TRITACE COMP 1. DESCRIPTION 1.1 Active Moiety(ies) / Active ...

TRITACE COMP
1. DESCRIPTION
1.1 Active Moiety(ies) / Active Ingredients
Ramipril Hydrochlorothiazide
Ramiprilat, the active metabolite of ramipril, is an inhibitor of the enzyme
dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme [ACE],
kininaseII). Hydrochlorothiazide is a thiazide diuretic.
1.2 Therapeutic or Pharmacological Class
ACE inhibitor plus diuretic. Antihypertensive.
1.3 Pharmaceutical Form(s)
Tablets.
1.4 Composition
Active ingredient
Each tablet *TM 1/1* contains, as active ingredients, 5 mg ramipril and 25 mg
hydrochlorothiazide.
Each tablet *TM 1/2* contains, as active ingredients, 2.5 mg ramipril and 12.5 mg
hydrochlorothiazide.
Excipients
See background documentation.
1.5 Nature and Contents of Container
See background documentation.
2. INDICATIONS
●
To lower blood pressure in essential hypertension, when treatment with a combination
preparation is indicated.
*TM* is not suitable for the treatment of hypertension resulting from primary
hyperaldosteronism.
3. DOSAGE AND ADMINISTRATION

Dosage
The dosage is based on the desired antihypertensive effect and on how the patient
tolerates the drug.
The following dosage applies in the absence of special circumstances defined below:
Usual initial dosage: 2.5 mg ramipril / 12.5 mg hydrochlorothiazide (corresponding to 1
tablet * TM 1/2 * or ½ tablet *TM 1/1 *) daily.
If necessary, the dose may be increased at intervals of 2 to 3 weeks.
Maximum permitted daily dose: 10 mg ramipril / 50 mg hydrochlorothiazide
(corresponding to 4 tablets * TM 1/ 2* or 2 tablets *TM 1/1*).
Generally, it is recommended that the daily dose be administered in the morning as a
single dose.
In most cases, blood pressure will fall sufficiently after 2.5 mg ramipril / 12.5 mg
hydrochlorothiazide to 5 mg ramipril / 25 hydrochlorothiazide (corresponding to 1 to 2
tablets *TM 1 /2 * or ½ to 1 tablet *TM 1/1 *) daily.
Special circumstances
●Dosage in patients pre-treated with diuretics
In patients pre-treated with a diuretic, consideration must be given to discontinuing the
diuretic at least 2 to 3 days or (depending on the duration of action of the diuretic) longer
before starting treatment with * TM*, or at least to reducing the diuretic dose.
Should discontinuation not be possible, it is recommended that treatment be initiated with
the smallest possible dosage or ramipril (1.25 mg daily) in a free combination. It is
recommended that, subsequently, a changeover be made to an initial daily dose of not
more than 2.5 mg ramipril / 12.5 mg hydrochlorothiazide (corresponding to 1 tablet *TM
1 /2 * or ½ tablet *TM 1/1*).
●Dosage in patients with impaired renal function
Creatinine clearance 60 to 30 ml/min per 1.73 m 2 body surface area: Treatment is started
with ramipril alone at a daily dose of 1.25 mg. After gradually increasing the dose of
ramipril, medication with the combination preparatiojn is started at a daily dose of 2.5 mg
ramipril / 12,5 mg hydrochlorothiazide (corresponding to 1 tablet *TM 1 /2 * or ½ tablet
*TM 1/1*).
Maximum permitted daily dose: 5 mg ramipril / 25 mg hydroclorothiazide
(corresponding to 2 tablets *TM 1 /2 * or 1 tablet *TM 1/1*).
In patients with impaired liver function, the response to the treatment with Tritace Comp
may be either increased or reduced. Treatment in these patients must therefore be

