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ZOZIDE 30 MG/12.5 MG FILM-COATED TABLETS

Active substance(s): HYDROCHLOROTHIAZIDE / ZOFENOPRIL CALCIUM

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Zozide 30 mg/12.5 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 28.7 mg of zofenopril as 30 mg of Zofenopril
Calcium and 12.5 mg of Hydrochlorothiazide.
Excipients with known effect: Each film-coated tablet contains 56.20 mg of lactose
monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
Pastel-red, round, slightly bi-convex tablets with a score line on one side.
The score line is to facilitate breaking for ease of swallowing and not to divide into
equal doses.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of mild to moderate essential hypertension.
This fixed dose combination is indicated in patients whose blood pressure is
not adequately controlled on Zofenopril alone.

4.2

Posology and method of administration
General
Zozide should be used once daily, with or without food.
Dose titration with the individual components (i.e. Zofenopril and
Hydrochlorothiazide) is recommended before changing to the fixed dose
combination.

When clinically appropriate direct change from monotherapy to the fixed
combination may be considered.
To ease swallowing, tablets may be broken in two parts and swallowed one half after
the other, at the prescribed time of administration.

Adults (18 to 65 years of age)
Patients without volume or salt depletion
The usual effective dose is one tablet once daily.
Patients suspected of volume or salt depletion
The use of Zozide is not recommended.

Older people (over 65 years)
In older people with normal creatinine clearance no dose adjustment is necessary.
In older people with reduced creatinine clearance (less than 45 mL/min) the use of
Zozide is not recommended.
Creatinine clearance may be estimated from serum creatinine by the following
Cockroft-Gault formula:
[(140-age) * weight (Kg)]
CrCl (mL/min) = __________________________
72 *serum Cr (mg/dL)
The above method provides creatinine clearance in males. For females the value
obtained should be multiplied by 0.85.

Paediatric population (under 18 years)
The safety and efficacy of Zozide in children and adolescents has not been
established.
Therefore, its use is not recommended.

Patients with renal impairment and dialysis
In hypertensive patients with mild impairment (creatinine clearance > 45 mL/min) the
same dose level and once-daily regimen of Zozide can be employed as for patients
with normal renal function.
In patients with moderate to severe impairment (creatinine clearance < 45 mL/min) its
use is not recommended (see section 4.4).
In patients with severe renal impairment (creatinine clearance <30 ml/min) Zozide is
contraindicated (see section 4.3).

In hypertensive patients maintained on dialysis the use of Zozide is not
recommended.

Patients with hepatic impairment
In hypertensive patients with mild to moderate hepatic impairment, where the 30 mg
dose of Zofenopril alone has been achieved, the same dose regimen can be employed
as for patients with normal hepatic function.
In hypertensive patients with severe liver impairment Zozide is contra-indicated.

4.3

Contraindications


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



Hypersensitivity to Zofenopril or any other ACE inhibitor.



Hypersensitivity to Hydrochlorothiazide or other sulphonamide-derived
substances.



Hypersensitivity to any of the excipients



History of angioneurotic oedema associated with previous ACE inhibitor
therapy.



Hereditary/idiopathic angioneurotic oedema.



Severe hepatic impairment.



Severe renal impairment (creatinine clearance < 30 mL/min)



Bilateral renal artery stenosis or unilateral renal artery stenosis in cases of a
solitary single kidney.



4.4

The concomitant use of Zozide 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).

Special warnings and precautions for use
ZOFENOPRIL
Hypotension:
As with other ACE inhibitors and diuretics, Zozide 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 Zozide 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 occurrence of
hypotension after the initial dose does not preclude subsequent careful dose titration
with each component of the medicinal product after effective management.

Patients with renovascular hypertension:
There is an increased risk of severe hypotension and renal insufficiency when patients
with bilateral renal artery stenosis or stenosis of the artery to a single functioning
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.
In these patients, therapy should be initiated under close medical supervision with
low dose, careful titration and monitoring of renal function.

