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ENALAPRIL AND HYDROCHLOROTHIAZIDE 20 MG / 12.5 MG TABLETS

Active substance(s): ENALAPRIL MALEATE / HYDROCHLOROTHIAZIDE / ENALAPRIL MALEATE / HYDROCHLOROTHIAZIDE / ENALAPRIL MALEATE / HYDROCHLOROTHIAZIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Enalapril and Hydrochlorothiazide 20mg/12.5mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet of Enalapril and Hydrochlorothiazide contains 20 mg enalapril
maleate and 12.5 mg hydrochlorothiazide.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
Enalapril and Hydrochlorothiazide is supplied as white, round (diameter ≈
9mm), biconvex tablets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Enalapril and Hydrochlorothiazide is indicated for the treatment of mild to
moderate hypertension in patients who have been stabilised on the individual
components given in the same proportions.
(See sections 4.3, 4.4, 4.5 and 5.1.)

4.2

Posology and method of administration
Posology
The dosage of Enalapril and Hydrochlorothiazide should be determined
primarily by the experience with the enalapril maleate component.
Adults
Essential hypertension
The usual dosage is one tablet, taken once daily. If necessary, the dosage may
be increased to two tablets, taken once daily.

Prior diuretic therapy: symptomatic hypotension may occur following the
initial dose of Enalapril and Hydrochlorothiazide; this is more likely in
patients who are volume and/or salt depleted as a result of prior diuretic
therapy. The diuretic therapy should be discontinued for 2-3 days prior to
initiation of therapy with Enalapril and Hydrochlorothiazide.
Dosage in renal insufficiency
Thiazides may not be appropriate diuretics for use in patients with renal
impairment and are ineffective at creatinine clearance values of 30 ml/min or
below (i.e. moderate or severe renal insufficiency).
In patients with creatinine clearance of >30 and <80 ml/min, Enalapril and
Hydrochlorothiazide should be used only after titration of the individual
components.
Use in the elderly
In clinical studies the efficacy and tolerability of enalapril maleate and
hydrochlorothiazide, administered concomitantly, were similar in both elderly
and younger hypertensive patients.
Paediatric population
Safety and efficacy of Enalapril and Hydrochlorothiazide in children have not
been established.
Method of administration
Oral use.
4.3

Contraindications
• Hypersensitivity to the active substances or to any of the excipients listed in
section 6.1.
• Severe renal impairment (creatinine clearance ≤30 ml/min).
• Anuria.
• History of angioneurotic edema associated with previous ACE-inhibitor
therapy.
• Hereditary or idiopathic angioedema.
• Hypersensitivity to sulfonamide-derived drugs.
• Second and third trimesters of pregnancy (see section 4.4 and 4.6).
• Severe hepatic impairment.
• Stenosis of the renal arteries
• The concomitant use of Enalapril and Hydrochlorothiazide with aliskirencontaining products is contraindicated in patients with diabetes mellitus or
renal impairment (GFR <60ml/min/1.73m2) (see sections 4.5 and 5.1).

