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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fosinopril sodium 20 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Fosinopril sodium 20 mg tablet contains: 20 mg Fosinopril sodium. Excipient with known effect: Each tablet contains 136 mg of lactose anhydrous.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

Fosinopril sodium 20 mg tabletsi

White to off white, round, biconvex, uncoated tablets with an "X" on one side and "84" on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of hypertension.

Treatment of symptomatic heart failure.

4.2 Posology and method of administration

Fosinopril sodium should be administered orally in a single daily dose. As with all other medicinal products taken once daily, it should be taken at approximately the same time each day. The absorption of fosinopril sodium is not affected by food.

The usual initial 10 mg dose has not been studied in patients with severe heart failure NYHA IV and in patients over 75 years treated for heart failure (see section 4.4).

In patients who are at particular risk of hypotension (since the renine-angiotensin-aldosteron system has been activated, See section 4.4), such as patients with severe cardiac heart failure (NYHA IV), patients over 75 years treated for heart failure, patients with severe renal and /or severe hepatic impairment, and patients treated with diuretics, it is however recommended to initiate the treatment with a reduced (5 mg) dose.

The maintenance dose should be individualised according to patient profile and blood pressure response (see section 4.4).

Hypertension

Fosinopril sodium may be used as a monotherapy or in combination with other classes of antihypertensive medicinal products, (see Sections 4.3, 4.4, 4.5 and 5.1).

Hypertensive patients not being treated with diuretics Starting dose

The initial recommended dose is 10 mg once a day. Patients with a strongly activated renin-angiotensin- aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation, or severe hypertension) may experience an excessive blood pressure fall following the initial dose. The initiation of treatment should take place under medical supervision.

Maintenance dose

The usual daily dose is 10 mg to a maximum of 40 mg administered in a single dose. In general if the desired therapeutic effect cannot be achieved in a period of 3 to 4 weeks on a certain dose level, the dose can be further increased.

Hypertensive patients being treated with concomitant diuretic therapy Symptomatic hypotension may occur following initiation of therapy with fosinopril sodium. This is more likely in patients who are being treated currently with diuretics, especially in patients with heart failure, elderly patients (over 75 years) and patients with renal dysfunction. Caution is recommended therefore, since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with fosinopril sodium. In hypertensive patients in whom the diuretic cannot be discontinued, therapy with fosinopril sodium should be initiated with a 5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of fosinopril sodium should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed (see section 4.4 and section 4.5). When treatment is initiated in a patient already taking diuretics, it is recommended that the treatment with fosinopril sodium is started under medical supervision for several hours and until blood pressure is stabilized (see sections 4.3, 4.4, 4.5 and 5.1)..

Heart failure

In patients with symptomatic heart failure and fluid retention, fosinopril sodium should be used as adjunctive therapy to diuretics and, where appropriate, digitalis. The recommended initial dose is 10 mg once daily,

initiated under close medical supervision. This initial 10 mg dose has not been studied in patients with severe heart failure NYHA IV and/or over 75 years (see section 4.4). If the initial dose is well tolerated patients should then be titrated to a dose of up to 40 mg once daily based on clinical response. The appearance of hypotension after the initial dose should not preclude careful dose titration of fosinopril sodium, following effective management of the hypotension (see sections 4.3, 4.4, 4.5 and 5.1).

Patients at high risk of symptomatic hypotension e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with fosinopril sodium.

Renal function and serum potassium should be monitored (see sections 4.3, 4.4, 4.5 and 5.1).

Patients with renal insufficiency

An initial dose of 10 mg per day is recommended, however caution is advised especially with a GFR of less than 10 ml/min.

Patients with impaired liver function

An initial dose of 10 mg per day is recommended, however caution is advised. Although the rate of hydrolysis may be slowed, the extent of hydrolysis is not appreciably reduced in patients with hepatic impairment. In this group of patients, there is evidence of reduced hepatic clearance of fosinoprilat with compensatory increase in renal excretion.

Children and adolescents:

Use in this age group is not recommended. There is limited clinical trial experience of the use of fosinopril in hypertensive children aged 6 years and above (see Section 4.8, 5.1, and 5.2). The optimum dosage has not been determined in children of any age. An appropriate dose strength is not available for children weighting less than 50 kg.

