Fosipres

FOSIPRES 10 mg tablets
fosinopril sodium salt
Pharmacotherapeutic category
ACE inhibitors (angiotensin-converting enzyme inhibitors), unassociated.
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 trimesters of pregnancy (see section "Special warnings").
Paediatric population (see section "Precautions for use").
The concomitant use of Fosipres with medicinal products containing aliskiren is contraindicated in patients with 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)
Evidence shows that 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, it should only be carried out under the supervision of a specialist, with close and frequent monitoring of renal function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists must not be used concomitantly in patients with diabetic nephropathy.
Angioedema of the head and neck
Cases of angioedema have been reported with the use of ACE inhibitors, including fosinopril, particularly after the first doses, although rarely even after prolonged treatment. This event requires discontinuation of therapy and replacement of the ACE inhibitor with another antihypertensive agent. This phenomenon may affect the extremities, face, lips, mucous membranes, tongue, glottis or larynx.
Angioedema involving the tongue, glottis and/or larynx may lead to airway obstruction and occasionally be fatal; therefore prompt emergency measures must be taken, including, among others, subcutaneous injection of a 1:1000 solution of adrenaline (0.3–0.5 ml).
In cases of angioedema localized to other areas, therapy must be immediately suspended and the patient appropriately treated and closely monitored until 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. Intestinal angioedema was diagnosed by abdominal CT scan or ultrasound, or during surgery, and 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 treated with ACE inhibitors during haemodialysis with high-flux dialysis membranes and during low-density lipoprotein (LDL) apheresis using dextran sulphate columns. These patients should be treated with particular caution, especially if they have a history of similar previous reactions. The use of alternative membranes or other antihypertensive drugs is recommended.
In two patients undergoing venom desensitisation for Hymenoptera (e.g., bees, wasps, etc.), the concomitant administration of another ACE inhibitor, enalapril, caused severe and sustained anaphylactoid reactions. Therefore, in such cases, an antihypertensive agent from a different class should be used.
Hypotension
As with other ACE inhibitors, marked hypotensive response may occur during treatment with FOSIPRES, especially after the first dose. Symptomatic hypotension is rare in uncomplicated hypertension.
It is more likely in certain categories of at-risk patients, such as those with salt and/or fluid depletion of any aetiology (e.g., intensive diuretic therapy) and in patients undergoing renal dialysis. In such cases, restoration of fluid and electrolyte balance is required before starting treatment. Tachycardia may occur in these patients.
ACE inhibitor-induced hypotension has been mainly reported in patients with severe heart failure or renal failure.
In patients with congestive heart failure, whether with or without renal dysfunction, ACE inhibitors may cause excessive hypotension, sometimes associated with azotemia or oliguria, progressing to acute renal failure, potentially fatal. In these patients, therapy should be initiated under careful medical supervision, preferably in a hospital setting; patients should be closely monitored, especially during the first two weeks of treatment and during dose increases. Consideration should also be given to discontinuing diuretic therapy or reducing the diuretic dose in patients with normal or low blood pressure who are on intensive diuretic therapy or who show signs of hyponatraemia. These precautions also apply to patients with ischaemic heart disease or cerebrovascular disorders in whom excessive hypotension may cause myocardial infarction or cerebrovascular accident.
If hypotension develops, place the patient in a supine position and, if necessary, administer physiological saline solution.
In patients with heart failure, a reduction in blood pressure is not by itself a sufficient reason to discontinue treatment. Such a reduction, often desirable in heart failure, is usually greater at the beginning of treatment. The effect tends to stabilise within the first two weeks and disappear thereafter, returning to pre-treatment blood pressure values without loss of 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. Concomitant diuretic therapy may be a contributing factor. In these patients, initiation of ACE inhibitor therapy and dose escalation should be performed under close medical supervision, preferably in a hospital setting. Diuretics should be discontinued and renal function monitored during the first weeks of therapy.
Impaired renal function
During treatment with ACE inhibitors, patients with pre-existing congestive heart failure, renovascular hypertension (renal artery stenosis affecting one or both kidneys) and severe fluid or salt depletion have an increased risk of developing signs of renal dysfunction (increased creatinine, azotemia and serum potassium; proteinuria; changes in urinary volume), which resolve upon discontinuation of therapy.
Mild and transient increases in azotemia and creatinine may occasionally occur even in patients with apparently intact renovascular function, particularly if concomitantly treated with diuretics.
This is more common in patients with pre-existing renal impairment. In patients with severe heart failure, renal function may depend on the renin-angiotensin-aldosterone system.
In these patients, treatment with ACE inhibitors may induce azotemia and oliguria, which rarely progress to acute renal failure, sometimes fatal.
Although such events have not been described with FOSIPRES, if they occur, discontinuation of concomitant diuretic therapy or reduction or discontinuation of FOSIPRES is advisable.
Hepatic impairment
Since FOSIPRES is partly converted into its active form at the hepatic level, in patients with severe hepatic impairment this conversion may be slowed, resulting in elevated plasma levels of fosinopril. In such cases, careful monitoring of the patient's response to the dose administered is recommended.
In a study in patients with alcoholic or biliary cirrhosis, total fosinopril clearance was reduced, with an AUC approximately doubled.
In rare cases, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this clinical picture is unknown. Patients treated with ACE inhibitors who develop marked increases in liver enzymes or jaundice should discontinue treatment and be appropriately monitored by their physician.
Hyperkalaemia
During treatment with ACE inhibitors, including fosinopril, the following conditions may increase the risk of hyperkalaemia: renal impairment, heart failure, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, use of other drugs that increase serum potassium (e.g., heparin). In these situations, regular monitoring of serum potassium is advisable.
Anaesthesia/Surgery
During surgery or anaesthesia with hypotensive agents, FOSIPRES may enhance the hypotensive response. If discontinuation of the ACE inhibitor is not possible, careful monitoring of circulating 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 concomitant renal impairment and/or collagenopathies (e.g., SLE, scleroderma) or immunosuppressive therapy. Available data are insufficient to demonstrate that fosinopril does not cause agranulocytosis. Periodic monitoring of white blood cells is advisable in patients with renal impairment and/or collagenopathies, and these patients should be warned to immediately report any signs of infection (e.g., sore throat, fever) which may indicate neutropenia.
Aortic stenosis/Hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.
Cough
Cough has been reported during treatment with ACE inhibitors, including FOSIPRES. It is typically a persistent, non-productive cough that resolves upon discontinuation of therapy. ACE inhibitors should be considered in the differential diagnosis of cough.
Elderly patients
In clinical studies, no differences in efficacy or safety of fosinopril use were observed between elderly patients and younger patients.
However, a greater antihypertensive response in some elderly patients cannot be excluded. Assessment of renal function and careful medical monitoring are recommended at the start of treatment.
Use in paediatrics
The product must not be used in the paediatric population, as there is insufficient experience to date.
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 is on a low-sodium diet or undergoing dialysis.
2. Antacids Concomitant administration of antacids (e.g., aluminium hydroxide, magnesium hydroxide, simethicone) may slightly reduce intestinal absorption of FOSIPRES. Therefore, if used together, they should be administered at least 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, etc.) or potassium salt supplementation may increase the risk of hyperkalaemia. Therefore, if such drugs are required, they should be used with caution and serum potassium levels monitored frequently.
4. Lithium Increased blood lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant ACE inhibitors and lithium. Therefore, concomitant administration of these two drugs should be done with caution and blood lithium levels monitored frequently. Concomitant administration of a diuretic may increase lithium toxicity.
5. Anaesthetics ACE inhibitors may potentiate the hypotensive effect of certain anaesthetics.
6. Narcotics/antipsychotics Concomitant administration of ACE inhibitors and narcotics/antipsychotics may cause orthostatic hypotension.
7. Hypoglycaemics Concomitant administration of ACE inhibitors and antidiabetic drugs (oral hypoglycaemics or insulin) may enhance the hypoglycaemic effect of the latter, increasing the risk of hypoglycaemia, especially during the first weeks of combined treatment and in patients with impaired renal function.
8. Prostaglandin inhibitors It has been reported that indometacin reduces the antihypertensive efficacy of ACE inhibitors, especially in patients with low-renin hypertension. Other non-steroidal anti-inflammatory agents (e.g., acetylsalicylic acid) may have similar effects.
9. Sympathomimetics May reduce the antihypertensive effect of ACE inhibitors.
10. Allopurinol, cytostatic agents or immunosuppressants, 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 at doses ≥325 mg/day, non-selective NSAIDs), attenuation of the antihypertensive effect may occur. 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 used with caution, particularly in the elderly. Patients should be adequately hydrated and renal function monitored at the start of concomitant therapy.
13. Interference with laboratory tests Fosinopril may interfere with plasma digoxin determination, resulting in falsely low values when measured by charcoal adsorption methods such as Digi-Tab. Alternatively, the Coat-A-Count method, based on "COATED-TUBE" antibodies, may be used. Furthermore, FOSIPRES therapy should be discontinued several days before laboratory evaluation of parathyroid function.
14. Other FOSIPRES and its metabolites do not cause interactions with food. Pharmacokinetic interaction studies, single or multiple dose, with acetylsalicylic acid, chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, warfarin, showed no changes in unbound fosinopril bioavailability. The bioavailability, protein binding and anticoagulant effect of warfarin (assessed by prothrombin time) were not altered by concomitant administration of FOSIPRES.

