Fosinopril Sodium Tablets USP 40mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

Fosinopril Sodium Tablets USP 10mg Taj Pharma
Fosinopril Sodium Tablets USP 20mg Taj Pharma
Fosinopril Sodium Tablets USP 40mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a) Each tablet contains:
Fosinopril sodium USP     10mg
Excipients                            q.s

b) Each tablet contains:
Fosinopril sodium USP      20mg
Excipients                            q.s

c) Each tablet contains:
Fosinopril sodium USP      40mg
Excipients                             q.s

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Hypertension

Fosinopril is indicated in adults for the treatment of hypertension. Fosinopril may be used alone as initial therapy or in combination with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1). The antihypertensive effects of fosinopril and diuretics used concomitantly are approximately additive.

Heart Failure

Fosinopril is indicated for adults for the treatment of heart failure in combination with a non-potassium sparing diuretic and where appropriate, digitalis. In these patients, fosinopril improves symptoms and exercise tolerance, reduces severity of heart failure and decreases the frequency of hospitalisation for heart failure.

4.2 Posology and method of administration

Posology

Hypertensive patients not being treated with diuretics:

The dose range is 10 to 40 mg per day administered in a single dose and without regard to meals. The normal starting dose for patients is 10 mg once a day. Dosage may need to be adjusted after approximately 4 weeks according to blood pressure response. No additional blood pressure lowering is achieved with doses greater than 40 mg daily. If blood pressure is not adequately controlled with fosinopril alone, a diuretic can be added.

Hypertensive patients being treated with concomitant diuretic therapy:

The diuretic should preferably be discontinued for several days prior to beginning therapy with fosinopril to reduce the risk of an excessive hypotensive response. If blood pressure is inadequately controlled after an observation period of approximately 4 weeks, diuretic therapy may be resumed. Alternatively, if diuretic therapy cannot be discontinued, an initial dose of 10 mg of fosinopril should be used with careful medical supervision for several hours, until blood pressure has stabilised. In diuretic treated hypertensive patients, mean cerebral blood flow is maintained between 4 and 24 hours after fosinopril, despite significant reduction in blood pressure.

Heart Failure:

The recommended initial dose is 10 mg once daily, initiated under close medical supervision. If the initial dose is well tolerated patients should then be titrated to a dose of up to 40 mg once daily. The appearance of hypotension after the initial dose should not preclude careful dose titration of fosinopril, following effective management of the hypotension. Fosinopril is used in addition to diuretics and digitalis.

Heart failure – High Risk Patients:

It is recommended that treatment is initiated in hospital for patients with severe cardiac failure (NYHA IV) and those at particular risk of first dose hypotension, i.e. patients on multiple or high dose diuretics (e.g.> 80 mg furosemide), patients with hypovolaemia, hyponatraemia (serum sodium < 130 mEq/l), pre-existing hypotension (systolic blood pressure <90 mmHg), patients with unstable cardiac failure and those on high-dose vasodilator therapy.

Paediatric population:

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 sections 4.8, 5.1 and 5.2 and). The optimum dosage has not been determined in children of any age. An appropriate dose strength is not available for children weighing less than 50 kg.

Older people:

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 (active form of fosinopril) have been found compared with younger subjects.

Impaired hepatic function:

Treatment should be initiated at a dose of 10 mg. The rate of hydrolysis may be slowed in patients with hepatic impairment and patients could develop elevated plasma levels of fosinopril (see section 4.4).

Renal Impairment:

Treatment should be initiated at a dose of 10 mg. Depending on the response, the dose should then be titrated to achieve the desired therapeutic effect.

Absorption, bioavailability, protein binding, biotransformation and metabolism are not appreciably altered by reduced renal function. In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than that in patients with normal renal function. However, since hepatobiliary elimination compensates at least partially for diminished renal elimination, the body clearance of fosinoprilat is not appreciably different over a wide range of renal insufficiency (creatinine clearances ranging from <10 to 80 ml/min/1.73m2, i.e. including end-stage renal failure).

Fosinopril / fosinoprilat is not well dialysed. In a study on radiolabelled intravenous fosinoprilat (7.5mg) and oral fosinopril (10mg), haemodialysis for four hours cleared only approximately 1.5% of the administered dose.

Clearance of fosinoprilat by haemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.

