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ZOFENIL 15MG FILM-COATED TABLETS

Active substance(s): ZOFENOPRIL CALCIUM

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
ZOFENIL 15 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ZOFENIL 15 mg film-coated tablet contains 15 mg of zofenopril
calcium as 14.3 mg of zofenopril.
Each ZOFENIL 15 mg film-coated tablet contains 34.7 mg of lactose
monohydrate
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet
ZOFENIL 15 mg:
White oblong film coated tablets with a breakline. The tablet can be
divided into equal doses.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Hypertension
ZOFENIL is indicated for the treatment of mild to moderate essential hypertension.
Acute Myocardial Infarction
ZOFENIL is indicated for the treatment initiated within the first 24 hours of patients
with acute myocardial infarction with or without signs and symptoms of heart failure,
who are haemodynamically stable and have not received thrombolytic therapy.

4.2

Posology and method of administration

ZOFENIL can be taken before, during or after meals. Dosage must be titrated
according to the therapeutic response of the patient.
Hypertension
The need for dosage titration should be determined by measurement of blood pressure
just before the next dose. The dose should be increased at an interval of four weeks.
Patients without volume or salt depletion:
Treatment should be started with 15 mg once daily and titrated upwards to achieve
optimal blood pressure control.
The usual effective dose is 30 mg once daily.
The maximum dose is 60 mg per day administered in a single or two divided doses.
In case of inadequate response, other antihypertensive agents such as diuretics may be
added (see Sections 4.3, 4.4, 4.5 and 5.1).
Patients suspected of volume or salt depletion:
First-dose hypotension may occur in high risk patients (see Special warnings and
precautions for use). Initiation of therapy with ACE inhibitors requires correction of
salt and/or volume deficiencies, discontinuation of an existing diuretic therapy for
two to three days before ACE inhibition and a starting dose of 15 mg daily. If this is
not possible, the initial dose should be 7.5 mg daily.
Patients at high risk for severe acute hypotension should be monitored closely
preferably in hospital, for as long as the maximal effect is expected after
administration of the first dose and whenever the dose of ACE inhibitor and/or
diuretic is increased. This also applies to patients with angina pectoris or
cerebrovascular disease in whom excessive hypotension could result in a myocardial
infarction or cerebrovascular accident.
Dosage in patients with renal impairment and dialysis:
In hypertensive patients with mild renal impairment (creatinine clearance > 45
ml/min.) the same dose level and once-daily regimen for ZOFENIL can be employed
as for patients with normal renal function. Patients with moderate to severe
impairment (creatinine clearance < 45 ml/min.) should be given one-half the
therapeutic dose of ZOFENIL; the once-daily dosage regimen does not require
modification.
The starting dose and the dosage regimen of ZOFENIL for hypertensive patients
maintained on dialysis should be one-quarter the dose used for patients with normal
renal function.
Recent clinical observations have shown a high incidence of anaphylactoid-like
reactions in patients on ACE inhibitors during haemodialysis with high-flux dialysis
membranes or during LDL apheresis (see section 4.4 «Special warnings and
precaution for use»).
Older people (over 65 years):
In older people with normal creatinine clearance no adjustment is necessary.
In older people with reduced creatinine clearance (less than 45 ml/min) half of the
daily dose is recommended.