4.4

Special warnings and precautions for use
Enalapril Maleate and Hydrochlorothiazide
Hypotension and Electrolyte Fluid Imbalance
Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In
hypertensive patients receiving Enalapril and Hydrochlorothiazide, symptomatic
hypotension is more likely to occur if the patient has been volume - depleted, e.g.,
by diuretic therapy, dietary salt restriction, diarrhoea or vomiting (see sections 4.5
and 4.8). Regular determination of serum electrolytes should be performed at
appropriate intervals in such patients. Special attention should be paid to patients
with ischemic heart or cerebrovascular disease in whom an excessive fall in blood
pressure could result in a myocardial infarction or cerebrovascular accident. In
hypertensive patients with heart failure, with or without associated renal
insufficiency, symptomatic hypotension has been observed. This is most 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 these patients, therapy should be started under medical supervision and the
patients should be followed closely whenever the dose of Enalapril and
Hydrochlorothiazide and/or diuretic is adjusted. Similar considerations may apply to
patients with ischaemic heart or cerebrovascular disease in whom an excessive fall
in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if
necessary, should receive an intravenous infusion of normal saline. A transient
hypotensive response is not a contra-indication to further doses, which can be
given usually without difficulty once the blood pressure has increased after
volume expansion.
In some patients with heart failure who have normal or low blood pressure,
additional lowering of systemic blood pressure may occur with Enalapril and
Hydrochlorothiazide. This effect is anticipated, and usually is not a reason to
discontinue treatment. If hypotension becomes symptomatic, a reduction of dose
and/or discontinuation of the diuretic and/or Enalapril and Hydrochlorothiazide may
be necessary.
Renal Function Impairment
Renal failure has been reported in association with enalapril and has been mainly
in patients with severe heart failure or underlying renal disease, including renal
artery stenosis. If recognised promptly and treated appropriately, renal failure
when associated with therapy with enalapril is usually reversible.
Enalapril and Hydrochlorothiazide should not be administered to patients with renal
insufficiency (creatinine clearance <80 ml/min. and >30 ml/min.) until titration of
enalapril has shown the need for the dose present in this formulation (see section
4.2).
Some hypertensive patients with no apparent pre-existing renal disease have
developed increases in blood urea and creatinine when enalapril has been given
concurrently with a diuretic (see Special warnings and precautions for use,
Enalapril Maleate, Renal Function Impairment; Hydrochlorothiazide, Renal
Function Impairment in section 4.4). If this occurs, therapy with Enalapril and

Hydrochlorothiazide should be discontinued. This situation should raise the
possibility of underlying renal artery stenosis (see Special warnings and
precautions for use, Enalapril Maleate, Renovascular Hypertension in section 4.4).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II
receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia, and
decreased renal function (including acute renal failure).
Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II
receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and
5.1). If dual blockade therapy is considered absolutely necessary, this should only
occur under specialist supervision and subject to frequent close monitoring of renal
function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used
concomitantly in patients with diabetic nephropathy.
Hyperkalemia
The combination of enalapril and a low-dose diuretic cannot exclude the possibility
of anhyperkalemia to occur (see Special warnings and precautions for use, Enalapril
Maleate, Hyperkalemia in section 4.4).
Lithium
The combination of lithium with enalapril and diuretic agents is generally not
recommended (see section 4.5).
Lactose
Enalapril and Hydrochlorothiazide contains less than 200 mg of lactose per tablet.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicinal product.
Paediatric population
Safety and efficacy in children have not been established.

Enalapril Maleate
Aortic Stenosis/Hypertrophic Cardiomyopathy
As with all vasodilators, ACE inhibitors should be given with caution in patients with
left ventricular valvular and outflow tract obstruction and avoided in cases of
cardiogenic shock and haemodynamically significant obstruction.
Renal Function Impairment
Renal failure has been reported in association with enalapril and has been mainly
in patients with severe heart failure or underlying renal disease, including renal
artery stenosis. If recognized promptly and treated appropriately, renal failure
when associated with therapy with enalapril is usually reversible (see section 4.2
and Special warnings and precautions for use, Enalapril MaleateHydrochlorothiazide, Renal Function Impairment; Hydrochlorothiazide, Renal
Function Impairment in section 4.4).

Renovascular Hypertension
There is an increased risk of 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. Loss of renal function may occur with only
mild changes in serum creatinine. In these patients, therapy should be initiated
under close medical supervision with low doses, careful titration, and monitoring of
renal function.
Haemodialysis Patients
The use of enalapril is not indicated in patients requiring dialysis for renal failure.
Anaphylactoid reactions have been reported in patients dialysed with high-flux
membranes (e.g., AN 69®) and treated concomitantly with an ACE inhibitor. In
these patients consideration should be given to using a different type of dialysis
membrane or a different class of antihypertensive agent.
Kidney Transplantation
There is no experience regarding the administration of enalapril in patients with a
recent kidney transplantation. Treatment with enalapril is therefore not
recommended.
Hepatic failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice or hepatitis 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 (see Special warnings and precautions for use,
Hydrochlorothiazide, Hepatic Disease in section 4.4).
Neutropenia/Agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in
patients receiving ACE inhibitors. In patients with normal renal function and no
other complicating factors, neutropenia occurs rarely. Enalapril should be used with
extreme caution in patients with collagen vascular disease, immunosuppressant
therapy, treatment with allopurinol or procainamide, or a combination of these
complicating factors, especially if there is pre-existing impaired renal function.
Some of these patients developed serious infections which in a few instances did
not respond to intensive antibiotic therapy. If enalapril is used in such patients,
periodic monitoring of white blood cell counts is advised and patients should be
instructed to report any sign of infection.
Hyperkalaemia
Elevations in serum potassium have been observed in some patients treated with
ACE inhibitors, including enalapril. Risk factors for the development of
hyperkalaemia include those with renal insufficiency, worsening of renal function,
age (>70 years), diabetes mellitus, inter-current events in particular dehydration,
acute cardiac decompensation, metabolic acidosis and concomitant use of
potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or
amiloride), potassium supplements or potassium-containing salt substitutes; or those
patients taking other drugs associated with increases in serum potassium (e.g.,
heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole). The use of
potassium supplements, potassium-sparing diuretics, or potassium-containing salt

