) which, however, regress upon discontinuation of therapy.
Mild and transient increases in azotemia and creatinine are occasionally possible
even in patients with apparently intact renovascular function, in particular if undergoing concomitant treatment with diuretics.
This event occurs more frequently in subjects with a history of
impaired renal function.
In subjects with severe heart failure, renal function may
depend on the renin-angiotensin-aldosterone system.
In these subjects, treatment with ACE-Inhibitor may induce hyperazotemia and
oliguria which rarely progresses to acute renal failure,
sometimes fatal.
Although this event has not been described with FOSIPRES, if such cases should
occur, it is advisable to suspend any diuretic therapy or reduce the dosage or suspension of FOSIPRES.
Hepatic insufficiency
Because FOSIPRES is partially converted into the active form at the hepatic level, in
subjects with severe hepatic insufficiency, such conversion may be slowed down,
generating elevated plasma levels of fosinopril. In these cases it is advisable to
observe the patient's response in function of the adopted dose.
In a study in patients with alcoholic or biliary cirrhosis, the total clearance of fosinopril
resulted decreased with an AUC approximately doubled.
In rare cases, ACE-Inhibitors have been associated with a syndrome that began with
cholestatic jaundice and progressed to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this clinical picture is unknown. Patients undergoing
treatment
with ACE-Inhibitors who show a marked increase in liver enzymes or jaundice
must interrupt the treatment and be appropriately followed by the doctor.
Hyperkalemia
In treatment with ACE-Inhibitors, including fosinopril, the presence of the following
conditions may determine a greater risk of hyperkalemia: renal insufficiency,
heart failure, diabetes mellitus, use of concomitant potassium-sparing diuretics, assumption of potassium supplements and/or salt substitutes containing
potassium, use of other drugs that cause increased serum potassium (e.g.:
heparin). In these situations, regular monitoring of potassium levels is appropriate.
Anesthesia/Surgery
During surgery or during anesthesia with hypotensive agents
FOSIPRES may increase the hypotensive response. If it is not possible to suspend
the ACE-Inhibitor, careful monitoring of the circulatory volume is required.
Neutropenia/Agranulocytosis
Treatment with other ACE-Inhibitors has been, in rare cases, associated with agranulocytosis
and bone marrow depression, in particular in patients with associated renal insufficiency
and/or collagen disease (e.g. SLE, scleroderma) or treatment with immunosuppressant drugs. The available data are not sufficient to demonstrate that
fosinopril does not cause agranulocytosis. Periodic monitoring of
white blood cells is recommended in patients with renal insufficiency and/or collagen diseases and these patients
must be warned to immediately report any indication of
infection (such as sore throat, fever) which may be a sign of
neutropenia.
Aortic stenosis/hypertrophic cardiomyopathy
ACE-Inhibitors should be used with caution in patients with obstruction of
the left ventricular outflow tract.
Cough
A cough has been reported during treatment with ACE-Inhibitors, including FOSIPRES. It
is typically a non-productive, persistent cough that resolves after
discontinuation of therapy. ACE-Inhibitors

vanno considerati nella diagnosi
differenziale della tosse.
Pazienti anziani
Negli studi clinici, non è stata notata alcuna differenza tra l’efficacia o la sicurezza
d’impiego del fosinopril nei pazienti anziani rispetto a quella osservata in quelli più
giovani.
Tuttavia, non è possibile escludere una maggiore risposta antipertensiva in alcuni tra
i pazienti più anziani. La valutazione della funzione renale e un attento controllo
medico sono raccomandati all’inizio del trattamento.
Gravidanza
La terapia con ACE inibitori non deve essere iniziata durante la gravidanza.
Per le pazienti che stanno pianificando una gravidanza si deve ricorrere a trattamenti
antiipertensivi alternativi, con comprovato profilo di sicurezza per l’uso in
gravidanza, a meno che non sia considerato essenziale il proseguimento della terapia
con un ACE inibitore. Quando viene diagnosticata una gravidanza, il trattamento con
ACE inibitori deve essere interrotto immediatamente e, se appropriato, deve essere
iniziata una terapia alternativa (vedere paragrafi 4.3 e 4.6).
Uso in pediatria
Il prodotto non va usato in età pediatrica, poichè finora non vi sono sufficienti
esperienze in merito.
Duplice blocco del sistema renina-angiotensina-aldosterone (RAAS)
Esiste l’evidenza che l'uso concomitante di ACE-inibitori, antagonisti del recettore
dell'angiotensina II o aliskiren aumenta il rischio di ipotensione, iperpotassiemia e
riduzione della funzionalità renale (inclusa l’insufficienza renale acuta). Il duplice
blocco del RAAS attraverso l'uso combinato di ACE-inibitori, antagonisti del
recettore dell'angiotensina II o aliskiren non è pertanto raccomandato (vedere
paragrafi 4.5 e 5.1).
Se la terapia del duplice blocco è considerata assolutamente necessaria, ciò deve
avvenire solo sotto la supervisione di uno specialista e con uno stretto e frequente
monitoraggio della funzionalità renale, degli elettroliti e della pressione sanguigna.
Gli ACE-inibitori e gli antagonisti del recettore dell'angiotensina II non devono essere
usati contemporaneamente in pazienti con nefropatia diabetica.
Le compresse contengono lattosio, non sono quindi adatte per i soggetti con deficit di
lattasi, galattosemia o sindrome da malassorbimento di glucosio/galattosio.