ACE inhibitors, angiotensin II receptor antagonists or aliskiren:
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and reduced renal function (including acute renal failure) compared to use of a single agent acting on the RAAS (see sections "Contraindications" and "Precautions for use").
Special warnings
If intolerance to sugars is known, consult your physician before taking this 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 trimesters of pregnancy (see section "Contraindications").
ACE inhibitor therapy must not be initiated 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 excluded.
For patients planning pregnancy, the physician must be informed immediately so that an alternative antihypertensive treatment with a proven safety profile in pregnancy can be initiated, unless continuation of ACE inhibitor therapy is considered essential.
When pregnancy is diagnosed, the physician must be informed immediately so that ACE inhibitor therapy can be discontinued immediately and, if appropriate, alternative therapy initiated.
If exposure to an ACE inhibitor occurs from the second trimester of pregnancy, renal and cranial ultrasound monitoring is recommended.
Newborns whose mothers have taken ACE inhibitors must be closely monitored for hypotension, oliguria and hyperkalaemia.
Breastfeeding
Since only very limited data are available on the use of FOSIPRES during breastfeeding, FOSIPRES is not recommended and alternative treatments with a proven safety profile during breastfeeding should be preferred, especially when breastfeeding newborns or preterm infants.
Effects on ability to drive and use machines
Although the medicine does not affect the ability to drive or use machines, adverse effects such as dizziness and visual disturbances may very rarely occur.
Dosage, method and timing of administration
Hypertension: the daily dosage required to maintain stable blood pressure control ranges between 10–40 mg. Most patients achieve adequate blood pressure control with a once-daily dose of 20 mg.
The recommended initial dose of FOSIPRES (fosinopril sodium salt) is 10 mg once daily. The daily dosage may subsequently be adjusted based on the patient's blood pressure response.
In some patients receiving once-daily dosing, a reduction in antihypertensive effect may occur towards the end of the dosing interval. In such cases, twice-daily dosing should be considered. If blood pressure is not adequately controlled with FOSIPRES monotherapy, a diuretic may be added.
Concomitant administration of FOSIPRES with potassium supplements, potassium-containing salt substitutes or potassium-sparing diuretics may lead to increased serum potassium levels.
Heart failure: the initial dose of FOSIPRES is 10 mg once daily. Therapy must be initiated under medical supervision. If the initial dose is well tolerated, dose escalation may proceed, according to clinical response, up to 40 mg once daily.
The occurrence of hypotension after the initial dose should not preclude subsequent dose escalation. However, hypotension must be carefully evaluated 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 section "Precautions for use").
Initiation of therapy requires, if possible, correction of any existing salt and/or fluid depletion, suspension of diuretic therapy for 2–3 days and use of the lowest dose. If this is not possible, the standard dose should be halved in high-risk patients.
In patients with malignant hypertension or severe heart failure, initiation of therapy or dose adjustment should be performed in a hospital setting.
At the time of the first administration of FOSIPRES and subsequent dose increases of the ACE inhibitor and/or diuretic, high-risk patients for severe acute hypotension (see section "Precautions for use") should be monitored, preferably in a hospital setting, for a sufficient period to cover at least the peak antihypertensive effect of fosinopril (3–6 hours).
This also applies to patients with ischaemic heart or cerebrovascular disease in whom severe hypotension may cause myocardial infarction or cerebrovascular accident.
Use in elderly patients
No dosage adjustment is necessary in elderly subjects, as neither pharmacokinetic parameters, antihypertensive response nor safety of use differ from those observed in younger subjects.
However, a greater response in some elderly patients cannot be excluded.
Use in renal and hepatic impairment
Due to its unique dual and compensatory elimination, FOSIPRES does not require dose adjustments. Only in patients with severe hepatic or renal impairment is it advisable to initiate therapy with a 10 mg dose, subsequently adjusting the dose according to the patient's blood pressure response.
Duration of treatment
As prescribed by the physician.
Overdose
No fosinopril overdose syndromes have been described in humans.
Symptoms of ACE inhibitor overdose include hypotension, shock, loss of consciousness, bradycardia, electrolyte disturbances and renal failure.
In case of overdose, the patient should be kept under close medical supervision, preferably in an intensive care unit, with frequent monitoring of serum electrolytes and creatinine. Recommended treatment includes induction of vomiting if ingestion was recent and/or gastric lavage or administration of adsorbents or sodium sulphate within 30 minutes of ingestion.
If hypotension occurs, the patient should be placed in a supine position and rapidly given intravenous fluid and saline supplements; if necessary, treatment with angiotensin II, atropine or a pacemaker should be considered.
FOSIPRES is poorly dialysable. The clearance of fosinoprilat by haemodialysis and peritoneal dialysis is 2% and 7% of urea clearance, respectively.
UNDESIRABLE EFFECTS
The incidence of adverse effects was equal in young and elderly (≥65 years) patients.
The most frequently reported adverse effects in controlled clinical trials with FOSIPRES in hypertension (treatment duration 2–3 months) are listed below:

Discontinuation of treatment due to adverse events or laboratory parameter abnormalities occurred in 3% of patients in the fosinopril group and in 1.2% of the placebo group.
Other disorders reported with fosinopril and other ACE inhibitors are listed below.

Adverse events possibly or probably related, or with uncertain relationship, to therapy occurring in at least 1% of patients treated with fosinopril in placebo-controlled clinical trials in heart failure are: 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 relationship, to therapy occurring in 0.4–1.0% of patients treated (exceptions in parentheses) with fosinopril in placebo-controlled clinical trials in heart failure are:

The following adverse 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, antinuclear antibody positivity, elevated ESR, eosinophilia, and leukocytosis.
Adhering to the instructions contained in the package leaflet reduces the risk of adverse effects.
It is important to inform your doctor or pharmacist about any adverse effect, even if not described in the package leaflet.
EXPIRY DATE AND STORAGE
Expiry date: see the date printed on the packaging
The expiry date refers to the product in its original, unopened packaging, correctly stored.
Warning: do not use the medicine after the expiry date stated on the packaging.
Special storage precautions: store at room temperature, protected from moisture.
Keep the medicine out of the reach and sight of children.
Composition
Each tablet contains: active substance: fosinopril sodium 10 mg; excipients: anhydrous lactose, microcrystalline cellulose, crospovidone, povidone, sodium stearil fumarate.
Pharmaceutical form and contents
Oral tablets.
FOSIPRES 10 mg tablets – 28 tablets
Marketing Authorization Holder:
A. Menarini Industrie Farmaceutiche Riunite s.r.l., Via Sette Santi, 3 - Florence
Responsible batch release manufacturer:
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.
PRODUCT CHARACTERISTICS SUMMARY