substitutes particularly in patients with impaired renal function may lead to a
significant increase in serum potassium. Hyperkalaemia can cause serious,
sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the abovementioned agents is deemed appropriate, they should be used with caution and with
frequent monitoring of serum potassium (see Special warnings and precautions for
use, Enalapril Maleate-Hydrochlorothiazide, Hyperkalemia; Hydrochlorothiazide,
Metabolic and Endocrine Effects in section 4.4 and section 4.5).
Hypoglycaemia
Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE
inhibitor should be told to closely monitor for hypoglycaemia, especially during the
first month of combined use (see Special warnings and precautions for use,
Hydrochlorothiazide, Metabolic and Endocrine Effects in section and section 4.5).
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx
has been reported in patients treated with angiotensin converting enzyme
inhibitors, including enalapril maleate. This may occur at any time during
treatment. In such cases, Enalapril and Hydrochlorothiazide should be
discontinued promptly and appropriate monitoring should be instituted to ensure
complete resolution of symptoms prior to dismissing the patient. Even in those
instances where swelling of only the tongue is involved, without respiratory
distress, patients may require prolonged observation since treatment with
antihistamines and corticosteroids may not be sufficient.
Very rarely, fatalities have been reported due to angioedema associated with
laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis
or larynx are likely to experience airway obstruction, especially those with a history
of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely
to cause airway obstruction, appropriate therapy, which may include subcutaneous
epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent
airway, should be administered promptly.
Black patients receiving ACE inhibitors have been reported to have a higher
incidence of angioedema compared to Whites. However, in general it appears
that Blacks have an increased risk for angioedema.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be
at increased risk of angioedema while receiving an ACE inhibitor. (Also see
section 4.3).
Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus):
Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus,
temsirolimus) therapy may be at increased risk of angioedema (e.g. swelling of
the airways or tongue, with or without respiratory impairment) (see section 4.5).
Anaphylactoid Reactions during Hymenoptera Desensitization
Rarely, patients receiving ACE inhibitors during desensitisation with
hymenoptera venom have experienced life-threatening anaphylactoid reactions.
These reactions were avoided by temporarily withholding ACE inhibitor therapy
prior to each desensitisation.
Anaphylactoid Reactions during LDL-Apheresis
Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)apheresis with dextran sulfate have experienced life-threatening anaphylactic

reactions. These reactions were avoided by temporarily withholding ACEinhibitor therapy prior to each apheresis.
Cough
Cough has been reported with the use of ACE inhibitors. Characteristically, the
cough is non-productive, persistent and resolves after discontinuation of therapy.
ACE inhibitor-induced cough should be considered as part of the differential
diagnosis of cough.
Surgery/Anaesthesia
Enalapril blocks angiotensin II formation and therefore impairs the ability of
patients undergoing major surgery or anaesthesia with agents that produce
hypotension to compensate via the renin-angiotensin system. Hypotension which
occurs due to this mechanism can be corrected by volume expansion (see section
4.5).
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).
Ethnic Differences
As with other angiotensin converting enzyme inhibitors, enalapril is apparently less
effective in lowering blood pressure in black people than in non-blacks, possibly
because of a higher prevalence of low-renin states in the black hypertensive
population.