Method of administration

For oral use.

4.3 Contraindications

Hypersensitivity to fosinopril or to any of the excipients listed in section 6.1, or any other ACE inhibitor.

History of angioneurotic oedema associated with previous ACE inhibitor therapy.

Hereditary / idiopathic angioneurotic oedema.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Renal artery stenosis.

Cardiogenic shock.

It should be noted that Fosinopril is not licensed for use in acute myocardial infarction.

The concomitant use of Fosinopril 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

Hypersensitivity / angioedema:

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.

Head and Neck Angioedema:

Angioedema has been seen in patients treated with ACE inhibitors, including fosinopril. 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.

Anaphylactoid- reactions during high-flux dialysis/lipoprotein apheresis membrane exposure:

Clinical observations have shown a high incidence of anaphylactoid-like reactions during haemodialysis with high-flux dialysis membranes (e.g. AN69) in patients receiving ACE inhibitors. Similar reactions during low-density lipoprotein (LDL) apheresis with dextran sulfate absorption have been observed. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication.

Anaphylactoid reactions during desensitisation:

Two patients undergoing desensitising treatment with hymenoptera venom whilst 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 desensitisation procedures.Hypotension:

Fosinopril 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, renovascular hypertension, 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 continuing therapy 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 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 dose of diuretic therapy in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatraemic.

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 stabilises within a week or two, and generally returns to pre-treatment levels without a decrease in therapeutic efficacy.

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 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.

Impaired Renal Function:

Hypertensive patients with pre-existing congestive heart failure, renovascular hypertension (especially renal artery stenosis in one or both kidneys), or salt and/or volume depletion of any aetiology are at increased risk of developing findings indicative of renal dysfunction, including: increases in blood urea nitrogen (BUN) and serum creatinine and potassium; proteinuria; changes in urine volume (including oliguria/anuria); and an abnormal urinalysis. 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 BUN 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 and/or discontinuation of diuretic and/or fosinopril 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.

Dialysis:

The dialysis clearance of fosinopril is not clinically significant; hence, supplemental dosing following dialysis should not be necessary.

Hepatic Failure:

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

Prior to starting treatment with fosinopril, renal and hepatic function should be assessed.

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.

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).

Patients at risk of developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, and those using concomitant potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, or other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole).

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.

Surgery/Anaesthesia:

ACE inhibitors may augment the hypotensive effects of anaesthetics, analgesics, or other agents that produce hypotension. If hypotension occurs in patients undergoing surgery/anaesthesia and concomitantly receiving ACE inhibitors, it can usually be corrected by intravenous administration of fluid.

Aortic stenosis, mitral stenosis / Hypertrophic cardiomyopathy:

ACE inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.

Ethnicity:

The antihypertensive effect of ACE inhibitors is generally lower in black patients than in non-black patients.

Cough:

Cough has been reported with the use of ACE inhibitors, including fosinopril. 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.

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 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).

Foetal/Neonatal Morbidity and Mortality:

When used in pregnancy, ACE inhibitors can cause injury and even death to the developing foetus.

Paediatric population:

There is limited clinical trial experience of the use of fosinopril in hypertensive children aged 6 years and above (see sections 4.2, 4.8, 5.1 and 5.2).

Older people:

Among patients who received fosinopril 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.

4.5 Interaction with other medicinal products and other forms of interaction

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).

Not recommended combination

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.

Take special care

Antacids:

Antacids (e.g. aluminum hydroxide, magnesium hydroxide, and simeticone) may impair absorption of fosinopril sodium. Administration of fosinopril and antacids should be separated by at least 2 hours

Inhibitors of Endogenous Prostaglandin Synthesis:

It has been reported that indometacin may reduce the antihypertensive effect of other ACE inhibitors, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (NSAIDs) (including aspirin) may have a similar effect.

Lithium:

Concomitant therapy with lithium may increase the serum lithium concentration and risk of lithium toxicity. Fosinopril and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

Other Anti-hypertensive agents:

Combination with other anti-hypertensive agents such as beta blockers, methyldopa and calcium antagonists may increase the anti-hypertensive 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.

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).

Immunosuppressants:

Concomitant administration of immunosuppressants with fosinopril may lead to an increased risk of leukopenia.