Creatinine clearance may be estimated from serum creatinine by the following
formula:
Clearance
(140-age) X weight (Kg)
Creatinine (ml/min) = _________________________
Serum Cr. (mg/dl) X 72
The above method provides creatinine clearance in males. For females the value
obtained should be multiplied by 0.85.
Dosage in hepatic impairment:
In hypertensive patients with mild to moderate hepatic impairment, the starting dose
of ZOFENIL is half of the dose for patients with normal hepatic function.
In hypertensive patients with severe liver impairment ZOFENIL is contraindicated
Paediatric population (under 18 years):
The safety and efficacy of ZOFENIL in children has not been established. Therefore
its use is not recommended.
Acute myocardial infarction:
Treatment with ZOFENIL should begin within 24 hours after the onset of symptoms
of acute myocardial infarction and continued for six weeks.
The posology should be as follows:
1st and 2nd day: 7.5 mg every 12 hours
3rd and 4th day: 15 mg every 12 hours
from 5th day and onwards: 30 mg every 12 hours
In the event of low systolic blood pressure (≤120mmHg) at the start of treatment or
during the first three days following myocardial infarction, the daily dose should not
be increased. In the event of hypotension (≤100mmHg), the treatment can be
continued with the dose that was previously tolerated. In the event of severe
hypotension (systolic blood pressure lower than 90mmHg in two consecutive
measurement at least one hour apart), ZOFENIL should be discontinued.
After 6 weeks treatment patients must be re-evaluated and the treatment should be
discontinued in patients without signs of left ventricular dysfunction or cardiac
failure. If these signs are present, treatment might be continued long term.
Patients should also receive, as appropriate, the standard treatment such as nitrates,
aspirin or β-blockers.
Dosage in older people:
ZOFENIL should be used with caution in myocardial infarction patients who are
more than 75 years of age.
Dosage in patients with renal impairment and dialysis:
The efficacy and safety of ZOFENIL in myocardial infarction patients with renal
impairment or who are undergoing dialysis has not been established. Therefore,
ZOFENIL should not be used in these patients.
Dosage in patients with hepatic impairment:

The efficacy and safety of ZOFENIL in myocardial infarction patients with hepatic
impairment has not been established. Therefore, it should not be used in these
patients.

4.3

Contraindications

• Hypersensitivity to zofenopril calcium, any other ACE inhibitor or any of the
excipients.
• History of angioneurotic oedema associated with previous ACE inhibitor therapy.
• Hereditary/idiopathic angioneurotic oedema.
• Severe hepatic impairment.
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
• Women of child-bearing potential unless protected by effective contraception.
• Bilateral renal artery stenosis or unilateral renal artery stenosis in cases of a
solitary single kidney.
• The concomitant use of ZOFENIL with aliskiren-containing products is
contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60
ml/min/1.73 m2) (see Sections 4.5 and 5.1).

4.4

Special warnings and precautions for use

Hypotension:
As with other ACE inhibitors, ZOFENIL may cause a profound fall in blood pressure
especially after the first dose, although. symptomatic hypotension is seen rarely in
uncomplicated hypertensive patients.
It is more likely to occur in patients who have been volume and electrolyte depleted
by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who
have severe renin-dependent hypertension (see section 4.5 and section 4.8).
In patients with heart failure, with or without associated renal insufficiency,
symptomatic hypotension has been observed. This is more likely to occur in those
patients with more severe degrees of heart failure, as reflected by the use of high
doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at
increased risk of symptomatic hypotension, treatment should be started under close
medical supervision preferably in the hospital, with low doses and careful dose
titration.
If possible, diuretic treatment should be discontinued temporarily when therapy with
ZOFENIL is initiated.
Such considerations apply also to patients with angina pectoris or cerebrovascular
disease in whom an excessive fall in blood pressure could result in myocardial
infarction or cerebrovascular accident.
If hypotension develops, the patient should be placed in a supine position. Volume
repletion with intravenous normal saline may be required. The appearance of
hypotension after the initial dose does not preclude subsequent careful dose titration
with drug after effective management.
In some patients with heart failure who have normal or low blood pressure, additional
lowering of systemic blood pressure may occur with ZOFENIL. This effect is
anticipated and is not usually a reason to discontinue treatment. If hypotension

