Fozitec

Hypertension

Fozitec is indicated in adults for the treatment of hypertension. Fozitec may be used alone as initial therapy or in combination with other antihypertensive agents. The antihypertensive effects of Fozitec and diuretics used concomitantly are approximately additive.

Heart Failure

Fozitec 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, Fozitec improves symptoms and exercise tolerance, reduces severity of heart failure and decreases the frequency of hospitalisation for heart failure.

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 Fozitec 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 Fozitec 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 Fozitec 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 Fozitec, 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 Fozitec, following effective management of the hypotension. Fozitec 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 Fozitec in hypertensive children aged 6 years and above. 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 Fozitecat (active form of Fozitec) 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 Fozitec.

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 Fozitecat 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 Fozitecat 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).

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

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

Method of administration

For oral use.

History of angioneurotic oedema associated with previous ACE inhibitor therapy.

Hereditary / idiopathic angioneurotic oedema.

Second and third trimesters of pregnancy.

Renal artery stenosis.

Cardiogenic shock.

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

The concomitant use of Fozitec with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

Hypersensitivity / angioedema:

Head and Neck Angioedema:

Angioedema has been seen in patients treated with ACE inhibitors, including Fozitec. 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 Fozitec; 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 mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus):

Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).

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:

Fozitec 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 Fozitec. 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, Fozitec 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 Fozitec 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 Fozitec. 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. 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 Fozitec 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 Fozitec 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 Fozitec 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 Fozitec, renal and hepatic function should be assessed.

Impaired Hepatic Function:

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

Hyperkalaemia:

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Fozitec. 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 Fozitec. 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.

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 Fozitec in hypertensive children aged 6 years and above.

Older people:

Among patients who received Fozitec 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.

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

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 Fozitec.

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 Fozitec 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 Fozitec 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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 Fozitec; 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. Fozitec /Fozitecat is poorly removed from the body by peritoneal dialysis or haemodialysis.

After ingestion of an overdose, therapy with Fozitec 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.

Pharmacotherapeutic group: ACE inhibitors, plain, ATC Code: C09AA09

Fozitec sodium salt is the ester prodrug of an angiotensin converting enzyme (ACE) inhibitor, Fozitecat. 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. Fozitec 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 Fozitec 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 Fozitec. 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.

The absolute absorption of Fozitec averaged 36% of an oral dose, and was not affected by the presence of food. Rapid and complete hydrolysis to active Fozitecat 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 Fozitec, the effective T½ for accumulation of Fozitecat averaged 11.5 hours. In patients with heart failure, the effective T½ was 14 hours. Fozitecat is highly protein bound (>95%), has a relatively small volume of distribution and negligible binding to cellular components in blood. The elimination of Fozitec 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 Fozitec.

Whether AUC and Cmax values of Fozitecat (active form of Fozitec) in children aged 6 to 16 years were comparable to those seen in adults receiving 20 mg of Fozitec as a solution, has to be demonstrated.

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

No special handling instructions