Use in the elderly

No dosage reduction is necessary in patients with clinically normal renal and hepatic function as no significant differences in the pharmacokinetic parameters or antihypertensive effect of fosinoprilat have been found compared with younger subjects. However, renal function and serum potassium should be monitored, since deterioration of renal function and hyperkaliemia may occur.

4.3 Contraindications

•    Hypersensitivity to fosinopril sodium, other angiotensin-converting enzyme (ACE) inhibitors or any of the excipients

•    History of angioedema associated with previous ACE inhibitor therapy,

•    Hereditary or idiopathic angioneurotic oedema,

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

•    “The concomitant use of Fosinopril sodium with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see Sections 4.5 and 5.1).”

4.4 Special warnings and precautions for use

The initial 10 mg dose has not been studied in patients over 75 years treated for heart failure and in patients with severe heart failure NYHA IV. There is an expected increased risk of major hypotension, hyperkaliemia and/or rapid increase in potassium levels when initiation of treatment with fosinopril is made using the 10 mg dose in patients with severe heart failure (NYHA IV) and/or in elderly patients and in patients with renal dysfunction treated for heart failure or hypertensive patients treated with concomitant diuretics.

Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. (see sections 4.3 and 4.6).

Symptomatic hypotension

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving fosinopril sodium, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see section 4.5 and section 4.8). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatremia or functional renal impairment and in the elderly patients. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. The safety of an initial 10 mg dose has not been studied in patients with severe heart failure NYHA IV. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of sodium chloride 9 mg/ml (%9%) solution. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with fosinopril sodium. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of fosinopril sodium may be necessary.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other angiotensin-converting enzyme (ACE) inhibitors, fosinopril sodium should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricule such as aortic stenosis or hypertrophic cardiomyopathy.

Renal Function Impairment

In cases of renal impairment, the initial dosage of fosinopril sodium need not be adjusted. Routine monitoring of potassium and creatinine is part of normal medical care for these patients.

In patients with heart failure, hypotension following the initiation of treatment with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.

In some patients with bilateral renal artery stenosis or with a stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributing factor to the above, they should be discontinued and renal function should be monitored during the first weeks of therapy with fosinopril sodium.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when fosinopril sodium has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or ACE inhibitor may be required.

Proteinuria

In patients with pre-existing renal impairment proteinuria may occur in rare cases. In clinically relevant proteinuria (greater than 1 g/day) Fosinopril should only be used after a very critical benefit/risk evaluation and with regular monitoring of the clinical and laboratory chemical parameters.

Hypersensitivity / Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including fosinopril sodium. This may occur at any time during therapy. In such cases, fosinopril sodium should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.

ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).

Anaphylactoid reactions in Haemodialysis Patients

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis

Rarely, patients receiving ACE inhibitors during LDL apheresis with dextran sulphate have, experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Desensitisation

Patients receiving ACE inhibitors during desensitisation treatment (e.g. to hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but have reappeared upon inadvertent re administration of the medicinal product.

Hepatic failure

High fosinopril plasma concentrations might occur in patients with impaired hepatic function.

Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving fosinopril sodium who develop jaundice or marked elevations of hepatic enzymes should discontinue fosinopril sodium and receive appropriate medical follow-up.

Neutropenia / Agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors Neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Fosinopril sodium should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors especially if there is pre-existing impaired renal function.

Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If fosinopril sodium is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Race

As with other ACE inhibitors, fosinopril sodium may be less effective in lowering blood pressure in Black patients than in non-Blacks, possibly because of a higher prevalence of low-renin states in the Black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Surgery / Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, fosinopril sodium may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including fosinopril sodium. Patients at risk for the development of hyperkalaemia include the elderly, those with renal insufficiency, severe cardiac failure, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients taking other medicinal products associated with increases in serum potassium (e.g. heparin). If concomitant use of the abovementioned products is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

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

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

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

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

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5)

Lithium

The combination of lithium and fosinopril sodium is generally not recommended (see section 4.5).

Excipient:

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

4.5 Interaction with other medicinal products and other forms of interaction

Diuretics

When a diuretic is added to the therapy of a patient receiving fosinopril sodium, the antihypertensive effect is usually additive.