becomes symptomatic, a reduction of dose or discontinuation of ZOFENIL may be
necessary.
Hypotension in acute myocardial infarction:
Treatment with ZOFENIL must not be initiated in acute myocardial infarction
patients if there is a risk of additional serious heamodynamic depression following
treatment with a vasodilator. These are patients with a systolic blood pressure of
<100mmHg or with cardiogenic shock. Treatment with ZOFENIL in acute
myocardial infarction patients may lead to severe hypotension. In the case of
persistent hypotension (systolic blood pressure <90mmHg for more than one hour),
ZOFENIL should be discontinued. In patients with severe heart failure following an
acute myocardial infarction ZOFENIL should only be administered if the patient is
haemodynamically stable.
Myocardial infarction patients with impaired hepatic function:
The efficacy and safety of ZOFENIL in myocardial infarction patients with hepatic
impairment has not been established. Therefore, it should not be used in these patients
Older people:
ZOFENIL should be used with caution in myocardial infarction patients ≥75 years of
age
Patients with renovascular hypertension:
There is an increased risk of severe hypotension and renal insufficiency when patients
with renovascular hypertension and pre-existing bilateral renal artery stenosis or
stenosis of the artery to a solitary kidney are treated with ACE inhibitors. Treatment
with diuretics may be a contributory factor. Loss of renal function may occur with
only mild changes in serum creatinine even in patients with unilateral renal artery
stenosis. If considered absolutely necessary, treatment with ZOFENIL should be
started in hospital under close medical supervision with low doses and careful dose
titration. Diuretic treatment should be discontinued temporarily when therapy with
ZOFENIL is initiated and renal function be closely monitored during the first few
weeks of therapy.
Patients with renal insufficiency:
ZOFENIL should be used with caution in patients with renal insufficiency as they
require reduced doses. Close monitoring of renal function during therapy should be
performed as deemed appropriate. Renal failure has been reported in association with
ACE inhibitors, mainly in patients with severe heart failure or underlying renal
disease, including renal artery stenosis. Some patients, with no apparent pre-existing
renal disease have developed increases in blood urea and creatinine concentrations,
particularly when a diuretic is given concomitantly. Dosage reduction of the ACE
inhibitor and/or discontinuation of the diuretic may be required. It is recommended
that the renal function be monitored closely during the first few weeks of therapy.
The efficacy and safety of ZOFENIL in myocardial infarction patients with renal
impairment has not been established. Therefore, in presence of renal impairment
(serum creatinine ≥ 2.1 mg/dl and proteinuria ≥500 mg/day) and myocardial
infarction ZOFENIL should not be used.

Patients who are dialysed:
Patients who are dialysed using high-flux polyacrylonitrile membranes (e.g. AN 69)
and treated with ACE inhibitors are likely to experience anaphylactoid reactions such
as facial swelling, flushing, hypotension and dyspnoea within a few minutes of
commencing haemodialysis. It is recommended to use an alternative membrane or an
alternative antihypertensive medicinal product.
The efficacy and safety of ZOFENIL in myocardial infarction patients undergoing
haemodialysis has not been established. Therefore, it should not be used in these
patients.
Patients on LDL apheresis:
Patients treated with an ACE inhibitor undergoing LDL apheresis with dextrane
sulphate may experience anaphylactoid reactions similar to those seen in patients
undergoing haemodialysis with high-flux membranes (see above). It is recommended
that an agent from another class of antihypertensive drugs is used in these patients.
Anaphylactic reactions during desensitisation or after insect bites:
Rarely, patients receiving ACE inhibitors during desensitisation treatment (e.g.
hymenoptera venom) or after insect bites have experienced life-threatening
anaphylactoid reactions. In the same patients, these reactions have been avoided when
ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent
re-administration of the medicinal product. Therefore, caution should be used in
patients treated with ACE inhibitors undergoing such desensitisation procedures.
Kidney transplantation:
There is no experience regarding the administration of ZOFENIL in patients with a
recent kidney transplantation.
Primary aldosteronism:
Patients with primary aldosteronism generally will not respond to antihypertensive
drugs acting through inhibition of the renin-angiotensin system. Therefore the use of
this product is not recommended.
Angioedema:
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or
larynx may occur in patients treated with ACE inhibitors which occurs most
frequently during the first weeks of treatment. However in rare cases severe
angioedema may develop after long-term treatment with an angiotensin converting
enzyme inhibitor. Treatment with ACE inhibitors should promptly be discontinued
and replaced by an agent belonging to another class of drugs.
Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy
should be given including, but not necessarily limited to, immediate subcutaneous
adrenaline solution 1:1000 (0.3 to 0.5 ml) or slow intravenous adrenaline 1 mg/ml
(which should be diluted as instructed) with close monitoring of ECG and blood
pressure. The patient should be hospitalised and observed for at least 12 to 24 hours
and should not be discharged until complete resolution of symptoms has occurred.
Even in such instances where swelling of only the tongue is involved, without
respiratory distress, patients may require observation since treatment with
antihistamines and corticosteroids may not be sufficient.
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black
patients than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at
increased risk of angioedema while receiving an ACE inhibitor (see 4.3
Contraindication).
Cough:
During treatment with ZOFENIL a dry and non-productive cough may occur which
disappears after discontinuation of ZOFENIL. ACE inhibitor-induced cough should
be considered as part of the differential diagnosis of cough.
Hepatic failure:
Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes)
death. The mechanism of this syndrome is not understood. Patients receiving ACE
inhibitors who develop jaundice or marked elevations of hepatic enzymes should
discontinue the ACE inhibitor and receive appropriate medical follow-up.
Hyperkalaemia:
Hyperkalaemia may occur during treatment with an ACE inhibitor.
Patients at risk for the development of hyperkalaemia include those with renal
insufficiency, diabetes mellitus or those using concomitant potassium-sparing
diuretics, potassium supplements or potassium-containing salt substitutes; or in
patients taking other active substances associated with increases in serum potassium
(e.g. heparin). If concomitant use of the above mentioned agents is deemed
appropriate, they should be used with frequent monitoring of serum potassium (see
section 4.5).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor
blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased
renal function (including acute renal failure). Dual blockade of RAAS through the
combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is
therefore not recommended (see Section 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur
under specialist supervision and subject to frequent close monitoring of renal
function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly
in patients with diabetic nephropathy.
Surgery/Anaesthesia:
ACE inhibitors may cause hypotension or even hypotensive shock in patients
undergoing major surgery or during anaesthesia, since they may block angiotensin II
formation secondary to compensatory renin release. If it is not possible to withhold
the ACE inhibitor, intravascular and plasma volumes should be carefully monitored.
Aortic and mitral valve stenosis/Hypertrophic cardiomyopathy:
ACE inhibitors should be used with caution in patients with mitral valve stenosis and
obstruction in the outflow of the left ventricule.
Neutropenia/Agranulocytosis:
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in
patients receiving ACE inhibitors. The risk of neutropenia appears to be dose- and
type-related and is dependent on patient's clinical status. It is rarely seen in
uncomplicated patients but may occur in patients with some degree of renal