1. NAME OF THE MEDICINAL PRODUCT: FOSIPRES 20 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION: each tablet contains. Active substance: fosinopril sodium 20 mg. For excipients, see section 6.1
3. PHARMACEUTICAL FORM: white oral tablets.
4. CLINICAL INFORMATION

4.1 Therapeutic indications
FOSIPRES is indicated for the treatment of arterial hypertension and
heart failure.
4.2 Posology and method of administration
Hypertension: the daily dose required to maintain stable blood pressure control ranges 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) is 10 mg once daily. The daily dosage may subsequently be adjusted based on the patient's blood pressure response.
In some patients receiving a single daily dose, a reduction in antihypertensive effect may occur towards the end of the dosing interval. In such cases, twice-daily dosing should be considered. If blood pressure is not adequately controlled with FOSIPRES monotherapy, a diuretic may be added.
Concomitant administration of FOSIPRES with potassium supplements, potassium-salt substitutes, or potassium-sparing diuretics may lead to increases in serum potassium levels.
Heart failure: the initial dose of FOSIPRES is 10 mg once daily. Therapy initiation must occur under medical supervision. If the initial dose is well tolerated, dose escalation may proceed, according to clinical response, up to 40 mg once daily.
The occurrence of hypotension after the initial dose should not preclude subsequent dose escalation. However, hypotension must be carefully evaluated and managed.
Fosinopril has a dual (hepatic and renal) elimination pathway; 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 section 4.4).
Initiation of therapy should, if possible, include correction of any salt and/or fluid depletion, temporary suspension of diuretic therapy for 2–3 days, and use of the lowest possible dose. If this is not feasible, the standard dose should be halved in high-risk patients.
In patients with malignant hypertension or severe heart failure, initiation of therapy or dose adjustment should be conducted in a hospital setting.
At the time of the first administration of FOSIPRES and subsequent dose increases of the ACE inhibitor and/or diuretic, high-risk patients (see section 4.4) should be monitored, preferably in a hospital setting, for a sufficient period to cover at least the peak antihypertensive effect of fosinopril (3–6 hours).
This also applies to patients with ischemic heart disease or cerebrovascular disease, in whom severe hypotension may lead to myocardial infarction or cerebrovascular accident.
Use in elderly patients
No dose adjustment is required in elderly subjects, as neither pharmacokinetic parameters, antihypertensive response, nor safety of use differ from those observed in younger subjects.
However, a greater response cannot be ruled out in some of the older patients.
Use in renal and hepatic impairment
Due to its unique dual and compensatory elimination, FOSIPRES does not require dose adjustments. However, in patients with severe hepatic or renal impairment, therapy should be initiated at a dose of 10 mg, with subsequent dose adjustments based on the patient's blood pressure response.
4.3 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 trimesters of pregnancy (see sections 4.4 and 4.6).
Pediatric use (see section 4.6).
The concomitant use of Fosipres with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR <60 ml/min/1.73m²) (see sections 4.5 and 5.1).
4.4 Special warnings and precautions for use
Angioedema of the head and neck
Cases of angioedema, particularly after initial doses, have been reported with ACE inhibitors, including fosinopril, although rarely occurring even after prolonged treatment. This event requires discontinuation of therapy and substitution with another antihypertensive agent. This phenomenon may affect extremities, face, lips, mucous membranes, tongue, glottis, or larynx.
Angioedema involving the tongue, glottis, and/or larynx may cause airway obstruction and occasionally be fatal; therefore, prompt emergency measures must be taken, including subcutaneous injection of a 1:1000 adrenaline solution (0.3–0.5 ml).
In cases of angioedema localized to other areas, therapy must be immediately discontinued, and the patient appropriately treated and closely monitored until complete resolution of symptoms.
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. Diagnosis was confirmed by abdominal CT scan, ultrasound, or surgery, and symptoms resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors who present with abdominal pain.
Anaphylactoid reactions
Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux dialysis membranes and during low-density lipoprotein (LDL) apheresis with dextran sulfate columns while on ACE inhibitor therapy. These patients should be treated with particular caution, especially if there is a history of similar reactions. The use of alternative membranes or other antihypertensive drugs is recommended.
In two patients undergoing desensitization to hymenoptera venom (e.g., bees, wasps, etc.), concomitant administration of another ACE inhibitor, enalapril, caused severe and sustained anaphylactoid reactions. Therefore, in such cases, an antihypertensive from a different class should be used.
Hypotension
As with other ACE inhibitors, marked hypotensive response may occur during FOSIPRES treatment, especially after the first dose.
Symptomatic hypotension is rare in uncomplicated hypertension.
It is more likely in certain high-risk patient groups, such as those with salt and/or fluid depletion of any cause (e.g., intensive diuretic therapy) and patients undergoing dialysis. In such cases, hydroelectrolytic balance should be restored before initiating treatment. Tachycardia may occur in these patients.
ACE inhibitor-induced hypotension has been mainly reported in patients with severe heart failure or renal failure.
In patients with congestive heart failure, with or without renal dysfunction, ACE inhibitors may cause excessive hypotension, sometimes associated with hyperazotemia or oliguria, potentially progressing to acute renal failure, which may be fatal. In such patients, therapy should be initiated under close medical supervision, preferably in a hospital setting; patients should be closely monitored, especially during the first two weeks of treatment and during dose increases. Consideration should also be given to suspending diuretic therapy or reducing the diuretic dose in patients with normal or low blood pressure who are on intensive diuretic therapy or who show evidence of hyponatremia. These precautions also apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive hypotension may cause myocardial infarction or cerebrovascular accident.