Hydrochlorothiazide
Renal Function Impairment
Thiazides may not be appropriate diuretics for use in patients with renal
impairment and are ineffective at creatinine clearance values of 30 ml/min or
below (i.e., moderate or severe renal insufficiency) (see section 4.2 and Special
warnings and precautions for use, Enalapril Maleate-Hydrochlorothiazide, Renal
Function Impairment; Enalapril Maleate, Renal Function Impairment in section
4.4).
Enalapril and Hydrochlorothiazide should not be administered to patients with
renal insufficiency (creatinine clearance <80 ml/min) until titration of the
individual components has shown the need for the doses present in the
combination tablet.
Hepatic Disease
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 (see Special warnings and precautions for use,
Enalapril Maleate, Hepatic Failure in section 4.4).

Metabolic and Endocrine Effects
Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic
agents, including insulin, may be required (see Special warnings and precautions
for use, Enalapril Maleate, Diabetic Patients in section 4.4). Thiazides may
decrease serum sodium, magnesium and potassium levels.
Increases in cholesterol and triglyceride levels may be associated with thiazide
diuretic therapy; however, at the 12.5 mg dose of hydrochlorothiazide contained in
Enalapril and Hydrochlorothiazide, minimal or no effect was reported. In addition,
in clinical studies with 6 mg of hydrochlorothiazide no clinically significant effect
on glucose, cholesterol, triglycerides, sodium, magnesium or potassium was
reported.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight
elevation of serum calcium in the absence of known disorders of calcium metabolism.
Marked hypercalcaemia may be evidence of latent hyperparathyroidism. Thiazides
should be discontinued before testing parathyroid function.
Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients.
This effect on hyperuricemia appears to be dose-related. In addition enalapril may
increase urinary uric acid and thus may attenuate the hyperuricaemic effect of
hydrochlorothiazide.
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 xerostomia, thirst, weakness, lethargy,
somnolence, restlessness, muscle pain or cramps, muscular fatigue, hypotension,
oliguria, tachycardia, and gastro-intestinal disturbances such as nausea and
vomiting.
Although hypokalaemia may develop during use of thiazide diuretics, concurrent
therapy with enalapril 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 with inadequate oral intake of electrolytes
and in patients receiving concomitant therapy with corticosteroids or ACTH (see
section 4.5).
Hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is
generally mild and does not usually require treatment.
Thiazides may have been shown to increase the urinary excretion of magnesium,
which may result in hypomagnesemia.
Anti-doping test
Hydrochlorothiazide contained in this product can produce a positive analytic
result in an anti-doping test.
Hypersensitivity
In patients receiving thiazides, sensitivity reactions may occur with or without a
history of allergy and bronchial asthma. Exacerbation or activation of systemic
lupus erythematosus has been reported with the use of thiazides.

4.5

Interaction with other medicinal products and other forms of interaction
Enalapril Maleate-Hydrochlorothiazide
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Clinical trial data have shown that dual blockade of the reninangiotensin-aldosterone-system (RAAS) through the combined use of
ACE-inhibitors, angiotensin II receptor blockers or aliskiren is
associated with a higher frequency of adverse events such as
hypotension, hyperkalaemia and decreased renal function (including
acute renal failure) compared to the use of a single RAAS-acting agent
(see sections 4.3, 4.4 and 5.1).
Other Antihypertensive Agents
Concomitant use of these agents may increase the hypotensive effects of enalapril
and hydrochlorothiazide. Concomitant use with nitroglycerine and other nitrates, or
other vasodilators, may further reduce blood pressure.
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 further increase lithium levels and
enhance the risk of lithium toxicity with ACE inhibitors.
Use of Enalapril and Hydrochlorothiazide with lithium is not recommended, but if
the combination proves necessary, careful monitoring of serum lithium levels
should be performed (see section 4.4).
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including
selective cyclooxygenase-2 (COX-2) inhibitors
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective
cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics
and other antihypertensive drugs. Therefore, the antihypertensive effect of
angiotensin II receptor antagonists, ACE inhibitors or diuretics may be attenuated
by NSAIDs including selective COX-2 inhibitors.
The co-administration of NSAIDs (including COX-2 inhibitors) and angiotensin II
receptor antagonists or ACE inhibitors exert an additive effect on the increase in
serum potassium, and may result in a deterioration of renal function. These effects
are usually reversible. Rarely, acute renal failure may occur, especially in patients
with compromised renal function (such as the elderly or patients who are volumedepleted, including those on diuretic therapy). Therefore, the combination should be
administered with caution in patients with compromised renal function.