• 4.5 Interazioni con altri medicinali ed altre forme d'interazione
• Diuretici - Come con altri ACE-Inibitori, una marcata risposta ipotensiva, più frequente nelle prime ore successive alla somministrazione, potrebbe

verificarsi con FOSIPRES, quando il paziente è stato pre-trattato con alte
dosi di diuretici o in caso di dieta iposodica o dialisi.

• Antiacidi - La somministrazione contemporanea di antiacidi (es. idrossido di alluminio, idrossido di magnesio, simeticone) può ridurre leggermente l'assorbimento intestinale di FOSIPRES. Pertanto, se associati, questi andranno somministrati a distanza di 2 ore.
• Potassio e diuretici risparmiatori di potassio - Il trattamento con FOSIPRES può ridurre la perdita di potassio causata dai diuretici tiazidici. I diuretici risparmiatori di potassio (spironolattone, amiloride, triamterene ed altri) o la somministrazione dei sali di potassio possono far aumentare il rischio di iperpotassiemia. Pertanto, l'impiego di tali farmaci, se richiesto, deve essere praticato con cautela ed i livelli di potassiemia controllati frequentemente.
• Litio - Nei pazienti in trattamento contemporaneo con ACE-Inibitori e litio sono stati descritti aumenti dei livelli ematici di litio e sintomi di intossicazione da litio. Pertanto, la contemporanea somministrazione dei due farmaci dovrebbe essere fatta con cautela ed i livelli ematici di litio controllati frequentemente. La contemporanea somministrazione di un diuretico può accrescere la tossicità del litio.
• Anestetici - Gli ACE-Inibitori possono potenziare l’effetto ipotensivo di alcuni anestetici.
• Narcotici/antipsicotici - La somministrazione concomitante di ACE-Inibitori e narcotici/antipsicotici può causare ipotensione ortostatica.
• Ipoglicemizzanti - La somministrazione contemporanea di ACE-Inibitori e farmaci antidiabetici (ipoglicemizzanti orali o insulina) può causare un aumento dell'effetto ipoglicemizzante di questi ultimi, con maggiore rischio di ipoglicemia, soprattutto durante le prime settimane di trattamento combinato ed in pazienti con funzionalità renale compromessa.
• Inibitori delle prostaglandine - E' stato riportato che l'indometacina riduce l'efficacia antipertensiva degli ACE-Inibitori, soprattutto in soggetti con ipertensione a bassa renina. Altri composti antinfiammatori non steroidei (es. acido acetilsalicilico) potrebbero avere effetti similari.
• Simpaticomimetici - Possono ridurre l’effetto antipertensivo degli ACE-Inibitori.
• Allopurinolo, agenti citostatici o immunodepressori, corticosteroidi sistemici o procainamide - La somministrazione concomitante agli ACE-Inibitori può aumentare il rischio di leucopenia.
• Alcool - Aumenta l’effetto ipotensivo.
• FANS: quando gli ACE inibitori sono somministrati simultaneamente con farmaci antinfiammatori non steroidei (per es. inibitori selettivi della Cox 2, acido acetilsalicilico a partire da 325 mg/die e FANS non selettivi), si può verificare un’attenuazione dell’effetto antipertensivo. L’uso concomitante di ACE inibitori e FANS può portare ad un aumentato rischio di peggioramento della funzione renale che comprende possibile insufficienza renale acuta ed aumento dei livelli del potassio sierico specialmente in pazienti con pre-esistente compromessa funzione renale. La combinazione deve essere somministrata con cautela specialmente negli anziani. I pazienti devono essere adeguatamente idratati e deve essere preso in considerazione il monitoraggio della funzione renale all’inizio della terapia concomitante.
• Interazione con i test di laboratorio - Il fosinopril può interferire con la