Patients with renal insufficiency:
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 individual components may
be required. It is recommended that the renal function be monitored closely during the
first few weeks of therapy.

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 zofenopril 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 dextran
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 products 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 Zozide in patients with a
recent kidney transplantation. Its use in transplant recipients is therefore not
recommended.

Primary aldosteronism:
Patients with primary aldosteronism generally will not respond to antihypertensive
products acting through inhibition of the renin-angiotensin system. Therefore the use
of zofenopril 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 antihypertensive products.
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
Contraindications).

Cough:
During treatment with ACE-inhibitors a dry and non-productive cough may occur
which disappears after discontinuation of therapy. 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. This effect is
usually attenuated by the potassium-losing effect of thiazide diuretics. 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, regular
monitoring of serum potassium is recommended (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
left ventricular outflow tract obstruction and avoided in cases of cardiogenic shock
and haemodynamically significant obstruction.

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 Zozide 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)
HYDROCHLOROTHIAZIDE
Renal impairment:
In patients with renal disease, thiazides may increase azotaemia. Cumulative effects
of this active substance may develop in patients with impaired renal function. If
progressive renal impairment becomes evident, as indicated by a rising non-protein
nitrogen, careful reappraisal of therapy is necessary, with consideration given to
discontinuing diuretic therapy.

Hepatic impairment:
Thiazides should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may
precipitate hepatic coma.

Metabolic and endocrine effects:
Thiazide therapy may impair glucose tolerance. Dosage adjustments of insulin or oral
hypglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may
become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide
diuretic therapy. Thiazide therapy may precipitate hyperuricaemia and/or gout in
certain patients.
Electrolyte imbalance:
As for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance
(hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of
fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension,
oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent
therapy with zofenopril may reduce diuretic-induced hypokalaemia. The risk of
hypokalaemia is greatest in patients with cirrhosis of the liver, in patients
experiencing brisk diuresis, in patients who are receiving inadequate oral intake of
electrolytes and in patients receiving concomitant therapy with corticosteroids or
ACTH (see section 4.5).
Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride
deficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and may cause an intermittent and
slight elevation of serum calcium in the absence of known disorders of calcium

metabolism. Marked hypercalcaemia may be evidence of hidden
hyperparathyroidism. Thiazides should be discontinued before carrying out test for
parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which
may result in hypomagnesaemia.
Lupus erythematosus:
Exacerbation or activation of systemic lupus erythematosus has been reported with
the use of thiazides.
Anti-doping test:
Hydrochlorothiazide contained in this medication could produce a positive analytic
result in an anti-doping test.

Other:
Sensitivity reactions may occur in patients with or without a history of allergy or
bronchial asthma.
Cases of photosensitivity reactions have been reported with thiazide diuretics (see
section 4.8). If photosensitivity reaction occurs during treatment, it is recommended
to stop the treatment. If re-administration of the diuretic is deemed necessary, it is
recommended to protect the areas exposed to the sun or artificial UVA
ZOFENOPRIL/HYDROCHLOROTHIAZIDE COMBINATION
In addition to the warnings related to the monocomponents, the following should be
observed:

Pregnancy:
Zozide is not recommended during the first trimester of pregnancy (see section 4.6).

Patients with renal insufficiency:
Considering the effect of zofenopril and hydrochlorothiazide in patients with
impaired renal function, Zozide should not be administered to patients with moderate
to severe renal insufficiency (creatinine clearance < 45 ml/min).

Risk of hypokalaemia:
The combination of an ACE inhibitor with a thiazide diuretic does not rule out the
occurrence of hypokalaemia. Regular monitoring of serum potassium should be
performed.

Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption:

This product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should
not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
ZOFENOPRIL
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.
Anaesthetics medicinal products: ACE inhibitors may enhance the hypotensive
effects of certain anaesthetic medicinal products.
Narcotics/Tricyclic antidepressants/Antipsychotics/Barbiturates: postural
hypotension may occur.