Other drugs:

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, hypoglycaemic agents, insulin, lipid-lowering agents, or oestrogen without evidence of clinically important adverse events.

Interference with serological testing:

Fosinopril 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 instead. Therapy with fosinopril 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 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).

Breastfeeding

Fosinopril is detectable in breast milk. Because only very limited information is available regarding the use of Fosinopril tablets during breastfeeding, Fosinopril tablets are not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on ability to drive and use machines

There are no studies on the effect of fosinopril on the ability to drive. However, adverse events such as hypotension, dizziness and fatigue may interfere with driving.

4.8 Undesirable effects

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 < 1/10), uncommon (≥1/1,000 <1/100), rare (≥1/10,000 <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

In placebo controlled studies, there were no significant differences in clinical adverse experiences. Hypotension or syncope was a cause for discontinuation of therapy in 0.3% of patients.

The incidence of side effects did not differ between older people (≥65 years old) and younger patients.

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

Laboratory test findings showed some modest, usually transient, decreases in haemoglobin and haematocrit values and infrequently, small increases in blood urea.

Paediatric population

Safety data in the paediatric population receiving fosinopril is still limited, as only short-term exposure has been evaluated. In a randomised 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 (CK) levels (2.9%). Different from adults are the 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.

4.9 Overdose

Symptoms of overdosage are severe hypotension, shock stupor, bradycardia, electrolyte disturbances and renal failure.

No specific information is available on the treatment of overdosage with fosinopril; therapeutic measures depend on the nature and severity of the symptoms and should be symptomatic and supportive.

Measures to prevent absorption, such as induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate, within 30 minutes after intake, to hasten elimination, should be applied if ingestion is recent. Blood pressure should be monitored and if hypotension occurs, the patient should be placed in the shock position and salt and volume supplementation should be given rapidly. If volume expansion alone does not restore blood pressure, treatment with angiotensin II should be considered. Fosinopril /fosinoprilat is poorly removed from the body by peritoneal dialysis or haemodialysis.

After ingestion of an overdose, therapy with fosinopril should be discontinued and the patients should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors, plain.

Fosinopril sodium salt is the ester prodrug of an angiotensin converting enzyme (ACE) inhibitor, fosinoprilat. Angiotensin converting enzyme is a peptidyl dipeptidase enzyme that catalyses a number of peptide conversions. These include the conversion of decapeptide Angiotensin I to the octapeptide, Angiotensin II. Fosinopril also inhibits kininase, the enzyme that degrades bradykinin.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the 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. Cardiovascular 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.

Paediatric population

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 253 children and adolescents aged 6 to 16 years 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 dosage response relationship was demonstrated between the three doses. The optimum dose has not been determined in children of any age. An appropriate dose strength is not available for children weighing less than 50kg.

5.2 Pharmacokinetic properties

The absolute absorption of fosinopril averaged 36% of an oral dose, and was not affected by the presence of food. 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.

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. Fosinoprilat is highly protein bound (>95%), has a relatively small volume of distribution and negligible binding to cellular components in blood. The elimination of fosinopril is by both hepatic and renal routes. Unlike other ACE-inhibitors, there is compensatory excretion by the alternative route in patients with renal insufficiency.

Limited pharmacokinetic data in children and adolescents were provided by a single-dose pharmacokinetic study in 19 hypertensive patients aged 6 to 16 years who received 0.3mg/kg of a solution of fosinopril.

Whether AUC and Cmax values of fosinoprilat (active form of fosinopril) in children aged 6 to 16 years 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 studied.

5.3 Preclinical safety data

Animal studies indicate a toxicity profile, which is an extension of the pharmacological effects of fosinopril. It has shown no evidence of carcinogenicity in rodent studies and no potential for mutagenicity in either in vitro or in vivo tests.

6. Pharmaceutical particulars

6.1 List of excipients

Maize starch, pregelatinised, cellulose, microcrystalline, sodium starch glycolate, hydroxypropylcellulose, crospovidone, and glycerol dibehenate.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 Months.

6.4 Special precautions for storage

Bottles: Do not store above 25°C. Store in the original package in order to protect from moisture. Keep the container tightly closed.

Blisters: Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

PVC/Aluminium blister strips.