Enalapril Maleate
Potassium-sparing Diuretics or Potassium Supplements
ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing
diuretics (e.g., spironolactone, eplerenone, 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

demonstrated hypokalaemia they should be used with caution and with frequent
monitoring of serum potassium (see section 4.4)
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 enalapril (see sections 4.2 and 4.4). The
hypotensive effects can be reduced by discontinuation of the diuretic or by
increasing volume or salt intake.
Tricyclic Antidepressants/Antipsychotics/Anaesthetics
Concomitant use of certain anaesthetic medicinal products, tricyclic
antidepressants and antipsychotics with ACE inhibitors may result in further
reduction of blood pressure (see section 4.4).
GOLD
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and
hypotension) have been reported rarely in patients on therapy with injectable gold
(sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients taking concomitant mTOR inhibitors therapy may be at increased risk for
angioedema (see section 4.4).
Co-trimoxazole (trimethoprim/sulfamethoxazole)
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be
at increased risk for hyperkalaemia (see section 4.4)
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors
(see section 4.5).
Alcohol
Alcohol enhances the hypotensive effect of ACE inhibitors.
Antidiabetics
Epidemiological studies have suggested that concomitant administration of ACE
inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may
cause an increased blood-glucose-lowering effect with risk of hypoglycaemia. This
phenomenon appeared to be more likely to occur during the first weeks of combined
treatment and in patients with renal impairment (see sections 4.4 and 4.8).
Acetyl Salicylic Acid, Thrombolytics and β -blockers
Enalapril can be safely administered concomitantly with acetyl salicylic acid
(at cardiologic doses), thrombolytics and β-blockers.

Hydrochlorothiazide

Non-depolarising Muscle Relaxants
Thiazides may increase the responsiveness to tubocurarine.

Alcohol, Barbiturates, or Opioid Analgesics
Potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (Oral Agents and Insulin)
Dosage adjustment of the antidiabetic drug may be required (see sections 4.4 and
4.8).
Colestyramine and Colestipol Resins
Absorption of hydrochlorothiazide is impaired in the presence of anionic
exchange resins. Single doses of either colestyramine or colestipol resins bind
the hydrochlorothiazide and reduce its absorption from the gastro-intestinal tract
by up to 85 and 43 percent, respectively.
Increasing the QT Interval (e.g., quinidine, procainamide, amiodarone, sotalol)
Increased risk of torsades de pointes.
Digitalis Glycosides
Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects
of digitalis (e.g., increased ventricular irritability).
Corticosteroids, ACTH
Intensified electrolyte depletion, particularly hypokalaemia.
Kaliuretic Diuretics (e.g., Furosemide), Carbenoxolone, or Laxative Abuse
Hydrochlorothiazide may increase the loss of potassium and/or magnesium.
Pressor Amines (e.g. Noradrenaline)
The effect of pressor amines may be decreased (see section 4.5).
Cytostatics (e.g., Cyclophosphamide, Methotrexate)
Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate
their myelosuppressive effects.

Paediatric population
Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation
Pregnancy
ACE inhibitors:
The use of ACE inhibitors is not recommended during the first trimester of
pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated 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 anti-hypertensive 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.
ACE inhibitors therapy exposure 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). Maternal oligohydramnios, presumably
representing decreased foetal renal function, has occurred and may result in limb
contractures, craniofacial deformations and hypoplastic lung development.
Should exposure to ACE inhibitors 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.
Breastfeeding
Enalapril:
Limited pharmacokinetic data demonstrate very low concentrations in breast milk
(see section 5.2). Although these concentrations seem to be clinically irrelevant, the
use of Enalapril and Hydrochlorothiazide in breast-feeding is not recommended for
preterm infants and for the first few weeks after delivery, because of the
hypothetical risk of cardiovascular and renal effects and because there is not enough
clinical experience. In the case of an older infant, the use of Enalapril and
Hydrochlorothiazide in a breast-feeding mother may be considered if this treatment
is necessary for the mother and the child is observed for any adverse effect.
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 Enalapril
and Hydrochlorothiazide during breast-feeding is not recommended. If Enalapril and
Hydrochlorothiazide is used during breast-feeding, doses should be kept as low as
possible.