If hypotension develops, place the patient in a supine position and, if necessary, administer physiological saline solution.
In patients with heart failure, a reduction in blood pressure is not by itself a sufficient reason to discontinue treatment. Such reduction, often desirable in heart failure, is usually greater at the beginning of treatment. The effect tends to stabilize within the first two weeks and disappear thereafter, returning to pre-treatment blood pressure values without loss of therapeutic efficacy.
Renovascular hypertension
In patients with renovascular hypertension, the risk of severe hypotension and renal failure is increased with ACE inhibitor administration. Diuretic therapy may be a contributing factor. In these patients, initiation of ACE inhibitor therapy and dose escalation should be conducted 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
During ACE inhibitor therapy, patients with pre-existing congestive heart failure, renovascular hypertension (renal artery stenosis affecting one or both kidneys), or severe fluid or salt depletion have an increased risk of developing signs of renal dysfunction (increased creatinine, azotemia, and serum potassium; proteinuria; changes in urine volume), which resolve upon discontinuation of therapy.
Mild and transient increases in azotemia and creatinine may occasionally occur even in patients with apparently intact renovascular function, particularly when concomitantly treated with diuretics.
This is more frequent in patients with pre-existing renal impairment.
In patients with severe heart failure, renal function may depend on the renin-angiotensin-aldosterone system.
In such patients, ACE inhibitor therapy may induce hyperazotemia and oliguria, rarely progressing to acute renal failure, sometimes fatal.
Although not described with FOSIPRES, if such cases occur, discontinuation of concomitant diuretic therapy or reduction or discontinuation of FOSIPRES is recommended.
Hepatic impairment
Since FOSIPRES is partially converted to its active form in the liver, this conversion may be slowed in patients with severe hepatic impairment, leading to elevated plasma levels of fosinopril. In such cases, the patient's response to the administered dose should be carefully monitored.
In a study in patients with alcoholic or biliary cirrhosis, total fosinopril clearance was reduced, with an AUC approximately doubled.
Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this clinical picture is unknown. Patients on ACE inhibitors who develop a marked increase in liver enzymes or jaundice should discontinue treatment and be appropriately followed by a physician.
Hyperkalemia
During treatment with ACE inhibitors, including fosinopril, the following conditions may increase the risk of hyperkalemia: renal impairment, heart failure, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, and use of other drugs that increase serum potassium (e.g., heparin). In these situations, regular monitoring of serum potassium is advisable.
Anesthesia/Surgery
During surgery or anesthesia with hypotensive agents, FOSIPRES may enhance the hypotensive response. If discontinuation of the ACE inhibitor is not possible, careful monitoring of circulating volume is required.
Neutropenia/Agranulocytosis
Treatment with other ACE inhibitors has rarely been associated with agranulocytosis and bone marrow depression, particularly in patients with concomitant renal impairment and/or collagen disorders (e.g., SLE, scleroderma) or immunosuppressive therapy. Available data are insufficient to demonstrate that fosinopril does not cause agranulocytosis. Periodic white blood cell counts are recommended in patients with renal impairment and/or collagen disorders, and these patients should be advised to immediately report any signs of infection (e.g., sore throat, fever), which may indicate neutropenia.
Aortic stenosis/Hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.
Cough
Cough has been reported during treatment with ACE inhibitors, including FOSIPRES. It is typically a persistent, non-productive cough that resolves after discontinuation of therapy. ACE inhibitors should be considered in the differential diagnosis of cough.
Elderly patients
In clinical studies, no differences in efficacy or safety of fosinopril were observed between elderly and younger patients.
However, a greater antihypertensive response cannot be excluded in some elderly patients. Renal function assessment and careful medical monitoring are recommended at the start of treatment.
Pregnancy
ACE inhibitor therapy should not be initiated during pregnancy.
For patients planning pregnancy, alternative antihypertensive treatments with a proven safety profile in pregnancy should be used, unless continuation of ACE inhibitor therapy is considered essential. When pregnancy is diagnosed, ACE inhibitor treatment must be immediately discontinued and, if appropriate, alternative therapy initiated (see sections 4.3 and 4.6).
Use in pediatrics
The product should not be used in pediatric patients, as sufficient experience is currently lacking.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS through combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, it should only be performed under specialist supervision with strict and frequent monitoring of renal function, electrolytes, and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
The tablets contain lactose and are therefore unsuitable for patients with lactase deficiency, galactosemia, or glucose-galactose malabsorption syndrome.
4.5 Interactions with other medicinal products and other forms of interaction

• 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 is on a low-sodium diet or undergoing dialysis.

• Antacids - Concomitant administration of antacids (e.g., aluminum hydroxide, magnesium hydroxide, simethicone) may slightly reduce the intestinal absorption of FOSIPRES. Therefore, if used together, they should be administered at least 2 hours apart.