impairment especially when it is associated with collagen vascular disease e.g.
systemic lupus erythematosus, scleroderma and therapy with immunosuppressive
agents, treatment with allopurinol or procainamide, or a combination of these
complicating factors. Some of these patients developed serious infections which in a
few instances did not respond to intensive antibiotic therapy.
If zofenopril is used in such patients, it is advised that white blood cell count and
differential counts should be performed prior to therapy, every 2 weeks during the
first 3 months of zofenopril therapy, and periodically thereafter. During treatment all
patients should be instructed to report any sign of infection (e.g. sore throat, fever)
when a differential white blood cell count should be performed. Zofenopril and other
concomitant medication (see section 4.5) should be withdrawn if neutropenia
(neutrophils less than 1000/mm3) is detected or suspected.
It is reversible after discontinuation of the ACE inhibitor.
Psoriasis:
ACE inhibitors should be used with caution in patients with psoriasis.
Proteinuria:
Proteinuria may occur particularly in patients with existing renal function impairment
or on relatively high doses of ACE inhibitors. Patients with prior renal disease should
have urinary protein estimation (dip-stick on first morning urine) prior to treatment,
and periodically thereafter.
Diabetic patients:
The glycaemia levels should be closely monitored in diabetic patients previously
treated with oral antidiabetic products or insulin, during the first month of treatment
with an ACE inhibitor (see section 4.5).
Lithium:
The combination of Lithium and ZOFENIL is generally not recommended (see
section 4.5).
Race:
As with other angiotensin converting enzyme inhibitors, zofenopril may be less
effective in lowering blood pressure in black people than in non-blacks.
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black
patients than in non-black patients.
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).
Other:
This medicinal product contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption
should not take this medicinal product.