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.
Sympathomimetics: May reduce the antihypertensive effects of ACE inhibitors;
patients should be carefully monitored to confirm that the desired effect is being
obtained.
Antacids: Reduce the bioavailability of ACE inhibitors.
Food: may reduce the rate but not the extent of absorption of Zofenopril.
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.

Additional information:
CYP enzymes: direct clinical data on the interaction of Zofenopril with other active
substances which are metabolised by CYP enzymes are not available. However, in
vitro metabolic studies with Zofenopril demonstrated no potential interaction with
active substances that are metabolised by CYP enzymes.
HYDROCHLOROTHIAZIDE
Concomitant use requiring caution
Cholestyramine and colestipol resins: absorption of Hydrochlorothiazide is
impaired in the presence of anionic exchange resins. Single doses of either
cholestyramine or colestipol resins bind the Hydrochlorothiazide and reduce its
absorption from the gastro-intestinal tract by up to 85% and 43%, respectively.
Sulphonamide diuretics should be taken at least one hour before or four to six hours
after these medications.

Corticosteroids, ACTH, amphotericin B (parenteral), carbenoxolone, stimulant
laxatives: there may be intensified electrolyte depletion, particularly hypokalaemia
when administered concomitantly with Hydrochlorothiazide.
Calcium salts: increased serum calcium levels due to decreased excretion may occur
when administered concurrently with thiazide diuretics.
Cardiac glycosides: Thiazide induced hypokalaemia or hypomagnesaemia favours
the occurrence of digitalis induced cardiac arrhythmia.
Medicinal products associated with torsade de pointes: because of the risk of
hypokalaemia, caution should be used when hydrochlorothiazide is coadministered
with medicinal products associated with torsade de pointes, e.g. some
antiarrhythmics, some antipsychotics, and other medicinal products known to induce
torsade de pointes.
Pressor amines (e.g. adrenaline): possible decreased response to pressor amines, but
not sufficient to preclude their use with Hydrochlorothiazide.
Skeletal muscle relaxants, non-depolarising (e.g. tubocurarine): possible
increased responsiveness to the muscle relaxant when used with Hydrochlorothiazide.
Amantadine: thiazide may increase the risk of undesirable effects caused by
amantadine.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone,
allopurinol): dosage adjustment of uricosuric medicinal products may be necessary
as hydrochlorothiazide may raise the level of serum uric acid. Increase of dosage of
probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide
diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Additional information
Laboratory test interactions: because of their effects on calcium metabolism,
thiazides may interfere with tests for parathyroid function.
ZOFENOPRIL/HYDROCHLOROTHIAZIDE COMBINATION
In addition to the interactions related to the monocomponents, the following should
be observed:
Concomitant use not recommended
Lithium: 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, Zozide is not recommended in association with lithium and careful
monitoring of serum lithium levels should be performed if the combination proves
necessary.
Clinical Chemistry: thiazides may decrease serum PBI (Protein Bound Iodine) levels
without signs of thyroid disturbance.
Concomitant use requiring caution
Non-Steroidal Anti-Inflammatory medicinal product (including ASA ≥ 3g/day):
the administration of non-steroidal anti-inflammatory agents may reduce the
antihypertensive effect of ACE inhibitors and diuretics. 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 impaired renal function. Rarely, acute
renal failure may occur, particularly in patients with compromised renal function such
as the elderly or dehydrated.
Alcohol: enhances the hypotensive effect of ACE and hydrochlorothiazide.
Trimethoprim: concomitant administration of ACE-inhibitors and thiazides with
trimethoprim increases the risk of hypercalaemia.