• Potassium and potassium-sparing diuretics - Treatment with FOSIPRES may reduce potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, etc.) or potassium salt supplementation may increase the risk of hyperkalemia. Therefore, use of these agents, if required, should be cautious, with frequent monitoring of serum potassium levels.

• Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant ACE inhibitors and lithium. Therefore, concomitant administration should be done with caution and serum lithium levels monitored frequently. Concomitant use of a diuretic may increase lithium toxicity.

• Anesthetics - ACE inhibitors may potentiate the hypotensive effect of certain anesthetics.

• Narcotics/antipsychotics - Concomitant administration of ACE inhibitors and narcotics/antipsychotics may cause orthostatic hypotension.

• Hypoglycemics - Concomitant administration of ACE inhibitors and antidiabetic drugs (oral hypoglycemics or insulin) may enhance the hypoglycemic effect of the latter, increasing the risk of hypoglycemia, especially during the first weeks of combined treatment and in patients with impaired renal function.

• Prostaglandin inhibitors - Indomethacin has been reported to reduce the antihypertensive efficacy of ACE inhibitors, especially in patients with low-renin hypertension. Other non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic acid) may have similar effects.

• Sympathomimetics - May reduce the antihypertensive effect of ACE inhibitors.

• Allopurinol, cytostatic agents or immunosuppressants, systemic corticosteroids or procainamide - Concomitant administration with ACE inhibitors may increase the risk of leukopenia.

• Alcohol - Enhances the hypotensive effect.

• NSAIDs: when ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (e.g., selective Cox-2 inhibitors, acetylsalicylic acid at doses ≥325 mg/day, and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including possible acute renal failure, and increased serum potassium levels, especially in patients with pre-existing renal impairment. The combination should be used with caution, particularly in the elderly. Patients should be adequately hydrated, and renal function should be monitored at the start of concomitant therapy.

• Interaction with laboratory tests - Fosinopril may interfere with plasma digoxin measurements, yielding falsely low values when determined by activated charcoal absorption methods such as Digi-Tab. Alternatively, the Coat-A-Count method, based on "COATED-TUBE" antibodies, may be used. Additionally, FOSIPRES therapy should be discontinued several days before laboratory assessment of parathyroid function.

• ACE inhibitors, angiotensin II receptor antagonists or aliskiren: Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure) compared to use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

• Others - FOSIPRES and its metabolites do not cause interactions with food. Pharmacokinetic interaction studies with single or multiple doses of acetylsalicylic acid, chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propanteline, digoxin, and warfarin showed no changes in unbound fosinopril bioavailability. The bioavailability, protein binding, and anticoagulant effect of warfarin (assessed by prothrombin time) were not altered by concomitant administration of FOSIPRES.

4.6 Pregnancy and lactation
Pregnancy
Use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). Use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence on teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy has not yielded conclusive results; however, a small increased risk cannot be excluded.
For patients planning pregnancy, alternative antihypertensive treatments with a proven safety profile in pregnancy should be used, unless continuation of ACE inhibitor therapy is considered essential.
When pregnancy is diagnosed, ACE inhibitor treatment must be immediately discontinued and, if appropriate, alternative therapy initiated.
It is known that exposure to ACE inhibitors during the second and third trimesters induces fetal toxicity (reduced renal function, oligohydramnios associated with limb contractures, pulmonary hypoplasia, intrauterine growth retardation, delayed cranial ossification), neonatal toxicity (renal failure, hypotension, hyperkalemia) (see section 5.3), and death.
Delayed intrauterine development, prematurity, patent ductus arteriosus, and fetal death have been reported, but it is not established whether these are related to ACE inhibitors or to pre-existing maternal conditions.
If exposure to an ACE inhibitor occurs from the second trimester of pregnancy, ultrasound monitoring of renal function and skull development is recommended.
Newborns whose mothers took ACE inhibitors must be closely monitored for hypotension (see sections 4.3 and 4.4).
Hypotension, oliguria, and hyperkalemia must be carefully assessed in neonates exposed to ACE inhibitors during gestation.
Lactation
Due to very limited data available on the use of FOSIPRES during lactation, FOSIPRES is not recommended, and alternative treatments with a proven safety profile during lactation should be preferred, especially when nursing newborns or preterm infants.
4.7 Effects on ability to drive and use machines
Although the medicine does not affect the ability to drive or operate machinery, very rarely adverse effects such as dizziness and visual disturbances may occur.
4.8 Undesirable effects
The incidence of adverse effects was similar in younger and elderly patients (≥ 65 years).
The most frequently reported adverse effects in controlled clinical trials with FOSIPRES in hypertension (treatment duration 2 to 3 months) are listed below:

Discontinuation of treatment due to adverse events or changes in laboratory parameters occurred in 3% of patients in the fosinopril group and in 1.2% of the placebo group.
Other adverse effects reported with fosinopril and other ACE inhibitors are listed below.

Adverse events possibly or probably related, or with uncertain relationship, to therapy occurring in at least 1% of patients treated with fosinopril in placebo-controlled clinical trials in heart failure are: 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 relationship, to therapy occurring in 0.4–1.0% of patients treated (exceptions in parentheses) with fosinopril in placebo-controlled clinical trials in heart failure are:

The following adverse reactions have been associated with ACE inhibitor therapy:
anaphylactoid reactions (see section 4.4), 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, antinuclear antibody positivity, elevated ESR, eosinophilia, and leukocytosis.