determinazione dei valori plasmatici di digossina facendo risultare valori
inferiori a quelli reali quando determinati con metodiche di assorbimento su
carbone attivo come il Digi-Tab. In alternativa può essere usato il metodo
Coat-A-Count, che si basa su anticorpi "COATED-TUBE". Inoltre, la
terapia con FOSIPRES va interrotta alcuni giorni prima della valutazione di
laboratorio della funzione paratiroidea.

• ACE-inibitori, antagonisti del recettore dell'angiotensina II o aliskiren: I dati degli studi clinici hanno dimostrato che il duplice blocco del sistema renina-angiotensina-aldosterone (RAAS) attraverso l'uso combinato di ACE-inibitori, antagonisti del recettore dell'angiotensina II o aliskiren, è associato ad una maggiore frequenza di eventi avversi quali ipotensione, iperpotassiemia e riduzione della funzionalità renale (inclusa l’insufficienza renale acuta) rispetto all'uso di un singolo agente attivo sul sistema RAAS (vedere paragrafi 4.3, 4.4 e 5.1).
• Altre - FOSIPRES e i suoi metaboliti non provocano interazioni con il cibo. Gli studi di interazione farmacocinetica in dose singola o multipla con acido acetilsalicilico, clortalidone, nifedipina, propranololo, idroclorotiazide, cimetidina, metoclopramide, propantelina, digossina, warfarin, non hanno mostrato modificazioni della biodisponibilità del fosinopril non legato. La biodisponibilità, il legame proteico e l'effetto anticoagulante del warfarin (valutato con il tempo di protrombina) non sono risultati alterati dalla contemporanea somministrazione di FOSIPRES.
• 4.6 Gravidanza e allattamento

Gravidanza
L’uso di ACE inibitori non è raccomandato durante il primo trimestre di gravidanza
(vedere paragrafo 4.4). L’uso di ACE inibitori è controindicato durante il secondo
ed il terzo trimestre di gravidanza (vedere paragrafi 4.3 e 4.4).
L’evidenza epidemiologica sul rischio di teratogenicità a seguito dell’esposizione ad
ACE inibitori durante il primo trimestre di gravidanza non ha dato risultati
conclusivi; tuttavia non può essere escluso un piccolo aumento del rischio.
Per le pazienti che stanno pianificando una gravidanza si deve ricorrere a trattamenti
antiipertensivi alternativi, con comprovato profilo di sicurezza per l’uso in
gravidanza, a meno che non sia considerato essenziale il proseguimento della terapia
con un ACE inibitore.
Quando viene diagnosticata una gravidanza, il trattamento con ACE inibitori deve
essere immediatamente interrotto e, se appropriato, si deve iniziare una terapia
alternativa.
E’ noto che nella donna l’esposizione ad ACE inibitori durante il secondo ed il terzo
trimestre induce tossicità fetale (ridotta funzionalità renale, oligoidramnios in
associazione con contratture degli arti, sviluppo polmonare ipoplastico e ritardo
sviluppo intrauterino, ritardo nell’ossificazione del cranio), tossicità neontale
(insufficienza renale, ipotensione, iperkaliemia) (vedere paragrafo 5.3) e morte.
Ritardato sviluppo intrauterino, prematurità, pervietà del dotto arterioso e morte
fetale sono stati riportati ma non è accertato se siano da porre in relazione agli ACE-
Inibitori o a preesistenti patologie materne.
Se dovesse verificarsi un’esposizione ad un ACE inibitore dal secondo trimestre di
gravidanza, si raccomanda un controllo ecografico della funzionalità renale e del
cranio.
I neonati le cui madri abbiano assunto ACE inibitori devono essere attentamente
seguiti per quanto riguarda l’ipotensione (vedere paragrafi 4.3 e 4.4).
Ipotensione, oliguria e iperpotassiemia devono essere accuratamente ricercate nei
neonati esposti ad ACE-Inibitori durante la gestazione.