In pack sizes of:  10, 14, 20, 28, 30, 50, 60, 84, 90, 100 and 250.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special handling instructions

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Fosinopril Sodium Tablets USP 10mg/20mg/40mg Taj Pharma
(Fosinopril sodium)

Package leaflet: Information for the patient

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Fosinopril is and what it is used for
2. What you need to know before you take Fosinopril
3. How to take Fosinopril
4. Possible side effects
5. How to store Fosinopril
6. Contents of the pack and other information.

1. WHAT FOSINOPRIL IS AND WHAT IS IT USED FOR

Fosinopril belongs to the class of medicines called Angiotensin Converting Enzyme (ACE) inhibitors that act on the heart and blood vessels. You may have been given Fosinopril to:

• lower your blood pressure if it is too high (a condition called hypertension)
• help your heart pump blood around your body if you have a condition known as heart failure and are also being treated with diuretics (medicines which help to remove excess fluid from the body).

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE FOSINOPRIL

Do not take Fosinopril:

• if you are allergic to fosinopril or any other ACE inhibitor, or any of the other ingredients of this medicine (listed in section 6). An allergic reaction may include rash, itching, swelling of face, lips, tongue, hands and feet, or breathing difficulties
• if you know you have, or know that someone in your close family has, a condition called angioneurotic oedema where the face, lips, hands or feet swell up, or you have breathing difficulties. If you develop these symptoms during treatment you should stop taking Fosinopril
• if you are more than 3 months pregnant (it is also better to avoid Fosinopril in early pregnancy – see Pregnancy section.)
• if you have a condition known as renal artery stenosis (narrowing of the artery supplying blood to the kidney)
• if you have recently had a heart attack, or if your heart is unable to maintain an adequate blood flow around the body due to a serious, sudden, decrease in blood pressure (cardiogenic shock).
• if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren.
• if you have taken or are currently taking sacubitril/valsartan, a medicine used to treat a type of long-term (chronic) heart failure in adults, as the risk of angioedema (rapid swelling under the skin in an area such as the throat) is increased.

Warnings and precautions

Talk to your doctor or pharmacist before taking Fosinopril

• if you are dehydrated, for example due to
• treatment with medicines such as diuretics
• a dietary restriction of salt
• vomiting or diarrhoea. You may be more likely to suffer from a large drop in blood pressure when you first start taking the tablets and may feel faint or light headed
• if you have kidney problems, or are undergoing dialysis treatment
• if you have liver problems
• if you are undergoing a desensitisation treatment to insect stings, such as that to bees or wasps
• if you have your blood fat (lipid) levels controlled using a method called LDL apheresis
• if you have diabetes
• if you suffer from a collagen vascular disease e.g. scleroderma, systemic lupus erythematosus (also known as lupus or SLE, an allergic condition causing joint pain, skin rashes and fever)
• if you suffer from heart valve disease, such as a narrowing of the aortic or mitral valve in the heart, or an enlarged heart
• if you are of African or Caribbean descent. This medicine may not be effective for you
• if you are (or might become) pregnant. Fosinopril tablets are not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see Pregnancy section).
• if you are taking any of the following medicines used to treat high blood pressure:
• an angiotensin II receptor blocker (ARBs) (also known as sartans – for example valsartan, telmisartan, irbesartan), in particular if you have diabetes-related kidney problems.
• Aliskiren
• if you are taking any of the following medicines, the risk of angioedema may be increased:
• racecadotril, a medicine used to treat diarrhoea;
• medicines used to prevent organ transplant rejection and for cancer (e.g. temsirolimus, sirolimus, everolimus)
• vildagliptin, a medicine used to treat diabetes.
• other medicines belonging to the class of mTOR inhibitors (used to avoid rejection of transplanted organs)

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g.

potassium) in your blood at regular intervals.

See also information under the heading “Do not take Fosinopril”

If you are taking Fosinopril for heart failure. Your doctor may want to check your blood pressure or how your kidneys are working regularly when you first start taking the tablets or when the amount of Fosinopril or other medicines, such as diuretics (medicines which help to remove excess fluid from the body), you take changes.