4.9 Overdose
No cases of fosinopril overdose syndromes have been reported in humans.
Symptoms of ACE inhibitor overdose include: hypotension, shock, loss of consciousness, bradycardia, electrolyte disturbances, and renal failure.
In case of overdose, the patient should be closely monitored under medical supervision, preferably in an intensive care unit, with frequent monitoring of serum electrolytes and serum creatinine. Recommended treatment includes induction of emesis if ingestion was recent and/or gastric lavage, or administration of adsorbents or sodium sulfate within 30 minutes of ingestion. If hypotension occurs, the patient should be placed in a supine position and rapidly administered intravenous fluid and saline replacement. If necessary, treatment may include, among others, angiotensin II, administration of atropine, or pacemaker insertion.
FOSIPRES is poorly dialyzable. The clearance of fosinoprilat by hemodialysis and peritoneal dialysis is approximately 2% and 7% of urea clearance, respectively.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitor, uncombined
ATC code: C09AA09
FOSIPRES (sodium fosinopril) is the esterified prodrug of a long-acting ACE inhibitor, fosinoprilat (fosinopril diacid). After oral administration, fosinopril is rapidly and completely hydrolyzed into its active compound.
Fosinopril, chemically designated as (1(S*(R*)),2a,4b)-4-cyclohexyl-1-(((2-methyl-1-(1-oxypropoxy)propoxy)(4-phenylbutyl)phosphinyl)acetyl)-L-proline, monosodium salt, is the first of a new class of ACE inhibitors, the phosphinic acid derivatives, which are characterized pharmacokinetically by partial extra-renal elimination.
Mechanism of action. Angiotensin-converting enzyme (ACE) regulates the conversion of the decapeptide angiotensin I into the octapeptide angiotensin II. Angiotensin II is a potent vasoconstrictor and also stimulates aldosterone secretion from the adrenal cortex, thereby causing fluid and sodium retention. The antihypertensive action of fosinopril is primarily due to specific and competitive inhibition of circulating and tissue ACE, resulting in suppression of the renin-angiotensin-aldosterone system.
ACE inhibition leads to a reduction in angiotensin II levels, thereby decreasing arteriolar vasoconstriction and aldosterone production, resulting in reduced fluid and sodium retention and a slight increase in potassium.
ACE inhibition also reduces the degradation of bradykinin, a potent vasodilator peptide. The resulting accumulation of bradykinin may contribute to the antihypertensive effect of ACE inhibitors, particularly in low-renin states. It has also been demonstrated that local production of angiotensin II within vascular walls plays an important role in blood pressure regulation, and that ACE inhibition at this level contributes to the magnitude and duration of the antihypertensive effect of ACE inhibitors. Furthermore, tissue systems producing angiotensin II have been identified in other organs (heart, brain, etc.), and their activation in various cardiovascular diseases is considered partly responsible for damage to these target organs.
Pharmacodynamics and clinical effects. Administration of FOSIPRES in patients with mild-to-moderate to severe hypertension results in a significant reduction in arterial pressure measured both in supine and upright positions, generally without causing postural hypotension.
After oral administration of a single dose of FOSIPRES, the onset of antihypertensive action occurs approximately 1 hour later, with peak antihypertensive effect occurring between 2 and 6 hours.
At recommended daily doses, the antihypertensive effect of FOSIPRES is maintained over the entire 24-hour period.
As with other ACE inhibitors, complete antihypertensive effect may require up to 2–4 weeks of treatment in some cases.
The antihypertensive effect of FOSIPRES remains consistent over time, with no evidence of tolerance development. Abrupt discontinuation of FOSIPRES does not result in rebound hypertension.
In both acute hemodynamic and long-term studies conducted in patients with mild-to-moderate hypertension, FOSIPRES produced a significant reduction in systemic vascular resistance and systemic blood pressure without altering cardiac performance, renal, splanchnic, muscular, and cutaneous blood flows, glomerular filtration, or plasma volumes.
Furthermore, physiological hemodynamic responses to various stimuli (isometric exercise, mental stress, tilt) are not altered by FOSIPRES, indicating maintenance of normal sympathetic nervous system function in treated hypertensive patients.
FOSIPRES therapy has also led, in hypertensive patients with left ventricular hypertrophy, to a significant reduction in ventricular mass and interventricular septum thickness, while maintaining ventricular performance.
Despite significant reduction in arterial pressure, FOSIPRES does not alter cerebral blood flow, demonstrating a positive cerebral circulatory adaptation to antihypertensive treatment.
Long-term therapy with FOSIPRES has not induced any changes in the metabolic profile of hypertensive patients, indicating complete absence of interference with either glucose or lipid metabolism. In hypertensive patients with demonstrated insulin resistance, FOSIPRES treatment normalized this condition, while in hypertensive diabetic patients it increased insulin sensitivity.
FOSIPRES is indicated for initial treatment and may be advantageously combined with other antihypertensive drugs. Combination with thiazide diuretics produces an additive antihypertensive effect.
In patients with heart failure, fosinopril use is associated with a reduction in pulmonary capillary pressure (preload) and mean arterial pressure and peripheral vascular resistance (afterload), as demonstrated in a specifically conducted clinical study. In patients treated for at least 10 weeks with once-daily fosinopril, this hemodynamic effect is maintained over the entire 24-hour period. Moreover, in symptomatic patients, heart rate decreases compared to baseline values, and cardiac output increases despite reduced left ventricular filling pressure. No tachyphylaxis phenomena have been reported.
In two placebo-controlled clinical trials, in which FOSIPRES was administered as a single daily dose for 6 months to patients with heart failure not receiving digitalis therapy, the following results were observed: improvement in symptoms, reduction in hospitalizations for heart failure (66% relative risk reduction), and reduced need for additional diuretic doses. All these clinical benefits were statistically significant.
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 combining an ACE inhibitor with an angiotensin II receptor antagonist.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes with evidence of organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes and diabetic nephropathy.
These studies did not demonstrate any significant benefit on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy.
These findings are relevant to other ACE inhibitors and angiotensin II receptor antagonists due to their similar pharmacodynamic properties.
ACE inhibitors and angiotensin II receptor antagonists should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was prematurely terminated due to an increased risk of adverse events. Cardiovascular death and stroke were numerically more frequent in the aliskiren group compared to the placebo group, and adverse events and serious adverse events of interest (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