Fertility
In preclinical studies, no effects of enalapril maleate and hydrochlorothiazide on
male and female fertility were observed (see section 5.3).

4.7

Effects on ability to drive and use machines
When driving vehicles or operating machines it should be taken into account
that occasionally dizziness or weariness may occur (see section 4.8).

4.8

Undesirable effects
Enalapril and hydrochlorothiazide is usually well tolerated. In clinical studies,
side effects have usually been mild and transient, and most instances have not
required interruption of therapy.
The most common side effects reported with enalapril and hydrochlorothiazide
were headache and cough.
The following undesirable side effects have been reported for enalapril and
hydrochlorothiazide, enalapril alone or hydrochlorothiazide alone either
during clinical studies or after the drug was marketed:
[Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known
(cannot be estimated from the available data).]
Blood and the Lymphatic System Disorders:
• uncommon: anaemia (including aplastic and haemolytic)
• rare: neutropenia, decreases in haemoglobin, decreases in haematocrit,
thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia,
pancytopenia, lymphadenopathy, autoimmune diseases
Endocrine disorders:
• not known: syndrome of inappropriate antidiuretic hormone secretion
(SIADH)
Metabolism and Nutrition Disorders:
• common: hypokalaemia, increase of cholesterol, increase of triglycerides,
hyperuricaemia


uncommon: hypoglycaemia (see section 4.4), hypomagnesemia, gout**



rare: increase in blood glucose



very rare: hypercalcaemia (see section 4.4)

Nervous System and Psychiatric Disorders:



common: headache, depression, syncope, taste alteration



uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia,
vertigo, decreased libido**



rare: dream abnormality, sleep disorders, paresis (due to hypokalemia)

Eye Disorders:
• very common: blurred vision
Ear and Labyrinth Disorders:
• uncommon: tinnitus
Cardiac and Vascular Disorders:
• very common: dizziness


common: hypotension, orthostatic hypotension, rhythm disturbances,
angina pectoris, tachycardia



uncommon: flushing, palpitations, myocardial infarction or
cerebrovascular accident*, possibly secondary to excessive hypotension in
high risk patients (see section 4.4)



rare: Raynaud's phenomenon

Respiratory, Thoracic and Mediastinal Disorders:
• very common: cough


common: dyspnoea



uncommon: rhinorrhoea, sore throat and hoarseness,
bronchospasm/asthma



rare: pulmonary infiltrates, respiratory distress (including pneumonitis and
pulmonary oedema), rhinitis, allergic alveolitis/eosinophilic pneumonia

Gastro-intestinal Disorders:
• very common: nausea


common: diarrhoea, abdominal pain



uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation,
anorexia, gastric irritations, dry mouth, peptic ulcer, flatulence**



rare: stomatitis/aphthous ulcerations, glossitis



very rare: intestinal angioedema

Hepatobiliary Disorders:
• rare: hepatic failure, hepatic necrosis (may be fatal), hepatitis – either
hepatocellular or cholestatic, jaundice, cholecystitis (in particular in
patients with pre-existing cholelithiasis)
Skin and Subcutaneous Tissue Disorders:



common: rash (exanthema), hypersensitivity/angioneurotic oedema:
angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or
larynx has been reported (see section 4.4)



uncommon: diaphoresis, pruritus, urticaria, alopecia



rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative
dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus
erythematosus, pemphigus, erythroderma



not known: A symptom complex has been reported which may include
some or all of the following: fever, serositis, vasculitis,
myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR,
eosinophilia, and leukocytosis. Rash, photosensitivity or other
dermatologic manifestations may occur.