4.5
interaction

Interactions with other medicinal products and other forms of

Concomitant use not recommended
Potassium sparing diuretics or potassium supplements. ACE inhibitors attenuate
diuretic induced potassium loss. Potassium sparing diuretics e.g. spironolactone,
triamterene, or amiloride, potassium supplements, or potassium-containing salt
substitutes may lead to significant increases in serum potassium. If concomitant use
is indicated because of documented hypokalemia they should be used with caution
and with frequent monitoring of serum potassium and ECG (see section 4.4.).
ACE-inhibitors, angiotensin II receptor blockers or aliskiren:
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 requiring caution
Diuretics (thiazide or loop diuretics). Prior treatment with high dose diuretics may
result in volume depletion and a risk of hypotension when initiating therapy with
zofenopril (see 4.4). The hypotensive effects can be reduced by discontinuation of the
diuretic, by increasing volume or salt intake or by initiating therapy with a low dose
of zofenopril.
Lithium. Reversible increases in serum lithium concentrations and toxicity have been
reported during concomitant administration of lithium with ACE inhibitors.
Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and
enhance the already increased risk of lithium toxicity with ACE inhibitors.
Therefore, Zofenil is not recommended in association with lithium and careful
monitoring of serum lithium levels should be performed if the concomitant use proves
necessary.
Gold. Nitritoid reactions (symptoms of vasodilatation including flushing, nausea,
dizziness and hypotension, which can be very severe) following injectable gold (for
example, sodium aurothiomalate) have been reported more frequently in patients
receiving ACE inhibitor therapy.
Anaesthetic medicinal products. ACE inhibitors may enhance the hypotensive effects
of certain anaesthetic medicinal products.
Narcotic drugs/Tricyclic
hypotension may occur.

antidepressants/Antipsychotics/Barbiturates.

Postural

Other antihypertensive substances (e.g. Beta-blockers, alpha-blockers, calcium
antagonists). There may be additive hypotensive effect or potentiation. Treatment
with nitroglycerine and other nitrates, or other vasodilators, should be used with
caution.
Cimetidine. May enhance the risk of hypotensive effect.

Cyclosporin. Increased risk of renal dysfunction when ACE inhibitors are used
concurrently.
Allopurinol procainamide, cytostatic or immunosuppressive agents. Increased risk of
hypersensitivity reactions when ACE inhibitors are used concurrently. Data from
other ACE inhibitors indicate an increased risk of leucopenia when used concurrently.
Antidiabetics. Rarely ACE inhibitors can potentiate the blood glucose-reducing
effects of insulin and oral antidiabetics like sulphonylurea, in diabetics. In such cases
it may be necessary to reduce the dose of the antidiabetic during simultaneous
treatment with ACE inhibitors.
Haemodialysis with high-flux dialysis membranes. Increased risk of anaphylactoid
reactions when ACE inhibitors are used concurrently.
Cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide.
Concomitant administration with ACE inhibitors may lead to an increased risk of
leucopenia.
To be taken into account with concomitant use
Non-Steroidal Anti-inflammatory medicinal products (including ASA ≥ 3g/day). The
administration of non-steroidal anti-inflammatory agents may reduce the
antihypertensive effect of an ACE inhibitor. Furthermore, it has been described that
NSAIDS and ACE inhibitors exert an additive effect on the increase in serum
potassium whereas renal function may decrease. These effects are in principle
reversible, and occur especially in patients with compromised renal function. Rarely,
acute renal failure may occur, particularly in patients with compromised renal
function such as the elderly or dehydrated.
Antacids. Reduce the bioavailability of ACE inhibitors.
Sympathomimetics. May reduce the antihypertensive effects of ACE inhibitors;
patients should be carefully monitored to confirm that the desired effect is being
obtained.
Food. May reduce the rate but not the extent of absorption of zofenopril calcium.
Additional information Direct clinical data on the interaction of zofenopril with
other drugs which are metabolised by CYP enzymes are not available. However, in
vitro metabolic studies with zofenopril demonstrated no potential interaction with
drug that are metabolised by CYP enzymes.

4.6

Fertility, pregnancy and lactation

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).
Lactation:
Because no information is available regarding the use of ZOFENIL during
breastfeeding, ZOFENIL is 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 ZOFENIL on the ability to drive. When driving
vehicles or operating machines it should be remembered that occasionally
drowsiness, dizziness or weariness may occur.