5.2 Pharmacokinetic properties
Pharmacokinetics and metabolism. Approximately 36% of an oral dose of FOSIPRES is absorbed in the upper intestine (duodenum/jejunum), and this absorption is not affected by food intake.
Hydrolysis of FOSIPRES to its active metabolite, fosinoprilat, occurs rapidly and completely in the gastrointestinal mucosa and liver. The rate of conversion of fosinopril to fosinoprilat may be slowed in patients with hepatic dysfunction, although the extent of conversion remains unchanged. The time to reach maximum plasma concentration (C_max) is approximately three hours, regardless of dose, consistent with the peak inhibition of the pressor response to angiotensin I (3–6 hours after oral administration). After single and multiple doses, pharmacokinetic parameters are directly proportional to the administered fosinopril dose.
The effective plasma half-life (T_1/2) of fosinoprilat is approximately 11.5 hours, which correlates with the 24-hour antihypertensive efficacy of a single dose. In patients with heart failure, the half-life of fosinopril (fosinoprilat) is approximately 14 hours. Fosinoprilat is highly protein-bound (>95%), has a low volume of distribution, and negligible binding to blood cellular elements. Animal studies indicate that neither fosinopril nor fosinoprilat crosses the blood-brain barrier, although fosinoprilat crosses the placenta in pregnant females.
In experimental animal studies (SHR rats), fosinopril has demonstrated activity in inhibiting the renin-angiotensin system, particularly at the vascular and cardiac levels.
Unlike other ACE inhibitors, which are primarily eliminated renally, FOSIPRES has dual hepatic and renal elimination pathways. In healthy subjects, FOSIPRES is eliminated in a balanced manner through both routes in approximately equal proportions. In patients with impaired renal function, after single and repeated doses, total clearance of fosinoprilat is reduced to about half, with a slight increase in AUC, without further alteration as renal insufficiency progresses. Absorption, bioavailability, and protein binding are not significantly altered. Pharmacokinetic studies have shown no evidence of drug accumulation. Furthermore, the dosing interval recommended in dosage regimens exceeds the drug's half-life. This substantial independence of fosinopril elimination from the degree of renal impairment is related to compensatory increased elimination of the active form via hepatobiliary excretion. Similarly, in hepatic impairment, renal compensation occurs, resulting in total body clearance of fosinoprilat approximately half that observed in patients with normal liver function. Therefore, dosage adjustments are not required in patients with severe hepatic or renal impairment beyond those recommended for initial treatment.
No differences in pharmacokinetic parameters were observed in elderly patients (65–74 years) compared to younger subjects (20–35 years).
Fosinoprilat is detectable in trace amounts, not quantifiable, in breast milk.

5.3 Preclinical safety data
SINGLE DOSE. In rodent studies, fosinopril was toxic only at extremely high doses, approximately 1,200 times the human therapeutic dose. The toxicity of the active metabolite (fosinoprilat) was even lower.
REPEATED DOSES. Repeated-dose studies of variable duration up to 2 years have demonstrated that animals tolerate high doses of fosinopril without significant harmful effects. Most observed effects were reversible and mild, and were essentially related to an exaggerated pharmacological effect of fosinopril, thus primarily hemodynamic in nature.
Combination with diuretics is particularly indicated due to their complementary and synergistic mechanisms of action.
The antihypertensive efficacy of FOSIPRES is comparable in both younger and elderly patients.

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 should be stored under normal environmental conditions, protected from moisture.
6.5 Nature and content of container: 14 tablets of 20 mg in blister packs.
6.6 Instructions for use and handling: No special instructions.

7. MARKETING AUTHORIZATION HOLDER
   A. Menarini Industrie Farmaceutiche Riunite s.r.l., Via Sette Santi, 3 - Florence, Italy.

8. MARKETING AUTHORIZATION NUMBER
   FOSIPRES 20 mg tablets - 14 tablets. A.I.C. No. 027747029.

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION
   Date of first authorization: 16 December 1991.
   Date of latest renewal: 16 December 2006.

10. DATE OF TEXT REVISION
    February 2015