initiated only under close medical supervision. Maximum permitted daily dose in this
case is Ramipril 2.5 mg.
Administration
*TM* tablets have to be swallowed whole with sufficient amounts of liquid (approx. ½
glass). The tablets must not be chewed or crushed.
*TM* may be taken before, during or after a meal.
4. CONTRAINDICATIONS
*TM* must not be used
●In patients with hypersensitivity to ramipril, any other ACE inhibitor,
hydrochlorothiazide, other thiazide diuretics, sulfonamides or any of the excipients of
*TM*.
●In patients with a history of angioneurotic oedema.
●In patients with severe impairment of renal function with a creatinine clearance below
30 ml/min per 1.73 m 2 body surface area, and in dialysis patients.
●In patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral
in the single kidney.
●In patients with haemodynamically relevant left-ventricular inflow or outflow
impediment (e.g., stenosis of the aortic or mitral valve).
●In patients with clinically relevant electrolyte disturbances which may worsen
following treatment with *TM* (e.g., hypokalaemia, hyponatraemia, or hypercalcaemia).
●In patients with severe impairment of liver function.
●During pregnancy.
●In breast feeding women.
Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of
blood with negatively charged surfaces must be avoided, since such use may lead to
severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or
haemofiltration with certain high-flux (e.g. polyacrylonitril) membranes and low-density
lipoprotein apheresis with dextran sulfate.

5. WARNINGS
Angioneurotic oedema occurring during treatment with an ACE inhibitor necessitates
immediate discontinuation of the drug.
Angioneurotic oedema may involve the tongue, glottis or larynx. Emergency treatment of
life-threatening angioneurotic oedema includes immediate administration of epinephrine
(subcutaneous or slow intravenous injection) accompanied by monitoring of ECG and
blood pressure. Hospitalization of the patient is advisable with observation for at least 12
to 24 hours and discharge only upon complete resolution of the symptoms.
Insufficient experience has been gained concerning the use of *TM* in children.
6. PRECAUTIONS
Treatment with *TM* requires regular medical supervision.
Patients with hyper-stimulated renin angiotensin system
In the treatment of patients with a hyper-stimulated renin-angiotensin system, particular
caution must be exercised (see also under "3. Dosage and administration"). Such patients
are at risk of an acute pronounced fall in blood pressure and deterioration of renal
function due to ACE inhibition, especially when an ACE inhibitor is given for the first
time or for the first time at an increased dose. Initial doses or initial dose increases must
be accompanied by close blood pressure monitoring until such time as no further acute
reduction in blood pressure is to be anticipated.
Significant activation of the renin angiotensin system is to be anticipated, for example:
in patients with severe, and particularly with malignant hypertension.The initial phase of
treatment requires special medical supervision.
in patients with concomitant, and particularly with severe heart failure. If heart failure is
severe, the initial phase of treatment requires special medical supervision.
in patients with haemodynamically relevant left-ventricular inflow or outflow
impediment (e.g., stenosis of the aortic or mitral valve). The initial phase of treatment
requires special medical supervision.
in patients with haemodynamically relevant renal artery stenosis. The initial phase of
treatment requires special medical supervision. See also under ‘Monitoring of renal
function’ below.
in patients pre-treated with diuretics. Where discontinuing use or reducing the dose of the

diuretic is not possible, the initial phase of treatment requires special medical supervision.
in patients in whom fluid or salt depletion exists or may develop (as a result of
insufficient fluid or salt intake, or as a result of, for example, diarrhoea, vomiting or
excessive sweating in cases where salt and fluid replacement is inadequate).
Generally, it is recommended that dehydration, hypovolaemia or salt depletion be
corrected before initiating treatment (in patients with heart failure, however, such
corrective action must be carefully weighed against the risk of volume overload). When
these conditions have become clinically relevant, treatment with *TM* must only be
started or continued if appropriate steps are taken concurrently to prevent an excessive
fall in blood pressure and deterioration of renal function.
Patients at particular risk from a pronounced reduction in blood pressure
In patients who would be at particular risk from an undesirably pronounced reduction in
blood pressure (e.g. patients with haemodynamically relevant stenoses of the coronary
arteries or of the blood vessels supplying the brain), the initial phase of treatment requires
special medical supervision.
Elderly
Some elderly patients may be particularly responsive to ACE inhibitors. Evaluation of
renal function at the beginning of treatment is recommended.
Monitoring of renal function
It is recommended that renal function be monitored, particularly in the initial weeks of
treatment. Particularly careful monitoring is required in patients with
heart failure
renovascular disease, including patients with haemodynamically relevant unilateral renal
artery stenosis. In the latter patient group, even a small increase in serum creatinine may
be indicative of unilateral loss of renal function.
impairment of renal function
kidney transplant patients.
Electrolyte monitoring
Treatment with *TM* requires regular monitoring of serum sodium, potassium, calcium,
uric acid, and blood glucose. More frequent monitoring of serum potassium is necessary
in patients with impaired renal function.
Haematological monitoring
It is recommended that the white blood cell count be monitored to permit detection of a
possible leucopenia. More frequent monitoring is advised in the initial phase of treatment