4.6

Fertility, pregnancy and lactation
Use in pregnancy
Zofenopril and HCTZ
Given the effects of the individual components in this combination product on
pregnancy, the use of Zozide is not recommended during the first trimester of
pregnancy (see section 4.4). The use of Zozide is contra-indicated during the 2nd and
3rd trimester of pregnancy (see section 4.3 and 4.4)
Zofenopril
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 trimesters 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).
Hydrochlorothiazide
There is limited experience with hydrochlorothiazide during pregnancy, especially
during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism
of action of hydrochlorothiazide its use during the second and third trimester may
compromise foeto-placental perfusion and may cause foetal and neonatal effects like
icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational
hypertension or preeclampsia due to the risk of decreased plasma volume and
placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women
except in rare situations where no other treatment could be used.
Use in lactation
Because no information is available regarding the use of Zozide during breastfeeding,
Zozide is not recommended and alternative treatments with better established safety
profiles during breastfeeding are preferable, especially while nursing a newborn or
preterm infant.
Hydrochlorothiazide
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high
doses causing intense diuresis can inhibit the milk production. The use of Zozide
during breast feeding is not recommended. If Zozide is used during breast feeding,
doses should be kept as low as possible.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. When driving vehicles or operating machines it should be
remembered that occasionally drowsiness, dizziness or weariness may occur.

4.8

Undesirable effects
In controlled clinical trials involving 597 patients randomised to receive Zofenopril
plus Hydrochlorothiazide, no adverse reactions peculiar to this combination product
have been observed. Adverse reactions have been limited to those that were reported

previously with Zofenopril Calcium or Hydrochlorothiazide. The incidence of
undesirable effects showed no correlation with gender or age of the patients.
The table below shows all the adverse reactions that have been reported during
clinical trials as at least probably-possibly related to treatment with
Zofenopril/Hydrochlorothiazide 30/12.5. They are listed by body-system 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).
Infections and infestations
Uncommon:

Infection, Bronchitis, Pharyngitis

Metabolism and nutrition disorders
Uncommon:

Hypercholesterolaemia, Hyperglycaemia,
Hyperlipidaemia, Hypokalaemia, Hyperkalaemia,
Hyperuricaemia.

Psychiatric disorders
Uncommon:

Insomnia

Nervous system disorders
Common:

Dizziness, Headache

Uncommon:

Somnolence, Syncope, Hypertonia

Cardiac disorders
Uncommon:

Angina pectoris, Atrial fibrillation, Myocardial infarction,
Palpitations

Vascular disorders
Uncommon:

Flushing, Hypotension, Hypertension

Respiratory, thoracic and mediastinal disorders
Common:

Cough

Uncommon:

Dyspnoea

Gastrointestinal disorders
Uncommon:

Nausea, Dyspepsia, Gastritis, Gingivitis, Dry mouth,
Abdominal pain

Skin and subcutaneous tissue disorders
Uncommon:

Angioedema, Psoriasis, Acne, Dry skin, Pruritus, Urticaria

Musculoskeletal and connective tissue disorders
Uncommon:

Back pain

Renal and urinary disorders
Uncommon:

Polyuria

General disorders and administration site conditions
Uncommon:

Asthenia, Influenza like illness, Oedema peripheral.

Reproductive system and breast disorders
Uncommon:

Erectile dysfunction

Investigations
Uncommon:

Creatinine increase, Liver Function tests abnormal

Additional information on individual component:
Adverse reactions known to occur with each component given as monotherapy may
occur during treatment with Zozide:
Zofenopril
The most common undesirable effects typical of ACE inhibitors occurred in clinical
trials in patients treated with zofenopril were the following:
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 spasms

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.
Endocrine disorders

Not known, inappropriate antidiuretic hormone secretion
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.
Hydrochlorothiazide
The adverse events reported that have been reported with the use of
hydrochlorothiazide alone include the following:
Blood and lymphatic system disorders

Leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anaemia,
haemolytic anaemia, bone marrow failure.
Immune system disorders:
Anaphylactic reaction.
Metabolism and nutrition disorders
Anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperuricaemia,
electrolyte imbalance (including hyponatraemia, hypokalaemia, hypomagnesaemia,
hypochloraemia, hypercalcaemia), hyperglycaemia, hyperamylasaemia.
Psychiatric disorders
Apathy, confusional state, depression, nervousness, restlessness, sleep disorder.
Nervous system disorders
Convulsions, depressed level of consciousness, coma, headache, dizziness,
paraesthesia, paresis.
Eye disorders
Xanthopsia, blurred vision, myopia (aggravated), lacrimation decreased.
Ear and labyrinth disorders
Vertigo.
Cardiac disorders
Cardiac arrhythmias, palpitations.
Vascular disorders
Orthostatic hypotension, thrombosis, embolism, shock.
Respiratory thoracic and mediastinal disorders
Pneumonitis, interstitial lung disease, pulmonary oedema.
Gastrointestinal disorders
Dry mouth, nausea, vomiting, stomach discomfort, diarrhoea, constipation, abdominal
pain, ileus paralytic, flatulence, sialoadenitis, pancreatitis.
Hepato-biliary disorders
Jaundice cholestatic, cholecystitis.

Skin and subcutaneous tissue disorders
Pruritus, purpura, urticaria, photosensitivity reactions, rash, cutaneous lupus
erythematosus, vasculitis necrotising, , toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders
Muscle spasm, myalgia.
Renal and urinary disorders: renal impairment, renal failure acute, nephritis
Interstitial, glycosuria.
Reproductive system and breast disorders
Erectile dysfunction.
General disorders and administration site conditions
Asthenia, pyrexia, fatigue, thirst.
Investigations
Electrocardiogram change, blood cholesterol increased, blood triglycerides increased.
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.
Treatment is symptomatic and supportive. 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.

Overdosage with Hydrochlorothiazide is associated with electrolyte depletion
(hypokalaemia, hypoclroraemia) and dehydration resulting from excessive diuresis.
The most common signs and symptoms of overdosage are nausea and somnolence.
Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias
associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic
medicinal products.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: ACE-inhibitors and diuretics
ATC code: C09B A 15
Zofenopril and Hydrochlorothiazide combination tablets
Zozide is a fixed dose combination product containing Zofenopril, an inhibitor of
angiotensin converting enzyme (ACE) and Hydrochlorthiazide, a thiazide diuretic.
Both components have complementary modes of action and exert an additive
antihypertensive effect.
Zofenopril is a sulfhydryl ACE inhibitor able to block the enzyme that catalyses the
conversion of angiotensin I to the vasoconstrictor peptide angiotensin II, which leads
to decreased vasopressor activity and to reduced aldosterone secretion. This latter
decrease may result in an increase in serum potassium concentration, 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 mechanism
through which Zofenopril lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system. ACE is identical to kininase
II, an enzyme that degrades bradykinin, a potent vasodilatatory peptide, that seems to
play a role in the therapeutic effect of ACE inhibitors.
Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the distal renal
tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases
excretion of sodium and chloride in approximately equivalent amounts. Natriuresis
may be accompanied by some loss of potassium and bicarbonate. Presumably through
blockade of the renin-angiotensin-aldosterone system, co-administration of
Zofenopril tends to reverse the potassium lost associated with these diuretics. With
hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts
about 6 to 12 hours.
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
Concomitant administration of Zofenopril and Hydrochlorothiazide has little or no
effect on the bioavailability of either active substance. The combination tablet is
bioequivalent to concomitant administration of the separate entities.
ZOFENOPRIL
Zofenopril is a prodrug, since the active inhibitor is the free sulfhydryl compound,
Zofenoprilat, resulting from thio-ester hydrolysis.

Absorption
Zofenopril 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 Zofenopril. Single dose kinetics are linear over a dose-range
of 10-80 mg of Zofenopril and no accumulation occurs after the administration of 1560 mg of Zofenopril 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 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. The main metabolite is
zofenoprilat (22%), which is the metabolized through several pathways, including
glucoronide conjugation (17%), cyclization and glucoronide conjugation (13%),
cysteine conjugation (9%) and S-methylation of the thiol group (8%).