4.8

Undesirable effects

ZOFENIL The table below shows all the adverse reactions that have been reported
during clinical practice in patients treated with ZOFENIL. They are listed by bodysystem and ranked under headings of frequency using the following convention: 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)
Nervous system disorders
Common:
dizziness, headache
Respiratory, thoracic and mediastinal disorders
Common:
cough
Gastrointestinal disorders
Common:
nausea/vomiting
Skin and subcutaneous tissue disorders
Uncommon:
rash
Rare:
angioedema
Musculoskeletal and connective tissue disorders

Uncommon:
muscle cramp
General disorders and administration site conditions
Common:
fatigue
Uncommon:
asthenia
The following adverse reactions have been observed associated with ACE inhibitors
therapy.
Blood and lymphatic system disorders
In a few patients agranulocytosis and pancytopenia may occur.
There are reports of haemolytic anaemia in patients with glucose-6-phosphate
dehydrogenase deficiency.
Metabolism and nutrition disorders
Very rare hypoglycaemia
Psychiatric disorders
Rarely, depression, mood altered, sleep disorders, confusional state.
Nervous system disorders
Occasionally paraesthesia, dysgeusia, balance disorder.
Eye disorders
Rarely, vision blurred.
Ear and labyrinth disorders
Rarely, tinnitus.
Cardiac disorders
Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial
infarction have been reported for ACE inhibitors in association with hypotension.
Vascular Disorders
Severe hypotension has occurred after initiation or increase of therapy. This occurs
especially in certain risk groups (see Special warnings and precautions for use). In
association with hypotension, symptoms like dizziness, feeling of weakness, impaired
vision, rarely with disturbance of consciousness (syncope).
Rarely flushing occurs.
Respiratory, thoracic and mediastinal disorders
Rarely dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have been
reported. ACE inhibitors have been associated with the onset of angioneurotic
oedema in a small subset of patients involving the face and oropharyngeal tissues. In
isolated cases angioneurotic oedema involving the upper airways has caused fatal
airway obstruction.
Gastro-intestinal disorders
Occasionally, abdominal pain, diarrhoea, constipation and dry mouth can occur.
Individual cases of pancreatitis and ileus have been described in association with
ACE inhibitors.

Very rare small bowel angioedema
Hepatobiliary disorders
Individual cases of cholestatic jaundice and hepatitis have been described in
association with ACE inhibitors.
Skin and subcutaneous tissue disorders
Occasionally allergic and hypersensitivity reactions can occur like pruritus, urticaria,
erythema multiforme, Stevens-Johnson syndrome, toxic epidermic necrolysis,
psoriasis-like efflorescences, alopecia.
This can be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased
ANA- titers.
Rarely hyperhidrosis occurs.
Musculoskeletal and connective tissue disorders
Occasionally, myalgia can occur.
Renal and urinary disorders
Renal insufficiency may occur or be intensified. Acute renal failure has been reported
(see Special warnings and precautions for use).
Rarely micturition disorders occur.
Reproductive system and breast disorders
Rarely, erectile dysfunction.
General disorders and administration site conditions.
Very rarely oedema peripheral and chest pain.
Investigations
Increases in blood urea and creatinine, reversible on discontinuation may occur,
especially in the presence of renal insufficiency, severe heart failure and renovascular
hypertension.
In a few patients, decreases in haemoglobin, haematocrit, platelets and white-cell
count have been reported.
Increases in serum levels of hepatic enzymes and bilirubin have also been reported.
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. Website: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms of overdosage are severe hypotension, shock, stupor, bradycardia,
electrolyte disturbances and renal failure.
After ingestion of an overdose, the patients should be kept under close supervision,
preferably in an intensive care unit. Serum electrolytes and creatinine should be
monitored frequently. Therapeutic measures depend on the nature and severity of the
symptoms. If the ingestion is recent, measures to prevent absorption such as gastric
lavage and administration of adsorbents and sodium sulphate may be implemented. If