Patients already on diuretics and especially those in whom diuretic therapy was recently instituted may occasionally experience an excessive reduction of blood pressure when fosinopril sodium is added. The possibility of symptomatic hypotension with fosinopril sodium can be minimised by discontinuing the diuretic prior to initiation of treatment with fosinopril sodium (see section 4.4).

Potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products associated with increase in serum potassium (e.g. heparin) (see section 4.4, Hyperkalaemia)

Although in clinical trials, serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients. Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride), potassium supplements, potassium-containing salt substitutes or other medicinal products associated with increases in serum potassium (e.g. heparin). The use of the above-mentioned products, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium.

If fosinopril sodium is given with a potassium- losing diuretic, diuretic induced hypokalaemia may be ameliorated.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of fosinopril sodium with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including acetylsalicylic acid > 3 g/day

Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor. NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.

Other antihypertensive agents

Combination with other antihypertensive agents such as beta-blockers, methyldopa, calcium antagonists, and diuretics may increase the antihypertensive efficacy. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4.).

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

Tricyclic antidepressants /Antipsychotics /Anesthetics Concomitant use of certain anesthetic medicinal products, tricyclic antidepressants and anti psychotics with ACE inhibitors may result in a further reduction of blood pressure (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors. Antidiabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

Fosinopril sodium may be used concomitantly with acetylsalicylic acid (at cardiological doses), thrombolytics, beta-blockers and/or nitrates.

Immunosuppressants, cytostatics, systemic corticosteroids or procainamide, allopurinol

The combination of fosinopril sodium with immunosuppressant medicinal products and/or medicinal products that can cause leucopenia should be avoided.

Alcohol

Alcohol enhances the hypotensive effect of fosinopril sodium.

Antacids

Antacids (e.g. aluminium hydroxide, magnesium hydroxide, simeticone) may impair absorption of fosinopril sodium and so the administration of both medicinal products should be separated by at least 2 hours.

Laboratory interactions

Fosinopril sodium may cause a false low measurement of serum digoxin levels with assays using the charcoal absorption method (Kit RIA Digi-Tab® for digoxin). It is recommended to suspend the treatment with fosinopril sodium for a few days before performing parathyroid tests.

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimester of pregnancy (see section 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Breast-feeding

Because no information is available regarding the use of fosinopril sodium during breastfeeding, fosinopril sodium is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on ability to drive and use machines

Although fosinopril sodium is not expected to affect directly, adverse reactions such as hypotension, dizziness and vertigo may interfere with driving or use of machines.

This occurs especially at the start of treatment, when increasing the dosage, when changing over from other preparations and during concomitant use of alcohol, depending on the individual’s susceptibility.

4.8 Undesirable effects

In patients treated with fosinopril sodium, the adverse reactions were in general mild and transient.

Very common (> 1/10),

Common (> 1/100 to <1/10),

Uncommon (> 1/1,000 to <1/100),

Rare (> 1/10,000 to <1/1,000),

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Uncommon:    Transient decrease    in    haemoglobin, decrease in

haematocrit

Rare:    Transient anaemia, eosinophilia, leucopenia,

lymphadenopathy, neutropenia, thrombocytopenia Very rare:    Agranulocytosis

Metabolism and nutrition disorders

Uncommon:    Decreased appetite, gout,    hyperkalaemia

Psychiatric disorders

Uncommon:    Depression, confusion

Nervous system disorders

Common:    Dizziness, headache

Uncommon:    Cerebral infarction, paraesthesia, somnolence,    stroke,

syncope, taste disturbances, tremor, sleep disturbance, Rare:    Dysphasia, memory disturbances, disorientation

Eye disorders

Uncommon:    Visual disturbances

Ear and labyrinth disorders

Cardiac disorders

Common:    Tachycardia

Uncommon:    Angina pectoris,    myocardial infarction or

cerebrovascular accident, palpitations, cardiac arrest, rhythm disturbances, conduction disturbances

Hypotension, orthostatic hypotension Hypertension, shock, transitory ischaemia Flush, haemorrhage, peripheral vascular disease

Respiratory, thoracic and mediastinal disorders Common:    Cough

Uncommon:    Dyspnoea, rhinitis, sinusitis,    tracheobronchitis

Rare:    Bronchospasm, epistaxis,    laryngitis/    hoarseness,

pneumonia, pulmonary congestion

Gastrointestinal disorders

Common:    Nausea, vomiting, diarrhoea

Uncommon:    Constipation, dry mouth, flatulence

Rare:    Oral lesions, pancreatitis, swollen tongue,

distension, dysphagia

Very rare:    intestinal angioedema, (sub) ileus

Hepatobiliary disorders Rare:    Hepatitis

Very rare:    hepatic failure

Skin and subcutaneous tissue disorders Common:    Rash, angioedema, dermatitis

Uncommon:    Hyperhidrosis, pruritus, urticaria

Rare:    Ecchymosis

A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.