Allattamento
Poiché sono disponibili solo dati molto limitati riguardanti l’uso di FOSIPRES
durante l’allattamento, FOSIPRES non è raccomandato e sono da preferire
trattamenti alternativi con comprovato profilo di sicurezza per l’uso durante
l’allattamento, specialmente in caso di allattamento di neonati o prematuri.

• 4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macchinari Sebbene il medicinale non influenzi la capacità di guidare veicoli e l’uso di macchinari, molto raramente possono manifestarsi effetti indesiderati come vertigini e disturbi alla vista.
• 4.8 Effetti indesiderati L’incidenza di effetti indesiderati è risultata uguale in pazienti giovani e anziani (≥ 65 anni). Gli effetti indesiderati segnalati più di frequente nel corso di studi clinici controllati con FOSIPRES nell’ ipertensione(durata del trattamento da 2 a 3 mesi) sono di seguito riportati:

L’interruzione del trattamento per evento avverso o alterazione di parametri di
laboratorio è stata del 3% nel gruppo fosinopril e 1,2% nel gruppo placebo.
Altri disturbi riportati con fosinopril e altri ACE-Inibitori sono elencati di seguito

colestatico o epatocellulare, eritema multiforme, sindrome di Stevens-Johnson,
necrolisi epidermica tossica, alopecia, ileo paralitico e una sindrome che include
artralgia/artrite, vasculite, sierosite, mialgia, febbre, rash, o altre manifestazioni
dermatologiche, positività per gli anticorpi antinucleo, VES elevata, eosinofilia e
leucocitosi.

• 4.9 Sovradosaggio Non sono state descritte nell'uomo sindromi da sovradosaggio da fosinopril. I sintomi da sovradosaggio da ACE-Inibitore sono: ipotensione, shock, perdita di coscienza, bradicardia, disordini elettrolitici e insufficienza renale. In caso di sovradosaggio il paziente dovrà essere mantenuto sotto stretto controllo medico preferibilmente in una unità di terapia intensiva, con controllo frequente degli elettroliti sierici e della creatininemia. Il trattamento suggerito include l'induzione di vomito se l’ingestione è recente e/o una lavanda gastrica o la somministrazione di adsorbenti o sodio solfato entro 30 minuti dalla ingestione. Se si verifica ipotensione il paziente dovrebbe essere mantenuto in posizione supina e gli devono essere somministrati rapidamente integratori liquidi e salini; se necessario, occorre considerare, tra l’altro, un trattamento con angiotensina II, la somministrazione di atropina o l’applicazione di un pacemaker. FOSIPRES è scarsamente dializzabile. La clearance del fosinoprilato tramite emodialisi e dialisi peritoneale risulta essere rispettivamente il 2% e il 7% della clearance dell’urea.
• 5. PROPRIETA’ FARMACOLOGICHE
• 5.1 Proprietà farmacodinamiche Categoria farmacoterapeutica: ACE-inibitore, non associato Codice ATC: C09AA09 FOSIPRES (fosinopril sale sodico) è il precursore esterificato di un ACE-Inibitore a lunga durata d'azione, il fosinoprilato (fosinopril diacido). Dopo somministrazione orale, fosinopril è rapidamente e completamente idrolizzato nel composto attivo. Fosinopril, chimicamente designato come (1(S*(R*)),2a, 4b)-4-cicloesil-1-(((2-metil- 1-(1-ossipropossi)propossi)(4-fenilbutil)fosfinil)acetil)-L-prolina, sale monosodico è il primo di una nuova classe di ACE-Inibitori, i derivati fosfinici, che hanno come principale caratteristica farmacocinetica, quella di essere eliminati in parte per via extra-renale. Meccanismo d’azione. L'enzima convertente l'angiotensina (ACE) regola la conversione del decapeptide angiotensina I nell'octapeptide angiotensina II. L'angiotensina II è un potente vasocostrittore ed inoltre stimola la secrezione di aldosterone da parte della corteccia surrenalica, determinando in questo modo ritenzione idrica e salina. L'azione antipertensiva del fosinopril è legata in massima parte alla inibizione specifica e competitiva dell'ACE circolante e tissutale ed alla conseguente soppressione del sistema renina-angiotensina-aldosterone. L'inibizione dell'ACE determina infatti una diminuzione dei livelli di angiotensina II e quindi una diminuzione della vasocostrizione arteriolare e della produzione di aldosterone con conseguente riduzione nella ritenzione idrica e salina e un leggero aumento del potassio. L'inibizione dell'ACE riduce anche la degradazione di un potente peptide ad azione vasodilatatrice, la bradichinina. L'accumulo di bradichinina che ne consegue può contribuire all'effetto antipertensivo degli ACE-Inibitori, soprattutto in quelli a bassa