hypotension occurs, the patient should be placed in shock position and the judicious
use of volume expanders and/or treatment with angiotensin II considered.
Bradycardia or extensive vagal reactions should be treated by administering atropine.
The use of a pacemaker may be considered. ACE inhibitors may be removed from the
circulation by hemodialysis. The use of high-flux polyacrylonitrile membranes
should be avoided.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitor, ATC code: C09AA15.
The beneficial effects of ZOFENIL in hypertension and acute myocardial infarction
appear to result primarily from the suppression of the plasma renin-angiotensin
aldosterone system. Inhibition of ACE (Ki 0.4 nM in rabbit lung for arginine salt of
zofenoprilat) results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to reduced aldosterone secretion. Although the latter
decrease is small, small increases in serum potassium concentrations may occur,
along with sodium and fluid loss. The cessation of the negative feedback of
angiotensin II on the renin secretion results in an increase of the plasma renin activity.
The plasma ACE activity is suppressed by 53.4% and 74.4% at 24 hours after
administration of single oral doses of 30 mg and 60 mg zofenopril calcium
respectively.
Inhibition of ACE results in an increased activity of circulating and local kallikreinkinin-system, which contributes to peripheral vasodilatation by activating the
prostaglandin system. It is possible that this mechanism is involved in the
hypotensive effect of zofenopril calcium and is responsible for certain side effects.
In patients with hypertension, administration of ZOFENIL results in a reduction of
supine and standing blood pressure to about the same extent, with no compensatory
increase of the heart rate. Mean systemic vascular resistance tends to decline after
ZOFENIL administration.
Achievement of optimal blood pressure reduction may require several weeks of
therapy in some patients. The antihypertensive effects are maintained during long
term therapy.
Abrupt withdrawal of therapy has not been associated with a rapid increase in blood
pressure. Currently there are no data regarding the effects of ZOFENIL on morbidity
and mortality in hypertensive patients.
Although antihypertensive effects have been found in all races studied, black
hypertensive patients (usually a low-renin hypertensive population) has a smaller
average response to ACE inhibitor monotherapy than non-black patients. This
difference disappears when a diuretic is added.
The clinical effect resulting from the early use of ZOFENIL following myocardial
infarction may be linked to many factors such as the reduction in plasma levels of
angiotensin II (in this way limiting the process of ventricular remodelling which can
negatively influence the quod vitam prognosis of the infarction patient), and the

increase in plasma/tissue concentrations of vasodilator substances (prostaglandinskinin system)
A randomised, placebo-controlled clinical trial of zofenopril was performed in 1,556
patients with anterior myocardial infarction who had not received thrombolytic
therapy. Treatment was begun within 24 hours and continued for 6 weeks. The
incidence of the primary combined endpoint (severe heart failure and/or death at 6
weeks) was reduced in zofenopril-treated patients (zofenopril 7.1%, placebo 10.6%).
At one year, the survival rate was improved in the ZOFENIL group.
Other information:
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone
and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The
Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of
an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or
cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of endorgan damage. VA NEPHRON-D was a study in patients with type 2 diabetes
mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or
cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia,
acute kidney injury and/or hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for
other ACE- inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used
concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal
Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a
standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients
with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or
both. The study was terminated early because of an increased risk of adverse
outcomes. CV death and stroke were both numerically more frequent in the aliskiren
group than in the placebo group and adverse events and serious adverse events of
interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently
reported in the aliskiren group than in the placebo group.

5.2

Pharmacokinetic properties

Zofenopril calcium is a prodrug, since the active inhibitor is the free sulfhydryl
compound, zofenoprilat, resulting from thio-ester hydrolysis.
Absorption:
Zofenopril calcium is rapidly and completely absorbed by the oral route and
undergoes nearly complete conversion to zofenoprilat, which reaches peak blood
levels after 1.5 h following an oral dose of ZOFENIL. Single dose kinetics are linear
over a dose-range of 10-80 mg of zofenopril calcium and no accumulation occurs
after the administration of 15-60mg of zofenopril calcium for 3 weeks. The presence
of food in the gastrointestinal tract reduces the rate but not the extent of absorption
and the AUCs of zofenoprilat are nearly identical in the fasted or fed state.
Distribution:
Approximately 88% of the circulating radioactivity measured ex-vivo following a
radiolabelled dose of zofenopril calcium is bound to plasma protein and the steady
state volume of distribution is 96 litres.