Elimination
Radiolabelled Zofenoprilat administered intravenously is eliminated in urine (76%)
and faeces (16%) while following an oral dose of radiolabelled Zofenopril, 69% and
26% of the radioactivity is recovered in urine and faeces respectively, indicating a
dual route of elimination (kidney and liver). Half-life of Zofenoprilat is 5.5 h and its
total body clearance is 1300 ml/min following oral Zofenopril.

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, 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.
In patients with end stage renal disease on haemodialysis and peritoneal dialysis, the
rate of elimination is reduced to 25% of normal.
Pharmacokinetics in hepatic dysfunction
In patients with mild to moderate hepatic dysfunction given single doses of
radiolabelled Zofenopril, 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 Zofenopril 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.
HYDROCHLOROTHIAZIDE
Absorption
Hydrochlorothiazide is well absorbed (65 to 75 %) following oral administration.
Plasma concentrations are linearly related to the administered dose. The absorption of
Hydrochlorothiazide is dependent on intestinal transit time, being increased when the
intestinal transit time is slow for example when given with food. When plasma levels
have been followed for at least 24 hours, the plasma half-life has been observed to

vary between 5.6 and 14.8 hours and peak plasma levels were observed within 1 and
5 h after dosing.

Distribution
The thiazides are widely distributed in body fluids and are extensively (92 %) bound
to plasma proteins, particularly so to albumin, the substituted molecules being the
most highly bound. This results in a lower renal clearance than the earlier compounds
and in a more prolonged duration of action. No relationship has been demonstrated
between Hydrochlorothiazide plasma levels and the degree of reduction of blood
pressure.
Elimination
Hydrochlorothiazide is eliminated primarily by renal pathway. Most of thiazide is
excreted in the urine unchanged and more than 95 % of hydrochlorothiazide appears
unchanged in the urine within 3-6 hours after an oral dose. In patients with renal
disease, plasma concentrations of Hydrochlorothiazide are increased and elimination
half-life is prolonged. Hydrochlorothiazide crosses the placental but not the bloodbrain barrier.

5.3

Preclinical safety data
The fixed combination zofenopril/hydrochlorothiazide revealed no special
risks for human use, based on acute toxicity, repeated dose toxicity and
genotoxicity studies.
Reproductive toxicity of the combination has been studied in rats and rabbits
and zofenopril and HCTZ did not show to be teratogenic. However in pregnant
rats and rabbits the combination markedly increased the maternal toxicity
induced by zofenopril alone.
Carcinogenicity studies were not performed with the combination zofenopril/
hydrochlorothiazide.
Carcinogenicity studies conducted in mice and rats with zofenopril alone
revealed no evidence of carcinogenicity.
Preclinical data of HCTZ reveal no special hazard for humans based on
conventional studies of safety pharmacology, repeated dose toxicity,
genotoxicity and carcinogenic potential.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet Core:
Microcrystalline cellulose
Lactose, monohydrate
Maize Starch
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate

Film Coat:
Opadry Pink 02B24436:
Hypromellose
Titanium dioxide (E 171)
Macrogol 400
Iron oxide Red (E 172)
Macrogol 6000

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
Do not store above 30ºC

6.5

Nature and contents of container
PVDC coated PVC/Aluminium blisters.
14, 28, 30, 50, 56, 90 or 100 film coated tablets/pack.
Not all pack sizes may be marketed.

9
DATE OF FIRST AUTHORISATION/RENEWAL OF
AUTHORISATION
Date of first authorisation: 29th September 2004
Date of renewal: 03rd March 2009

7

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

8

MARKETING AUTHORISATION NUMBER(S)
PL 16239/0021

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

Date of first authorisation: 29th September 2004
Date of renewal: 03rd March 2009

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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