Other medicines and Fosinopril

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription, or the following:

• potassium supplements (including salt substitutes), potassium sparing diuretics and other medicines that may increase levels of potassium in your blood (e.g. trimethoprim and co-trimoxazole for infections caused by bacteria; ciclosporin, an immunosuppressant medicine used to prevent organ transplant rejection; and heparin, a medicine used to thin blood to prevent clots.)
• antacids (to relieve indigestion). Do not take antacids within 2 hours of your Fosinopril
• pain killers called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) used to treat pain and inflammation e.g. aspirin, ibuprofen, naproxen, indomethacin
• lithium (used to treat certain mental illnesses)
• other medicines to treat high blood pressure e.g. methyldopa, atenolol, verapamil or diltiazem
• immunosuppressants (used to suppress the immune system) such as corticosteroids (used to treat arthritis and allergic reactions), ciclosporin (used to prevent rejection of organ transplants)
• medicines which are most often used to avoid rejection of transplanted organs (sirolimus, everolimus and other medicines belonging to the class of mTOR inhibitors). See section “Warnings and precautions”
• digoxin (a heart medicine) as Fosinopril may interact with certain lab tests used to monitor this medicine.

Your doctor may need to change your dose and/or to take other precautions:

• If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings “Do not take Fosinopril” and “Warnings and precautions”).

If you are going to have an operation or need an anaesthetic tell your doctor or dentist that you are taking Fosinopril. ACE inhibitors can cause your blood pressure to fall (hypotension) during surgery or anaesthesia.

If you are on dialysis, serious allergic reactions may occur if your machine has components made of high flux membranes and dextran sulfate. This medicine should not be used in such cases.

If you are having a test for the function of your parathyroid (small glands in the neck which produce the parathyroid hormone) tell the doctor that you are taking Fosinopril.

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Your doctor will normally advise you to stop taking Fosinopril before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Fosinopril . Fosinopril tablets are not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding

If you are breast-feeding or about to start breast-feeding, ask your doctor or pharmacist for advice before taking this medicine. Fosinopril tablets are not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines

Do not drive or operate machinery if you feel dizzy, faint or tired while taking this medicine.

3. HOW TO TAKE FOSINOPRIL

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

• Swallow the tablets with a glass of water
• You can take Fosinopril with or without food
• To help you remember to take your medicine, try to get into the habit of taking it at the same time each day.
• At the start of treatment your doctor may monitor your condition closely, take blood tests, check your kidney function and monitor the level of salts in your blood from time to time. This will happen more often if you have a kidney problems or a collagen vascular disease.

The scoreline is only there to help you break the tablet if you have difficulty swallowing it whole.

Adults, including older people

To treat high blood pressure: The recommended starting dose is 10 mg once a day. Your doctor may increase this after 4 weeks, to a dose which best controls your blood pressure. The recommended daily dose needed is between 10 mg and 40 mg taken as a single dose. If you are already taking a diuretic (“water” tablet) your doctor may either monitor you very closely or stop the diuretic treatment for a few days before starting Fosinopril.

To treat heart failure: You will also be taking other medicine for your condition, such as a diuretic (“water” tablet). The recommended starting dose is 10 mg once a day. Your doctor will slowly increase this, if necessary, up to 40 mg once a day. At the start of treatment your doctor will monitor your condition closely. In some cases your doctor may wish to take the precaution of placing you in hospital just for the start of therapy.

People with liver or kidney problems – If you have liver or kidney problems, you may be more sensitive to the effects of Fosinopril. Your doctor will give you the lowest dose possible to control your condition.

Children and adolescents

Children and adolescents who weigh less than 50 kg in weight should not take Fosinopril.

If you take more Fosinopril than you should – Contact your doctor or nearest hospital emergency department immediately. Take the container and any remaining tablets with you. Symptoms of overdose include a severe decrease in blood pressure, which may make you feel dizzy or faint, a feeling of confusion or loss of consciousness, a slow heartbeat, and serious kidney problems.

If you forget to take Fosinopril – Take your next dose when it is due. Do not take a double dose to make up for a forgotten dose.