Musculoskeletal and connective tissue disorders Uncommon:    Myalgia

Rare:    Arthritis

Renal and urinary disorders Uncommon:    Renal failure, proteinuria

Rare:    Prostatic disorders

Very rare:    acute renal failure

Reproductive and breast disorders

General disorders and administration site conditions

Chest pain (non-cardiac), weakness

Fever, peripheral oedema, sudden death, thoracic pain

Weakness in one extremity

Increase in alkaline phosphatase, increase in bilirubin,

increase in LDH, increase in transaminases

Weight increase, increases in blood urea, increases in

serum creatinine, hyperkalaemia

Slight increase in haemoglobin, hyponatremia

In the clinical studies performed with fosinopril, the incidence of adverse effects did not differ between elderly (more than 65 years of age) and younger patients.

Safety data in the paediatric population receiving fosinopril is still limited, there was only evaluated a short-term exposure. In a randomized clinical trial of 253 children and adolescents aged 6 to 16 years, the following adverse events occurred in the 4 week double blind phase: headache (13.9%), hypotension (4.8%), cough (3.6%) and hyperkalaemia (3.6%), elevated serum creatinine levels (9.2%), elevated serum creatinine kinase levels (2.9%). Different from the adults are this elevated CK reported in this trial (even transient and with no clinical symptoms). The long-term effects of fosinopril on growth, puberty, and general development have not been studied.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

The recommended treatment of overdose is intravenous infusion of normal saline solution.

After ingestion of an overdose, the patients should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently. Therapeutic measures depend on the nature and severity of the symptoms. Measures to prevent absorption such as gastric lavage, administration of adsorbents and sodium sulphate within 30 minutes after intake and hasten elimination should be applied if ingestion is recent. If hypotension occurs, the patient should be placed in the shock position and salt and volume supplementation should be given rapidly.

Treatment with angiotensin II should be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered.

Fosinoprilat cannot be removed from the body by dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: angiotensin converting enzyme (ACE) inhibitors, plain ATC code: C09A A09

Mechanism of action

Fosinopril sodium is the ester prodrug of the long-acting ACE inhibitor fosinoprilaat. After oral administration, fosinopril is quickly and fully metabolised to the active fosinoprilat. Fosinopril sodium contains a phosphinic group capable of specific binding to the active site of the peptidyl dipeptidase angiotensin-converting enzyme, preventing the conversion of decapeptide angiotensin I to the octapeptide, angiotensin II. The resulting reduction in angiotensin II levels leads to a reduction in vasoconstriction and a decrease in aldosterone secretion, that might induce a slight increase in serum potassium and a loss of sodium and fluid. Usually, there is no change in renal blood flow or glomerular filtration rate.

ACE inhibition also prevents the degradation of the potent vasodepressor bradykinin, contributing to the antihypertensive effect; fosinopril sodium presents a therapeutic action in hypertensive patients with low renin levels.

In patients with heart failure, it is assumed that the beneficial effects of fosinopril sodium are mainly due to suppression of the renin-angiotensin-aldosterone system; ACE inhibition produces a reduction in pre-load and after-load.

Pharmacodynamics

Administration of fosinopril sodium to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.

In hypertension, fosinopril sodium reduces blood pressure within one hour of administration, the maximum effect being observed within 3-6 hours. With the usual daily dosage the anti-hypertensive effect lasts for 24 hours

In some patients receiving lower dosages the effect may be reduced at the end of the dosage interval.

The orthostatic effects and tachycardia are rare but might occur in patients with salt depletion or in hypovolemia (see section 4.4). In some patients the development of optimal blood pressure reduction may require 3-4 weeks of therapy. Fosinopril sodium and thiazide diuretics have additive effects.

In heart failure, fosinopril sodium improves symptoms and exercise tolerance and reduces the severity of and frequency of hospitalisation due to cardiac failure.