renina. E' stato inoltre dimostrato che la produzione locale di Angiotensina II a livello
delle pareti vascolari ha un ruolo importante nella regolazione della pressione
arteriosa e che l'inibizione dell'ACE a tale livello contribuisce alla entità e alla durata
dell'effetto antiipertensivo degli ACE-Inibitori. Inoltre, sistemi tissutali di produzione
di Angiotensina II sono stati individuati anche in altri organi (cuore, cervello, etc.) e
la loro attivazione in varie patologie cardiovascolari è considerata in parte
responsabile del danno a tali organi-bersaglio.
Farmacodinamica ed effetti clinici. La somministrazione di FOSIPRES in pazienti
con ipertensione arteriosa da lieve-moderata a severa, determina una riduzione
significativa delle pressioni arteriose misurate sia in clino- che in ortostatismo,
senza determinare generalmente ipotensione posturale.
Dopo somministrazione orale di una singola dose di FOSIPRES, l'inizio dell'azione
antipertensiva si verifica all'incirca dopo 1 ora ed il picco di effetto antipertensivo
dopo 2-6 ore.
Alle dosi giornaliere raccomandate, l'effetto antipertensivo di FOSIPRES è
mantenuto per tutto l'arco delle 24 ore.
Come per gli altri ACE-Inibitori, il raggiungimento di un completo effetto
antipertensivo può richiedere in alcuni casi un periodo di 2-4 settimane di
trattamento.
L'effetto antipertensivo di FOSIPRES è mantenuto costante nel tempo non
verificandosi il fenomeno della tolleranza. La sospensione improvvisa di FOSIPRES
non determina alcun effetto di rimbalzo sulla pressione arteriosa.
Sia in studi emodinamici acuti che in studi a lungo termine condotti in pazienti con
ipertensione lieve-moderata, FOSIPRES ha determinato una riduzione significativa
delle resistenze vascolari sistemiche e della pressione arteriosa sistemica senza
alterazione della performance cardiaca, dei flussi renale, splancnico, muscolare e
cutaneo, della filtrazione glomerulare e dei volumi plasmatici.
Inoltre, le fisiologiche risposte emodinamiche a stimoli di varia natura (esercizio
isometrico, mental stress, tilt) non sono alterate da FOSIPRES, indicando il
mantenimento di un normale funzionamento del sistema nervoso simpatico nel
paziente iperteso in trattamento.
La terapia con FOSIPRES ha inoltre determinato, in pazienti con ipertensione ed
ipertrofia del ventricolo sinistro, a livello cardiaco, una significativa riduzione della
massa ventricolare e dello spessore del setto interventricolare, con mantenimento
della performance ventricolare.
Nonostante la significativa riduzione della pressione arteriosa, FOSIPRES non
modifica il flusso ematico cerebrale, a dimostrazione di un positivo fenomeno di
riadattamento circolatorio cerebrale al trattamento antipertensivo.
La terapia a lungo termine con FOSIPRES non ha indotto alcuna modificazione del
quadro metabolico del paziente iperteso, indicando la completa assenza di
interferenza tanto sul metabolismo glicidico che su quello lipidico. In pazienti ipertesi
nei quali è stata dimostrata una insulino-resistenza, l'impiego di FOSIPRES ha
normalizzato tale alterata condizione, mentre nei pazienti diabetici ipertesi ha
determinato un aumento della sensibilità insulinica.
FOSIPRES è indicato per il trattamento iniziale e può essere vantaggiosamente
associato ad altri farmaci antipertensivi. L’associazione di fosinopril con diuretici
tiazidici produce un effetto antipertensivo di tipo additivo.
Anche nei soggetti con insufficienza cardiaca, l'uso del fosinopril è associato ad una
riduzione della pressione a livello dei capillari polmonari (pre-carico) e della
pressione arteriosa media e delle resistenze vascolari periferiche (post-carico), come
dimostrato da uno studio clinico appositamente condotto. Nei pazienti trattati per
almeno 10 settimane con singola somministrazione quotidiana di fosinopril, il
suddetto effetto emodinamico si mantiene per l'intero arco delle 24 ore. Inoltre, nei
soggetti sintomatici, la frequenza cardiaca si riduce rispetto ai valori di base, e si
assiste ad un incremento della gittata cardiaca nonostante la riduzione della pressione
di riempimento ventricolare sinistra. Non sono stati descritti fenomeni di tachifilassi.
In due studi clinici controllati con placebo, nel corso dei quali FOSIPRES è stato
somministrato in dose singola giornaliera, per la durata di 6 mesi, a soggetti con
insufficienza cardiaca non in trattamento digitalico, sono stati evidenziati i seguenti
risultati: miglioramento della sintomatologia, riduzione delle ospedalizzazioni per
scompenso cardiaco (riduzione del rischio relativo del 66%) e riduzione del ricorso
a dosi supplementari di diuretici. Tali benefici clinici risultavano tutti statisticamente
significativi.

