This information is intended for use by health professionals

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 tablets:

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

Posology

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 maintainance 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 hypotens ion 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 stabilised(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

• Fosinopril sodium is contraindicated in patients who are hypersensitive to fosinopril, otherangiotencin-converting enzyme (ACE) inhibitors or any other component of the fosinopril sodium formulation.

• History of angioedema associated with previous ACE inhibitor therapy,

• Hereditary or idiopathic angioneurotic oedema,

• The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy.

• “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).”

• Concomitant use with sacubitril/valsartan therapy. Fosinopril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 4.5).

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).

Fetal/Neonatal Morbidity and Mortality: When used in pregnancy, ACE inhibitors can cause injury and even death to the developing fetus.

Hypotension: Fosinopril sodium has been rarely associated with hypotension in uncomplicated hypertensive patients. As with other ACE inhibitors, symptomatic hypotension is most likely to occur in salt/volume depleted patients such as those treated vigorously with diuretics and/or salt restriction, or those patients undergoing renal dialysis. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril. A transient hypotensive response is not a contraindication to further doses which may be given without difficulty after replenishment of salt and/or volume.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, fosinopril sodium therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased. Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatremic.

Hypotension is not per se a reason to discontinue fosinopril. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilizes within a week or two, and generally returns to pretreatment levels without a decrease in therapeutic efficacy.

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.

Impaired Renal Function: In hypertensive patients with renal artery stenosis in one or both kidneys, increases in blood urea nitrogen and serum creatinine may occur during treatment with an ACE inhibitor. These increases are usually reversible upon discontinuation of therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease develop increases in blood urea nitrogen and serum creatinine, usually minor or transient, when fosinopril is given concomitantly with a diuretic. This effect is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of fosinopril sodium may be required.

In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with an ACE inhibitor may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

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).

Head and Neck Angioedema: Angioedema has been seen in patients treated with ACE inhibitors, including fosinopril sodium. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and can be fatal. Emergency therapy, should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of fosinopril; some cases required medical therapy.

Intestinal Angioedema: Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C -1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of fosinopril. Treatment with fosinopril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving another ACE inhibitor, enalapril, sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitizations procedures.

Anaphylactoid reactions during high-flux dialysis/lipoprotein apheresis membrane exposure: Anaphylactoid reactions have been reported in patients hemodialyzed with high-flux dialysis membranes while on therapy with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication.

Hepatic failure

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

Impaired Hepatic Function: Patients with impaired liver function could develop elevated plasma levels of fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled.

Neutropenia/Agranulocytosis: ACE inhibitors have been reported rarely to cause agranulocytosis and bone marrow depression; these occur more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Monitoring of white blood cell counts should be considered in such patients.

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 may augment the hypotensive response. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Paediatric use: Safety and effectiveness in children have not been established.

Geriatric use: Among patients who received fosinopril sodium in clinical studies, overall differences in efficacy or safety were not observed between older patients (65 years or older) and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

Serum potassium

ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (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).

Excipients:

Fosinopril sodium contains lactose

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.

Fosinopril sodium contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per each tablet, that is to say essentially 'sodium-free'.

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 on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restrictions or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of fosinopril sodium.

Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes: Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with fosinopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when fosinopril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of fosinopril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Ciclosporin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Heparin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Medicines increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).

Lithium: Increased serum lithium levels and risk of lithium toxicity have been reported in patients receiving ACE inhibitors concomitantly with lithium. Fosinopril sodium and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

Inhibitors of Endogenous Prostaglandin Synthesis: It has been reported that indomethacin may reduce the antihypertensive effect of other ACE inhibitors, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (eg, aspirin) may have a similar effect.

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 anti-hypertensive 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. Therefore, if concomitant administration of these agents is indicated, dosing should be separated by 2 hours.

Interference with serological testing: Fosinopril sodium may cause a false low measurement of serum digoxin levels with assays utilizing the charcoal absorption method. Other kits, which utilizes the antibody coated-tube method, may be use instead. Therapy with fosinopril sodium should be interrupted for a few days before carrying out tests for parathyroid function.