Musculoskeletal, Connective Tissue and Bone Disorders:
• common: muscle cramps†


uncommon: arthralgia**

Renal and Urinary Disorders:
• uncommon: renal dysfunction, renal failure, proteinuria


rare: oliguria, interstitial nephritis

Reproductive System and Breast Disorders:
• uncommon: impotence


rare: gynecomastia

General Disorders and Administration Site Conditions:
• very common: asthenia


common: chest pain, fatigue



uncommon: malaise, fever

Investigations:
• common: hyperkalaemia, increases in serum creatinine


uncommon: increases in blood urea, hyponatraemia



rare: elevations of liver enzymes, elevations of serum bilirubin

*Incidence rates were comparable to those in the placebo and active control
groups in the clinical trials.
** only seen with doses of hydrochlorothiazide 12.5 mg and 25 mg
† The frequency of muscle cramps as common pertains to doses of
hydrochlorothiazide 12.5 mg and 25 mg, whereas, the frequency of the event
is uncommon as it pertains to 6 mg doses of hydrochlorothiazide.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk
balance of the medicinal product. Healthcare professionals are asked to
report any suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.

4.9

Overdose
No specific information is available on the treatment of overdosage with
Enalapril and Hydrochlorothiazide. Treatment is symptomatic and supportive.
Therapy with Enalapril and Hydrochlorothiazide should be discontinued and
the patient observed closely. Suggested measures include induction of emesis,
administration of activated charcoal, and administration of a laxative if
ingestion is recent, and correction of dehydration, electrolyte imbalance and
hypotension by established procedures.
Enalapril Maleate
The most prominent features of overdosage reported to date are marked
hypotension, beginning some six hours after ingestion of tablets, concomitant
with blockade of the renin-angiotensin system, and stupor. Symptoms
associated with overdosage of ACE inhibitors may include circulatory shock,
electrolyte disturbances, renal failure, hyperventilation, tachycardia,
palpitations, bradycardia, dizziness, anxiety, and cough. Serum enalaprilat
levels 100- and 200-fold higher than usually seen after therapeutic doses have
been reported after ingestion of 300 mg and 440 mg of enalapril maleate,
respectively.
The recommended treatment of overdosage is intravenous infusion of normal
saline solution. If hypotension occurs, the patient should be placed in the
shock position. If available, treatment with angiotensin II infusion and/or
intravenous catecholamines may also be considered. If ingestion is recent, take
measures aimed at eliminating enalapril maleate (e.g., emesis, gastric lavage,
administration of absorbents, and sodium sulphate). Enalaprilat may be
removed from the general circulation by hemodialysis (see section 4.4).
Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs,
serum electrolytes and creatinine concentrations should be monitored
continuously.
Hydrochlorothiazide
The most common signs and symptoms observed are those caused by
electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and
dehydration resulting from excessive diuresis. If digitalis has also been
administered, hypokalaemia may accentuate cardiac arrhythmias.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: enalapril and diuretics, ATC code: C09 BA02.
Enalapril maleate
Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which
catalyses the conversion of angiotensin I to the pressor substance angiotensin
II. After absorption, enalapril is hydrolysed to enalaprilat, which inhibits ACE,
which leads to increased plasma renin activity (due to removal of negative
feedback on renin release), and decreased aldosterone secretion.
ACE is identical to kininase II. Thus enalapril may also block the degradation
of bradykinin, a potential vasodepressor peptide. However, the role that this
plays in the therapeutic effects of enalapril remains to be elucidated.
Mechanism of action
While the mechanism through which enalapril lowers blood pressure is
believed to be primarily suppression of the renin-angiotensin-aldosterone
system, which plays a major role in the regulation of blood pressure, enalapril
is antihypertensive even in patients with low-renin hypertension.
Enalapril maleate - hydrochlorothiazide
Hydrochlorothiazide is a diuretic and antihypertensive agent which increases
plasma renin activity. Although enalapril alone is antihypertensive even in
patients with low-renin hypertension, concomitant administration of
hydrochlorothiazide in these patients leads to greater reduction of blood
pressure.
Dual Blockade
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 the combination of an ACE-inhibitor with an angiotensin
II receptor blocker.
ONTARGET was a study conducted in patients with a history of
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus
accompanied by evidence of end-organ damage. VA NEPHRON-D was a
study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or
cardiovascular outcomes and mortality, while an increased risk of
hyperkalaemia, acute kidney injury and/or hypotension as compared to
monotherapy was observed. Given their similar pharmacodynamic properties,
these results are also relevant for other ACE-inhibitors and angiotensin II
receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be
used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and
Renal Disease Endpoints) was a study designed to test the benefit of adding
aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II
receptor blocker in patients with type 2 diabetes mellitus and chronic kidney

disease, cardiovascular disease, or both. The study was terminated early
because of an increased risk of adverse outcomes. Cardiovascular death and
stroke were both numerically more frequent in the aliskiren group than in the
placebo group and adverse events and serious adverse events of interest
(hyperkalaemia, hypotension and renal dysfunction) were more frequently
reported in the aliskiren group than in the placebo group.