Biotransformation:
Eight metabolites, accounting for 76% of the urinary radioactivity, were identified in
human urine following a radiolabelled dose of zofenopril calcium. The main
metabolite is zofenoprilat (22%), which is then metabolized through several
pathways, including glucuronide conjugation (17%), cyclization and glucuronide
conjugation (13%), cysteine conjugation (9%) and S-methylation of the thiol group
(8%). Half-life of zofenoprilat is 5.5 h and its total body clearance is 1300 ml/min
following oral zofenopril calcium.
Elimination:
Radiolabelled zofenoprilat administered intravenously is eliminated in urine (76%)
and faeces (16%) while following an oral dose of radiolabelled zofenopril calcium,
69% and 26% of the radioactivity is recovered in urine and faeces respectively,
indicating a dual route of elimination (kidney and liver).
Pharmacokinetics in older people:
In older people, no dose adjustment is required when the renal function is normal.
Pharmacokinetics in renal dysfunction:
Based on comparison of key pharmacokinetic parameters of zofenoprilat measured
after oral administration of radiolabelled zofenopril calcium, patients with mild renal
impairment (creatinine clearance >45 and <90 ml/min) eliminate zofenopril from the
body at the same rate as normal subjects (creatinine clearance > 90 ml/min).
In patients with moderate to severe renal impairment (7- 44 ml/min), the rate of
elimination is reduced to about 50% of normal. This indicates that these patients
should be given half the usual starting dose of ZOFENIL.
In patients with end stage renal disease on haemodialysis and peritoneal dialysis, the
rate of elimination is reduced to 25% of normal. This indicates that these patients
should be given a quarter of the usual starting dose of ZOFENIL.
Pharmacokinetics in hepatic dysfunction:
In patients with mild to moderate hepatic dysfunction given single doses of
radiolabelled zofenopril calcium, the Cmax and Tmax values for zofenoprilat were
similar to those in normal subjects. However, AUC values in cirrhotic patients were
about twice those obtained for normal subjects, indicating that the initial dose of
ZOFENIL for patients with mild to moderate hepatic dysfunction should be half of
that for patients with normal hepatic function.
There are no pharmacokinetic data of zofenopril and zofenoprilat in patients with
severe hepatic dysfunction, therefore zofenopril is contraindicated in these patients.

5.3

Preclinical safety data
In repeat oral dose toxicity studies conducted in three mammalian species most of the
treatment related effects where those usually reported for ACE inhibitors. These
changes included a decrease in erythrocytic parameters, an increase in serum urea
nitrogen, a decrease in heart weight and hyperplasia of the juxta-glomerular cells
which occurred at dose levels much higher than the maximum recommended human
dose.
In a repeat dose oral toxicity study in the dog, species-specific
immunologically-mediated blood dyscrasias occurred at high dose levels.

No significant changes in cytochrome P450 enzyme activities have been observed in
a 1 year repeated oral toxicity study in the monkey.
In reproductive toxicity studies, zofenopril caused a dose related reduction in growth
rate in offspring and also nephrotoxicity and reduced postnatal viability at dose levels
of 90 and 270 mg/kg in the F1 generation. Treatment with zofenopril during
pregnancy caused feetal and developmental toxicity in offspring in the rat and also
embryo- and feto-toxicity in the rabbit but only at maternally toxic dose levels.
Genotoxicity studies showed that zofenopril was not mutagenic or clastogenic.
Carcinogenicity studies conducted in mice and rats revealed no evidence of
carcinogenicity. An increased incidence of testicular atrophy occurred only in the
mouse study, the clinical significance of which is unknown.

6.1

List of excipients

Core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium,
magnesium stearate, colloidal anhydrous silica
Coat: hypromellose, titanium dioxide (E171), macrogol 400, macrogol 6000

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
No special precautions for storage

6.5

Nature and contents of container

Blister PVDC /PVC/aluminium or Aclar/Aluminium, packs of:
ZOFENIL 15 mg - 12, 14, 15, 28, 30, 50, 50 unit doses, 56, 56 unit doses, 90 or 100
film coated tablets
(Not all pack sizes may be marketed)

6.6

Special precautions for disposal

No special requirements

7

MARKETING AUTHORISATION HOLDER
Menarini International Operations Luxembourg S.A.
1 Avenue de La Gare
L-1611 Luxembourg

8

MARKETING AUTHORISATION NUMBER(S)
PL 16239/0003

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/07/2008

10

DATE OF REVISION OF THE TEXT
14/11/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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