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

Fosinopril is detectable in breast milk.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. The list of undesirable effects shown below is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories:

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)

Infections and infestations

Common:

Upper respiratory infection, pharyngitis, rhinitis, viral infection

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

Not known:

appetite disorder, weight fluctuation

Psychiatric disorders

Common:

Mood altered, sleep disorder

Uncommon:

Depression, confusion

Not known:

abnormal behavior

Nervous system disorders

Common:

Dizziness, headache, paraesthesia

Uncommon:

Cerebral infarction, somnolence, stroke, syncope, tremor

Rare:

Dysphasia, memory disturbances, disorientation

Not known:

balance disorder

Eye disorders

Common:

Eye disorder, Visual disturbances

Ear and labyrinth disorders

Uncommon:

Ear ache, tinnitus, vertigo

Cardiac disorders

Common:

Tachycardia, arrhythmia, palpitations, angina pectoris

Uncommon:

myocardial infarction or cerebrovascular accident, cardiac arrest, rhythm disturbances, conduction disturbances

Not known:

Cardio-respiratory arrest

Vascular disorders

Common:

Hypotension, orthostatic hypotension

Uncommon:

Hypertension, shock, transitory ischaemia

Rare:

Flush, haemorrhage, peripheral vascular disease

Not known:

Hypertensive crisis.

Respiratory, thoracic and mediastinal disorders

Common:

Cough, sinus disorder

Uncommon:

Dyspnoea, sinusitis, tracheobronchitis

Rare:

Bronchospasm, epistaxis, laryngitis/ hoarseness, pneumonia, pulmonary congestion

Not known:

Dysphonia, pleuritic pain

Gastrointestinal disorders

Common:

Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, dysgeusia

Uncommon:

Constipation, dry mouth, flatulence

Rare:

Oral lesions, pancreatitis, swollen tongue, abdominal 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

Common:

Musculoskeletal pain, myalgia

Rare:

Arthritis

Not known:

Muscular weakness

Renal and urinary disorders

Common:

Micturition disorder

Uncommon:

Renal failure, proteinuria

Very rare:

acute renal failure

Reproductive and breast disorders

Common:

Sexual dysfunction

Not known:

Prostatic disorder

General disorders and administration site conditions

Common:

Chest pain (non-cardiac), fatigue, oedema, asthenia

Uncommon:

Fever, sudden death, thoracic pain

Rare:

Weakness in one extremity

Not known:

pain

Investigations

Common:

Increase in alkaline phosphatase, increase in bilirubin, increase in LDH, increase in transaminases

Uncommon:

Weight increase, increases in blood urea, increases in serum creatinine

Rare:

Slight increase in haemoglobin, hyponatremia

Not known:

Liver function test abnormal

During clinical trials with fosinopril sodium, the incidence of adverse events in the elderly (≥65 years old) was similar to that of younger patients

Hypotension or syncope was a cause for discontinuation of therapy in 0.3% of patients.

A symptom-complex of cough, bronchospasm, and eosinophilia has been observed in two patients treated with fosinopril.

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.

No specific information is available on the treatment of overdosage with fosinopril sodium; treatment should be symptomatic and supportive. Therapy with fosinopril sodium should be discontinued and the patient closely monitored. Suggested measures include induction of emesis and/or gastric lavage, and correction of hypotension by established procedures.

Fosinopril is poorly removed from the body by hemodialysis or peritoneal 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.

Pharmacodynamic effects:

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 Cmax 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 T½ for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective T½ 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 single-dose 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 Cmax 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

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PE/PVdC/ Aluminium blister pack:

Pack size: 10, 14, 20, 21, 28, 30, 42, 50, 56, 60, 90, 98, 100 and 400 tablets

HDPE bottle with polypropylene cap containing silica gel sachet and cotton coil

Pack size: 28 and 500 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Milpharm Limited

Ares, Odyssey Business Park, West End Road,

South Ruislip HA4 6QD.

United Kingdom

8. Marketing authorisation number(s)

PL 16363/0314

9. Date of first authorisation/renewal of the authorisation

14/10/2011

10. Date of revision of the text

05/11/2020.