Informazioni aggiuntive:
Due grandi studi randomizzati e controllati (ONTARGET (ONgoing Telmisartan
Alone and in combination with Ramipril Global Endpoint Trial) e VA Nephron-D
(The Veterans Affairs Nephropathy in Diabetes)) hanno esaminato l'uso della
combinazione di un ACE-inibitore con un antagonista del recettore dell’angiotensina
II.
ONTARGET è stato uno studio condotto in pazienti con anamnesi di patologia
cardiovascolare o cerebrovascolare, o diabete mellito tipo 2 associato all’evidenza di
danno d'organo. VA NEPHRON-D è stato uno studio condotto in pazienti con
diabete mellito tipo 2 e nefropatia diabetica.
Questi studi non hanno dimostrato alcun significativo effetto benefico sugli esiti e
sulla mortalità renale e/o cardiovascolare, mentre è stato osservato un aumento del
rischio di iperpotassiemia, danno renale acuto e/o ipotensione rispetto alla
monoterapia.
Questi risultati sono pertinenti anche per gli altri ACE-inibitori e per gli antagonisti
del recettore dell'angiotensina II, date le loro simili proprietà farmacodinamiche.
Gli ACE-inibitori e gli antagonisti del recettore dell'angiotensina II non devono quindi
essere usati contemporaneamente in pazienti con nefropatia diabetica.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal
Disease Endpoints) è stato uno studio volto a verificare il vantaggio di aggiungere
aliskiren ad una terapia standard di un ACE-inibitore o un antagonista del recettore
dell'angiotensina II in pazienti con diabete mellito di tipo 2 e malattia renale cronica,
malattia cardiovascolare, o entrambe. Lo studio è stato interrotto precocemente a
causa di un aumentato rischio di eventi avversi. Morte cardiovascolare e ictus sono
stati entrambi numericamente più frequenti nel gruppo aliskiren rispetto al gruppo
placebo e gli eventi avversi e gli eventi avversi gravi di interesse (iperpotassiemia,
ipotensione e disfunzione renale) sono stati riportati più frequentemente nel gruppo
aliskiren rispetto al gruppo placebo.

• 5.2 Proprietà farmacocinetiche Farmacocinetica e metabolismo. Circa il 36% di una dose orale di FOSIPRES viene assorbita nella prima parte dell'intestino (duodeno/digiuno) e tale assorbimento non è influenzato dalla presenza del cibo. L'idrolisi di FOSIPRES nel composto attivo fosinoprilato avviene in maniera rapida e completa a livello della mucosa gastro-intestinale e del fegato. La velocità di conversione del fosinopril in fosinoprilato può essere rallentata nei pazienti con disfunzione epatica, rimanendo tuttavia inalterata l’entità della conversione. Il tempo necessario per raggiungere la massima concentrazione ematica (C ) è di circa tre ore, indipendentemente dalla dose somministrata ed in accordo con il picco di inibizione della risposta pressoria all'angiotensina I (3-6 ore dopo la