and in patients with impaired renal function, those with concomitant collagen disease
(e.g. lupus erythematosus or scleroderma) or those treated with other drugs that can cause
changes in the blood picture. See also under "12. Adverse reactions".
7. DRIVING A VEHICLE OR PERFORMING OTHER HAZARDOUS TASKS
Some adverse effects (e.g. some symptoms of a reduction in blood pressure such as
lightheadedness, dizziness) may impair the patient's ability to concentrate and react and,
therefore, constitute a risk in situations where these abilities are of particular importance
(e.g. operating a vehicle or machinery).
8. INTERACTIONS
8.1 Food
Absorption or ramipril is not significantly affected by food.
8.2 Drug interactions
8.2.1 Contraindicated combinations
Extracorporeal treatments leading to contact of blood with negatively charged surfaces
such as dialysis or haemofiltration with certain high-flux membranes (e.g.
polyacrylonitril membranes) and low-density lipoprotein apheresis with dextran sulfate:
Risk of severe anaphylactoid reactions, see also under "4. Contraindications".
8.2.2 Not recommended associations
POTASSIUM SALTS POTASSIUM-RETAINING DIURETICS, HEPARIN: Rise in
serum potassium concentration possible. Concomitant treatment with potassium-retaining
diuretics (e.g. spironolactone) or with potassium salts requires close monitoring of serum
potassium.
8.2.3 Precautions for use
ANTHYPERTENSIVE AGENTS AND OTHER SUBSTANCES WITH
ANTIHYPERTENSIVE POTENTIAL (E.G., NITRATES, TRICYCLIC
ANTIDEPRESSANTS, ANAESTHETICS):
Potentiation of the anithypertensive effect is to be anticipated (concerning diuretics see
also “6: Precautions”, 12. Adverse reactions” and “3 Dosage and administration”).
Vasopressor sympathomimetics: These may reduce the antihypertensive effect of *TM*.
Particularly close blood pressure monitoring is recommended. Furthermore, tThe effect
of the vasopressor sympathomimetics may be attenuated by hydrochlorothiazide.

LITHIUM SALTS: Reduction of the excretion of lithium salts. This may lead to
increased serum lithium levels and increased lithium toxicity. Lithium levels must,
therefore, be monitored.
ALLOPURINOL, IMMUNOSUPPRESSANTS, CORTICOSTEROIDS,
PROCAINAMIDE, CYTOSTATICS AND OTHER SUBSTANCES THAT MAY
CHANGE THE BLOOD PICTURE: Increased likelihood of haematological reactions
( see also under “6: Precautions”).
ANTIDIABETIC AGENT (E.G. INSULIN AND SULFONYLUREA DERIVATIVES):
ACE inhibitors may reduce insulin resistance. In isolated cases, such reduction may lead
to hypoglycaemic reactions in patients concomitantly treated with antidiabetics.
Hydrochlorothiazide may attenuate the effect of antidiabetics. Particularly close blood
glucose monitoring is, therefore, recommended in the initial phase of co-administration.
8.2.4 Take into account
SALT: Possible attenuation of the antihypertensive effect by increase dietary salt intake.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (e.g. INDOMETHACIN) and
acetylsalicylic acid : Possible attenuation of the effect of *TM* as well
as development of acute renal failure or an increase in serum potassium.
PRESSOR AMINES (E.G. EPINEPHRINE): Possible attenuation of the effect of pressor
amines.
CORTICOSTEROIDS, CARBENOXOLONE, LARGE AMOUNTS OF LIQUORICE,
LAXATIVES (IN CASE OF A PROLPNGED USE), AND OTHER KALIURETIC
AGENTS: Promotion of the development of hypokalaemia.
DIGITALIS PREPARATIONS: Possible intensification of digitalis toxicity as a result of
changes in electrolyte concentrations (e.g. hypokalaemia, hypomagnesaemia).
METHYLDOPA: Haemolysis possible.
ENTERALLY ADMINISTERED ION EXCHANGERS SUCH AS
COLESTYRAMINE: Reduced absorption of hydrochlorothiazide.
CURARE-TYPE MUSCLE RELAXANTS: Possible intensification and prolongation of
the muscular relaxing effect.
ALCOHOL: Ramipril may lead to increased vasodilation and thus potentiate the effect
of alcohol.