5.2

Pharmacokinetic properties
Absorption
Oral enalapril maleate is rapidly absorbed, with peak serum concentrations of
enalapril occurring within one hour. Based on urinary recovery, the extent of
absorption of enalapril from oral enalapril maleate is approximately 60%.
Following absorption, oral enalapril is rapidly and extensively hydrolysed to
enalaprilat, a potent angiotensin-converting enzyme inhibitor. Peak serum
concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril
maleate. The principal components in urine are enalaprilat, accounting for
about 40% of the dose, and intact enalapril. Except for conversion to
enalaprilat, there is no evidence of significant metabolism of enalapril. The
serum concentration profile of enalaprilat exhibits a prolonged terminal phase,
apparently associated with binding to ACE. In subjects with normal renal
function, steady state serum concentrations of enalaprilat were achieved by the
fourth day of administration of enalapril maleate. The absorption of oral
enalapril maleate is not influenced by the presence of food in the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar
for the various doses in the recommended therapeutic range.
Distribution
Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if
at all; enalaprilat does not enter the brain. Enalapril crosses the placental
barrier. Hydrochlorothiazide crosses the placental but not the blood-brain
barrier.
Biotransformation
Except for conversion to enalaprilat, there is no evidence for significant
metabolism of enalapril. Hydrochlorothiazide is not metabolised but is
eliminated rapidly by the kidney.
Elimination
Excretion of enalapril is primarily renal. The principal components in urine are
enalaprilat, accounting for about 40% of the dose, and intact enalapril. The
effective half-life for accumulation of enalaprilat following multiple doses of
oral enalapril maleate is 11 hours. When plasma levels of hydrochlorothiazide
have been followed for at least 24 hours, the plasma half-life has been
observed to vary between 5.6 and 14.8 hours. Hydrochlorothiazide is not
metabolised but is eliminated rapidly by the kidney. At least 61% of the oral
dose is eliminated unchanged within 24 hours.
Renal impairment
Enalaprilat may be removed from the general circulation by haemodialysis.

Lactation
After a single 20 mg oral dose in five postpartum women, the average peak
enalapril milk level was 1.7μg/L (range 0.54 to 5.9 μg/L) at 4 to 6 hours after
the dose. The average peak enalaprilat level was 1.7μg/L (range 1.2 to
2.3μg/L); peaks occurred at various times over the 24-hour period. Using the
peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage. A
woman who had been taking oral enalapril 10 mg daily for 11 months had
peak enalapril milk levels of 2 μg/L 4 hours after a dose and peak enalaprilat
levels of 0.75 μg/L about 9 hours after the dose. The total amount of enalapril
and enalaprilat measured in milk during the 24 hour period was 1.44μg/L and
0.63 μg/L of milk respectively. Enalaprilat milk levels were undetectable
(<0.2μg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10
mg in two mothers; enalapril levels were not determined.
5.3

Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity and
carcinogenic potential. Reproductive toxicity studies suggest that enalapril has
no effects on fertility and reproductive performance in rats, and is not
teratogenic. In a study in which female rats were dosed prior to mating
through gestation, an increased incidence of rat pup deaths occurred during
lactation.
The compound has been shown to cross the placenta and is secreted in milk.
Angiotensin converting enzyme inhibitors, as a class, have been shown to be
fetotoxic (causing injury and/or death to the fetus) when given in the second or
third trimester.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate,
Sodium hydrogen carbonate,
Pregelatinised maize starch,
Croscarmellose sodium,
Magnesium stearate.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Do not store above 30ºC.
Store in the original package in order to protect from light.

6.5

Nature and contents of container
OPA/Al/PVC/Al blister packs containing 28 tablets.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Units 3 & 4, Quidhampton Business Units,
Polhampton Lane, Overton,
Hampshire RG25 3ED
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0268

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/07/2016

10

DATE OF REVISION OF THE TEXT
16/06/2017

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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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