If you stop taking Fosinopril – Do not stop taking Fosinopril without speaking to your doctor first. If you stop taking the medicine your symptoms may return. You should check with your doctor or pharmacist if you are not sure.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If any of the following happen, stop taking Fosinopril and tell your doctor immediately or go to your nearest hospital emergency department:

Uncommon (may affect up to 1 in 100 people):

• if you begin to itch, get short of breath or wheezy, and develop swelling of the face, hands, feet, mouth, throat or eyes. These are symptoms of an allergic reaction
• a potentially serious decrease of blood pressure, which if untreated, may lead to collapse, a coma and death

Rare (may affect up to 1 in 1000 people):

• inflammation of the pancreas which causes severe pain in the abdomen and back

Not known (frequency cannot be estimated from the available data):

• yellowing of your skin or whites of your eyes or an increase of the liver markers in your blood (these may be signs of a liver problem)
• little or no urine being produced, cloudy urine or blood in the urine (these may be signs of kidney problems)
• sudden collapse, numbness or weakness in the arms or leg, headache, dizziness and confusion, disturbances in vision, difficulty swallowing, slurred or loss of speech (these may be signs of a stroke caused by a clot or bleed affecting blood supply to parts of the brain)
• sudden chest pain which may spread to the neck and shoulders and cause you to feel clammy and short of breath (these may be signs of a heart attack or other problems with your heart)
• a very large increase in blood pressure that can cause organs of the body to not work effectively (you may have a severe headache, be sick)
• an increase in the number of infections you get such as fever, severe chills, sore throat or mouth ulcers (this may be a sign of changes in the number of white blood cells in your blood)
• chest infections, including pneumonia which is a serious chest infection (if you have pneumonia you may also have a fever, chills, shortness of breath and a cough which may produce phlegm or occasionally blood), fluid on the lungs, pain when breathing in and out

Other side effects include:

Common (may affect up to 1 in 10 people):

• low blood pressure, especially when moving from sitting or lying down to standing (you may feel faint or light headed)
• an irregular or fast heartbeat, a sensation of thumping in the chest (these may be signs of a problem with your heart)
• swelling or infection of the sinus, itchy, runny nose
• a dry persistent cough, which does not produce phlegm on the chest
• swelling or infection of the throat, which may cause some difficulty in swallowing or you to lose your voice
• taste changes, feeling sick, being sick, indigestion or heartburn, pain and bloating in the stomach and abdomen, diarrhea
• tingling or numbness in the fingers and toes, muscle, joint or bone pain
• itchy red skin, rashes
• difficulty in passing urine, difficulties during sexual activity
• changes in mood, problems sleeping, feeling unusually tired, a general feeling of weakness or loss of strength

Uncommon (may affect up to 1 in 100 people):

• fainting

Not known (frequency cannot be estimated from the available data):

• an increase in blood pressure, reduced blood flow in the arms and legs (which may cause pain on walking)
• problems balancing, shaking, loss of memory, feeling depressed, feeling very sleepy, unusual behavior
• swelling of glands (such as those in the armpits), tongue or joints, excessive sweating, pinkish itchy swellings on the skin (known as hives or nettle rash)
• bleeding or bruising, nose bleeds
• painful, swollen joints caused by uric acid crystals (gout), pain
• changes in appetite, weight gain or fluctuations of weight, dry mouth, passing wind, constipation, prostate problems in men
• a sensation of ringing in the ear, pain in the ear
• flushing
• laboratory tests may show: • a small decrease of the substance (haemoglobin) or red blood cells that carry oxygen in your blood • a small increase of your blood urea level • an increase of your blood potassium level • an increase in blood urea nitrogen (BUN) • an increase of your blood creatinine level.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. HOW TO STORE FOSINOPRIL

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry date refers to the last day of that month.

Do not store above 25°C. Store in the original package in order to protect from moisture. Keep the container tightly closed .

Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Fosinopril tablets contain

The active substance is fosinopril sodium.

a) Each tablet contains:
Fosinopril sodium USP     10mg
Excipients                            q.s

b) Each tablet contains:
Fosinopril sodium USP      20mg
Excipients                            q.s

c) Each tablet contains:
Fosinopril sodium USP      40mg
Excipients                             q.s

The other ingredients are maize starch, pregelatinised, cellulose, microcrystalline, sodium starch glycolate, hydroxypropylcellulose, crospovidone, and glycerol dibehenate.

What Fosinopril tablets looks like and contents of the pack

Fosinopril tablets comes as a white to off-white tablet.

PVC/Aluminium blister strips.

In pack sizes of:  10, 14, 20, 28, 30, 50, 60, 84, 90, 100 and 250.

Not all pack sizes may be marketed.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com