Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord-UK Ltd (Trading style: Accord) Whiddon Valley, Barnstaple, Devon, EX32 8NS
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, those patients undergoing renal dialysis, dietary salt restriction, diarrhoea or vomiting, or has severe renin-dependent hypertension (see sections 4.5 and 4.8). 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.
The safety of an initial 10mg 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 a 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 9mg/ml (0.9%) solution.
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 ventricle such as aortic stenosis or hypertrophic cardiomyopathy.
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 practice for these patients. 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.
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.
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.
Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of therapy with fosinopril sodium.
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.
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 have been reported in patients hemodialyzed with highflux dialysis membranes while on therapy with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
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 sodium. Treatment with fosinopril sodium 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.
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).
Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors. If such symptoms occur during treatment with Fosinopril Sodium 10mg Tablets, therapy should be discontinued.
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 (epinephrine) 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. 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.
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.
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 Tablets who develop jaundice or marked elevations of hepatic enzymes should discontinue Fosinopril sodium Tablets and receive appropriate medical follow-up.
Patients with impaired liver function could develop elevated plasma levels of fosinopril. In a study in patients with alcoholic or bilary cirrhosis, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled.
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including fosinopril. 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).
Patients at risk for the development of hyperkalemia include those with renal insufficiency, diabetes mellitus, hypoaldosteronism or those using concomitant potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs associated with increases in serum potassium (e.g, heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).
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.
ACE inhibitors may augment the hypotensive effects of anaesthetics and analgesics. If hypotension occurs in patients undergoing surgery/anaesthesia and concomitantly receiving ACE inhibitors, it can usually be corrected by intravenous administration of fluid.
Safety and effectiveness in children have not been established.
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.
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
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)
Evaluation of the hypertensive patient should include assessment of renal function prior to initiation of therapy and during treatment where appropriate.
See section 4.2 regarding use of fosinopril in patients receiving haemodialysis or peritoneal dialysis.
In severe cases of these conditions where patients have fixed cardiac output, fosinopril may cause a large fall in blood pressure as such patients cannot compensate for the reduction in peripheral resistance with an increase in cardiac output.
ACE inhibitors cause a higher rate of angioedema in black than in non-black patients. When fosinopril is given as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response.
ACE inhibitors should not be initiated during pregnancy. 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 (see sections 4.3 and 4.6).
When used in pregnancy, ACE inhibitors can cause injury and even death to the developing fetus.
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 sections 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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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).
Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Antacids (ie, aluminum hydroxide, magnesium hydroxide, and simethicone) may impair absorption of fosinopril. Administration of Fosinopril Sodium 10mg Tablets and antacids should be separated by at least 2 hours.
Non-steroidal anti-inflammatory drugs and more than 3g/day aspirin may interfere with the antihypertensive effect. However, the concomitant use of fosinopril and NSAIDs (including aspirin) is not associated with an increase in clinically significant adverse reactions. As with any ACE inhibitor, in some patients with compromised renal function the co-administration of fosinopril and NSAIDs may result in a further deterioration of renal function.
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see section 4.4).
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).
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
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.
Fosinopril sodium may be used concomitantly with acetylsalicylic acid (at cardiological doses), thrombolytics, beta-blockers and/or nitrates.
The combination of fosinopril sodium with immunosuppressant medicinal products and/or medicinal products that can cause leucopenia should be avoided.
Alcohol enhances the hypotensive effect of fosinopril sodium.
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.
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.
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 (see section 4.4).
Combination with other anti-hypertensive agents such as beta blockers, methyldopa, calcium antagonists, and diuretics may increase the anti-hypertensive effect. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosteronesystem (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).
Concomitant use of fosinopril with immunosuppressants (e.g. azathioprine) may increase the risk of leucopenia developing.
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with fosinopril sodium. 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 sodium 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 sodium 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. 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 abovementioned 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.
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.
In pharmacokinetic studies with nifedipine, propranolol, cimetidine, metoclopramide and propantheline the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.
Fosinopril has been used concomitantly with paracetamol, antihistamines, lipid-lowering agents or oestrogen without evidence of clinically important adverse events.
Fosinopril Sodium 10mg Tablets may cause a false low measurement of serum digoxin levels with assays using the charcoal absorption method for digoxin. Other kits which use the antibody coated-tube method may be used. Therapy with fosinopril sodium should be interrupted for a few days before carrying out tests for parathyroid function.
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence 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 foetotoxicity (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).
Fosinoprilat, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion.
Because only very limited information is available regarding the use of Fosinopril Tablets during breastfeeding, Fosinopril tablets is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Whilst fosinopril is not expected to directly affect performance, it can cause adverse effects such as dizziness, vertigo or hypotension which 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.
Patients should make sure they are not affected before driving or operating machinery.
In the patients treated with Fosinopril sodium Tablets, the adverse effects were in general mild and transient.
Very common: ≥1/10
Common: ≥1/100 and <1/10
Uncommon: ≥1/1000 and <1/100
Rare: ≥1/10 000 and <1/1000
Very rare: <1/10000 including isolated cases
Not Known: (cannot be estimated from the available data)
Common: Upper respiratory infection, pharyngitis, rhinitis, viral infection
Uncommon: Sinusitis, tracheobronchitis
Rare: Pneumonia
Not known: Laryngitis
Uncommon: Transient decrease in haemoglobin, decrease in haematocrit
Rare: Transient anaemia, eosinophilia, leucopenia, lymphadenopathy, neutropenia, thrombocytopenia
Very rare: Agranulocytosis
Uncommon: Decreased appetite, gout, hyperkalaemia
Not Known: Appetite disorder, weight fluctuation
Common: Mood altered, sleep disorder
Uncommon: Depression, confusion
Not Known: abnormal behaviour
Common: Dizziness, headache, paraesthesia
Uncommon: Syncope, cerebral infarction, somnolence, tremor, stroke, taste disturbances, sleep disturbance
Rare: Dysphasia, memory disturbances, disorientation
Not Known: balance disorder
Common: Eye disorder, visual disturbances
Uncommon: Ear pain, tinnitus, vertigo
Common: Tachycardia, arrhythmia, palpitations, angina pectoris
Uncommon: Myocardial infarction or cerebrovascular accident, cardiac arrest, rhythm disturbances, conduction disturbances
Not known: cardio-respiratory arrest,
Common: Hypotension, orthostatic hypotension
Uncommon: Shock, hypertension, transitory ischaemia
Rare: Flush, haemorrhage, peripheral vascular disease
Not known: Hypertensive crisis
Common: Cough
Uncommon: Dyspnoea
Rare: Bronchospasm, epistaxis, pulmonary congestion
Not known: Dysphonia, pleuritic pain
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
Rare: Hepatitis
Very rare: Hepatic failure
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.
Common: Musuloskeletal pain, myalgia
Rare: Arthritis
Common: Micturition disorder
Uncommon: Renal failure, proteinuria
Rare: Prostatic disorders
Very rare: acute renal failure
Common: Sexual dysfunction
Common: Fatigue, chest pain (non-cardiac), oedema, asthenia, weakness
Uncommon: Fever, peripheral oedema, sudden death, thoracic pain
Rare: Weakness in one extremity
Not known: Pain pyrexia
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
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.
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, only a short-term exposure has been evaluated. 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%) and 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 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 the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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