DESENSITIZATION THERAPY: The likelihood and severity of anaphylactic and
anaphylactoid reactions to insect venoma is increased under ACE inhibition. It is
assumed that this effect may also occur in connection with other allergens.
8.2.4 Absence of pharmacokinetic drug interaction
No information currently deemed necessary.
9. INTERFERENCE WITH LABORATORY AND DIAGNOSTIC TEST
TESTS FOR PARATHROID FUNCTION: Hydrochlorothiazide stimulates renal calcium
reabsorption and may cause hypercalcaemia. This must be considered when carrying out
tests for parathyroid function.
10. PREGNANCY
*TM* must not be taken during pregnancy. Therefore, pregnancy must be excluded
before starting treatment.
Pregnancy must be avoided in cases where changeover to a treatment regimen without
ACE inhibitors and diuretics is not possible. Otherwise there is a risk of harm to the
fetus.
11. LACTATION
If treatment with *TM* is necessary during lactation, the patient must not breast feed in
order to prevent the infant from ingesting small quantities of ramipril and
hydrochlorothiazide with breast milk.
12. ADVERSE REACTIONS
As *TM* is an antihypertensive, many of its adverse reactions are effects secondary to its
blood-pressure-lowering action which results in adrenergic counter-regulation or organ
hypoperfusion. Numerous other effects (e.g. effects on electrolyte balance, certain
anaphylactoid reactions or inflammatory reactions of the mucous membranes) are due to
the ACE inhibition or to other pharmacologic actions of ramipril or hydrochlorothiazide.
The following adverse effects have been observed during therapy with *TM*, its
constituents ramipril and hydrochlorothiazide, other ACE inhibitors, or comparable
diuretics, and may, therefore, occur.
Blood pressure
At the start of treatment in particular, symptoms such as lightheadedness – sometimes

accompanied by concentration disturbances – as well as impaired reactions, fatigue,
weakness, and dizziness may occur as a result of vasodilatation, or as result of the
lowering of raised blood pressure even to the desired level.
Other symptoms including tachycardia ,palpitations ,disturbed orthostatic regulation,
disorders of balance ,nausea ,sweating ,tinnitus ,disturbed hearing ,disturbed vision,
headache , anxiety ,drowsiness and somnolence may supervene following an excessive
reduction in blood pressure. Then syncope may also occur.
In rare instances, cardiac arrhythmias may occur, they may be caused for example by an
excessive reduction in blood pressure or by disturbances in electrolyte balance.
An undesirably pronounced fall in blood pressure may occur particulary after the initial
dose and after every first increased dose of *TM*.
A pronounced fall in blood pressure, sometimes progressing to shock, may be more likely
in patients with:
●Severe and particularly with malignant hypertension.
●Concomitant, and particularly with severe heart failure.
●Previous diuretic therapy.
●Fluid or salt depletion.
●Haemodynamically relevant renal artery stenosis.
Perfusin disturbances due to vascular stenoses may be exacerbated during treatment with
*TM*. Mainly in patients with coronary heart disease or a haemodynamically relevant
stenosis of blood vessels supplying the brain, myocardial ischaemia (e.g. with ensuing
angina pectoris and myocardial infarction) or cerebral ischaemia (e.g. with ensuing
transient ischaemic attack of stroke) may occur, particularly as a result of an excessive
fall in blood pressure.
Once an adequate blood pressure and fluid balance have been regained, treatment with
*TM* can generally be continued.
Kidney and electrolyte balance
During treatment with *TM* , there may be a deterioration in renal function, under
certain circumstances progressing to acute renal failure, particularly
●In patients with renovascular disease (e.g. haemodynamically relevant renal artery
stenosis).
●In kidney transplant patients.
●In conjunction with a more pronounced fall in blood pressure, mainly in patients with
concomitant heart failure.