somministrazione orale). Dopo dosi singole e multiple, i parametri farmacocinetici
sono direttamente proporzionali alla dose di fosinopril somministrata.
L'emivita plasmatica (T 1/2) effettiva del fosinoprilato è all'incirca di 11,5 ore: anche
a ciò è correlata l'efficacia antipertensiva per 24 ore di una dose singola del
farmaco. Nei pazienti con insufficienza cardiaca, l’emivita del fosinopril
(fosinoprilato) è di circa 14 ore. Il fosinoprilato è altamente legato alle proteine
plasmatiche (>95%), ha un basso volume di distribuzione e un legame trascurabile
agli elementi cellulari del sangue. Studi negli animali indicano che sia il fosinopril che
il fosinoprilato non passano la barriera ematoencefalica ma il fosinoprilato attraversa
la placenta nelle femmine gravide.
In studi condotti sull'animale da esperimento (ratti SHR), il fosinopril ha dimostrato
di essere attivo nella inibizione del sistema renina-angiotensina particolarmente a
livello vasale e cardiaco.
A differenza degli altri ACE-Inibitori, eliminati principalmente per via renale,
FOSIPRES possiede una duplice via di eliminazione epatica e renale; FOSIPRES,
infatti, nei soggetti normali viene eliminato in maniera bilanciata attraverso i due
emuntori all'incirca nella stessa misura. Nei pazienti con ridotta funzionalità renale si
osserva, dopo dose singola e ripetuta, una riduzione della clearance totale del
fosinoprilato a circa la metà e un lieve aumento della AUC, senza che tali valori si
alterino ulteriormente con il progredire dell'insufficienza renale. L’assorbimento, la
biodisponibilità e il legame proteico non risultano modificati in misura apprezzabile.
Gli studi di farmacocinetica eseguiti hanno documentato che non si hanno fenomeni
di accumulo del farmaco. Inoltre l'intervallo di somministrazione della dose di
fosinopril previsto dagli schemi posologici, ha una durata maggiore dell'emivita del
farmaco stesso. Questa sostanziale indipendenza del processo di eliminazione del
fosinopril dal grado di insufficienza renale è in relazione ad una maggiore e
compensatoria eliminazione della forma attiva del farmaco per escrezione epato-
biliare. Allo stesso modo, in caso di insufficienza epatica, la funzione vicariante è
svolta dal rene, con una clearance corporea totale del fosinoprilato pari a circa la
metà rispetto ai pazienti con funzione epatica normale. Pertanto nei pazienti affetti daa
Severe hepatic or renal insufficiency does not require dosage adjustments compared to the planned regimens unless in the initial phase of treatment.
In elderly patients (65-74 years) no difference was found in pharmacokinetic parameters compared to younger subjects (20-35 years).
Fosinoprilate is detectable in minimal, unmeasurable traces in breast milk.

• 5.3 Preclinical safety data SINGLE DOSE. In studies conducted on rodents, fosinopril proved toxic at extremely high dosages, approximately 1,200 times the human use dose. The toxicity of the active metabolite (fosinoprilate) was even lower. REPEATED DOSES. Studies of repeated administrations for variable periods up to 2 years have demonstrated the possibility of tolerating, in the animal species considered, remarkably high doses of fosinopril without any significant harmful effects occurring. Most of the effects recorded in these studies were reversible and of slight entity, and appeared essentially related to an exaggeration of the normal pharmacological effect of fosinopril and therefore to hemodynamic-type problems. The association with diuretics, due to the complementary and synergistic mechanism of action, is particularly indicated. The antihypertensive efficacy of FOSIPRES is of equal entity in the young as well as in the elderly patient.
• 6. PHARMACEUTICAL INFORMATION

• 6.1 List of excipients Anhydrous lactose, microcrystalline cellulose, crospovidone, povidone, sodium stearyl fumarate.
• 6.2 Incompatibilities None known.
• 6.3 Shelf life: 2 years.
• 6.4 Special precautions for storage: the product is storable under normal environmental conditions protected from humidity.
• 6.5 Nature and content of container: 14 tablets of 20 mg in blisters.
• 6.6 Instructions for use and handling: no particular instructions
• 7. MARKETING AUTHORISATION HOLDER
• A. Menarini Industrie Farmaceutiche Riunite s.r.l., Via Sette Santi, 3 - Florence.
• 8. MARKETING AUTHORISATION NUMBERFOSIPRES 20 mg tablets - 14 tablets. A.I.C. N° 027747029.
• 9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION:Date of first authorisation: 16 December 1991. Date of last renewal: 16 December 2006
• 10. DATE OF TEXT REVISIONFebruary 2015