In a study of 8 cirrhotic patients, fosinopril 20 mg/day for one month did not change hepatic (alanine transferase, gamma-glutamyl-transpeptidase, galactose clearance test and antipyrine clearance test) or renal functions.

Reduction of blood pressure with low (0.1mg/kg), medium (0.3mg/kg) and high (0.6mg/kg) target doses of once-daily fosinopril was evaluated in a randomised double-blind study of 252 children and adolescents aged 6 - 16 years of age with hypertension or high-normal blood pressure. At the end of the four weeks of treatment, the mean reduction from baseline in trough systolic blood pressure was similar for children treated with low, medium and high dose fosinopril. No dose response relationship was demonstrated between the three doses. The optimum dosage has not been determined in children of any age. An appropriate dose strength is not available for children weighting less than 50kg.

“Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.

Given their similar pharmacodynamic properties, these results are also relevant for other ACE- inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers 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 test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. CV death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

5.2 Pharmacokinetic properties

Absorption

After oral administration, the extension of the absorption of fosinopril averages 30% to 40%. The absorption of fosinopril is not affected by the presence of food in gastrointestinal tract, however the rate of absorption might be reduced. Rapid and complete hydrolysis to active fosinoprilat occurs in the gastrointestinal mucosa and liver.

The time to reach C_max is independent of dose, achieved in approximately three hours and consistent with peak inhibition of the angiotensin I pressor response 3 to 6 hours following administration. After multiple or single doses, the pharmacokinetic parameters (Cmax, AUC) are directly proportional to the fosinopril dose that has been taken.

Distribution

Fosinoprilat is highly protein bound (> 95%), has a relatively small volume of distribution and negligible binding to cellular components in blood.

Biotransformation

One hour after oral administration of fosinopril sodium, less than 1% fosinopril in plasma remains unchanged; 75% is present as active fosinoprilat, 15-20% as fosinoprilat glucuronide (inactive), and the remainder (~5%) as the 4-hydroxy metabolite of fosinoprilat (active).

Elimination

After intravenous administration, the elimination of fosinopril is by both hepatic and renal routes. In hypertensive patients with normal renal and hepatic function who received repeated doses of fosinopril, the effective T._/2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective T_/2 was 14 hours. The elimination of fosinopril is by both hepatic and renal routes.

Special patient groups

In patients with renal failure (creatinine clearance < 80 ml/min/1.73 m²), the total body clearance of fosinoprilat is approximately half of that observed in patients with normal renal function, while no significant changes are seen in the absorption, the bioavailability and the plasma protein binding. The clearance of fosinoprilat does not vary according with the degree of renal failure; the reduction in renal elimination is compensated by the increase in hepato-biliary elimination. A slight increase in AUC values (less than the double of normal values) has been observed in patients with several degrees of renal failure, including terminal renal failure (creatinine clearance < 10 ml/min/1.73 m²).

In patients with hepatic failure (alcoholism or biliary cirrhosis), the fosinopril sodium hydrolysis is not significantly reduced, although the rate of the hydrolysis might be reduced; the total fosinoprilat clearance is almost half of the clearance observed in patients with normal hepatic function.

Limited pharmacokinetic data in children and adolescents were provided by singledose pharmacokinetic study in 19 hypertensive patients 6 to 16 years of age who received 0.3mg/Kg of a solution of fosinopril.

Whether AUC and C_max values of fosinoprilat (active form of fosinopril) in children from 6 to 16 years of age were comparable to those seen in adults receiving 20 mg of fosinopril as a solution, has to be demonstrated.

The terminal elimination half-life for fosinoprilat was 11-13 hours and similar at all stages studies.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that fosinopril has no negative effects on fertility and reproductive performance in rats, and is not teratogenic. ACE inhibitors, as a class, when given in the second or third trimester, have been shown to induce adverse effects on the late foetal development, resulting in foetal death and congenital efects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal renin-angiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrient delivery to the foetus. In a study in which female rats were dosed with fosinopril prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The substance has been shown to cross the placenta and is secreted in milk.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Anhydrous lactose

Microcrystalline cellulose Crospovidone Sodium stearyl fumarate Povidone (K-30)

6.2 Incompatibilities

Not applicable

DATE OF REVISION OF THE TEXT

14/11/2014