In isolated cases, interstitial nephritis may develop during therapy with
hydrochlorothiazide.
As signs of impaired renal function, serum creatinine and serum urea may increase.
Pre-existing proteinuria may deteriorate (though ACE inhibitors usually reduce
proteinuria). Particularly in patients with diabetics nephropathy, however, renal protein
excretion may also be reduced.
*TM* may cause, or contribute to a decline in serum sodium concentration, particularly
in conjunction with restricted salt intake. Hydrochlorothiazide may contribute or lead to
the development of hypochloraemia, hypomagnesaemia, as well as hypercalcaemia. In
addition, *TM* may contribute to the development or aggravation of a metabolic
alkalosis.
Ramipril may cause, or contribute to an increase in the concentration of serum potassium,
whereas hydrochlorothiazide may cause or contribute to a decrease in potassium
concentration. Thus, during therapy with *TM*, both a decline and an increase in the
concentration of serum potassium are possible, the latter effect being encountered mainly
in patients with impaired renal function (e.g. due to diabetic nephropathy) or where
potassium-retaining diuretics or potassium salts are administered concomitantly.
General signs of disturbances in the electrolyte balance include tiredness, headache,
drowsiness, sleepiness, confusion, apathy, muscle cramps, tetany, but also muscular
weakness, gastrointestinal disturbances and intensified thirst.
Particularly at the commencement of treatment, a transiently increased fluid excretion
may occur. This may be the expression of the diuretic effect of hydrochlorothiazide, but
also of cardiac recompensation. If fluid depletion develops – particularly in older
patients – haemoconcentration or, in especially severe cases, thromboses may occur.
Skin, blood vessels, anaphylactic and anaphylactoid reactions
Angioneurotic oedema occur rarely during treatment with *TM*. They are due to the
desired ACE inhibition, and necessitate immediate discontinuation of *TM* therapy;
other ACE inhibition of similar combination preparations are also ruled out in such cases.
Angioneurotic oedema, for example, of the tongue, throat of larynx may become lifethreatening
and necessitate emergency measures.
Milder non-angioneurotic oedema, e.g., involving the ankle, are also possible.
Uncommonly, pharmacologically mediated mild angioneurotic oedema may occur (the
incidence of ACE inhibitor angio-oedema seems to be increased in black, i.e. Afro-
Caribbean, patients as compared with non-black patients). Serious reactions of this type
and other, not pharmacologically mediated anaphylactic or anaphylactoid reactions to
ramipril or any of the other ingredients are rare.

In addition, the following cutaneous of mucosal reactions may occur, e.g., as
manifestations of an allergic reacton: reddening of skin areas with accompanying heat
sensation, conjunctivitis, pruritus and urticaria; rarely, reactions such as maculopapular
and lichenoid exanthema and enanthema, erythema multiform, Stevens-johnson
syndrome,toxic epidermal necrolysis alopecia, hypersensitivity of the skin to light ,and
precipitation or intensification of Raynaud’s phenomenon may also occur.
With other ACE inhibitors, pemphigus,exacerbation of psoriasis, psoriasiform or
pemphigoid exanthema and enanthema, and onycholysis have been observed.
Anaphylactic reactions to hydrochlorothiazide are possible.
In the event of pruritus with urticaria, the patient must inform a physician immediately.
The likelihood and the severity of anaphylactic and anaphylactoid reaction to insect
venoma is increased under the influence of ACE inhibitors. It is assumed that this effect
may also occur in conection with other allergens.
This must be considered when desensitization is performed.
Respiratory Tract
Due possibly to ACE inhibition, a dry (non-productive) tickling cough frequently occurs.
This is often worse at night and when the patient is lying down and occurs more
frequently in women and non-smokers. In some cases a changeover to another
ACE inhibitor is successful. However, the cough may force patients to stop taking ACE
inhibitors altogether.
Also possibly due to ACE inhibition, nasal congestion, rhinitis, sinusitis, bronchitis and,
especially in patients with tickling cough, bronchospasm and dyspnoea may occur.
Administration of hydrochlorothiazide may include pneumonitis and pulmonary oedema,
presumably due to an allergic reaction.
In the event dyspnoea develops or worsens, the patient must inform a physician
immediately.
Digestive tract,liver
Uncommonly, nausea, increases in serum levels of hepatic enzymes and/or bilirubin as
well as cholestatic jaundice may occur. Rarely, dryness of the mouth, glossitis,
inflammatory reactions of the oral cavity and gastrointestinal tract, abdominal discomfort,
gastric pain (including gastritic-like gastric pain), digestive disturbances, constipation,
diarrhoea, vomiting and increased levels of pancreatic enzymes may develop. In isolated
cases, pancreatitis, or liver damage (including acute liver failure) may occur.

Blood picture
The following blood picture changes may occur: a mild –severe reduction in the red
blood cell count and haemoglobin content (in isolated instances also due to haemolytic
anaemia) , blood platelet count and white blood cell count (even presenting as
neutropenia), agranulocytosis, bone marrow depression and pancytopenia.
Such changes of the blood picture are more likely to occur in patients with impaired
renal function and in patients with concomitant collagen disease (e.g. lupus
erythematosus or scleroderma) or in patients treated with other drugs that may cause
changes of the blood picture. See also under “Interactions” and “Special warning and
precautions”.
In isolated cases, haemolytic anaemia may develop.
Other adverse effects
Peripheral oedema, flushing,disturbances of balance, visual disorders, headache,
nervousness, restlessness, tremor, sleep disturbances, confusion, loss of appetite,
depressed mood, feeling of anxiety, paraesthesiae, taste change (e.g. metallic taste), taste
reduction and sometimes even loss of taste, smell disturbances, muscle cramps as well as
erectile impotence and reduced libido may occur.
The possibility of exacerbation of activation of systemic lupus erythmatosus has been
reported.
Vasculitis, myalgia, arthalgia, fever and eosinophilia may also occur. Raised titres of
antinuclear antibodies may occur . In temporal relationship with the administration of
hydrochlorothiazide, the development of a lupus erythematosus has been described.
During therapy with hydrochlorothiazide- and thus with *TM*- increased serum
concentrations of uric acid may occur. This may lead to gout attacks, particularly in those
patients whose uric acid levels are already elevated.
Hydrochlorothiazide may lower tolerance to glucose. In patients with diabetes mellitus,
this may lead to a deterioration of the metabolic control. A latent diabetes mellitus may
become manifest for the first time.
Hydrochlorothiazide may cause an increase in serum cholesterol and triglycerides.
13. OVERDOSE
Symptoms
Possible signs and symptoms of overdose included: persistent diuresis excessive
peripheral vasodilatation (with marked hypotension, shock), bradycardia, ,renal failure
electrolyte disturbances, cardiac arrhythmias, impairment of consciousness up to and
including coma, cerebral convulsions, pareses and paralytic ileus.

In patients with obstruction of urinary outflow (e.g. from prostatic hyperplasia), sudden
diuresis may induce acute urinary retention with overdistension of the bladder.
Management
The treatment given depends on how and when the drug was taken and on the type and
severity of symptoms.
Steps must be taken to eliminate any *TM* which has not yet been absorbed (e.g. gastric
lavage, administration of adsorbants, sodium sulfate, if possible during the first 30
minutes). Vital and organ functions must be monitored under intensive care conditions,
and safeguarded if necessary. Monitoring must also include frequent checks of water,
electrolyte and acid -base balance. In the event of hypotension administration of
α1-adrenergic agonists (e.g. norepinephrine, dopamine) and angiotensin II
(angiotensinamide) must be considered in addition to volume and salt substitution.
No experience is available concerning the efficacy of forced diuresis, altering urine pH,
haemofiltration or dialysis in speeding up the elimination of ramipril or ramipirilat. If
dialysis or haemofiltration is nevertheless contemplated, see also under
“Contraindications”.
Hydrochlorothiazide is dialyzable.
14. ABUSE AND DEPENDENCE
Not applicable.
15. PHARMACODYNAMICS
*TM* has antihypertensive and diuretic effects. Ramipiril and hydrochlorothiazide are
used singly or together for antihypertensive therapy. The antihpertensive effects of both
substances are complementary.
The blood-pressure-lowering effects of both components are approximately additive.
Whereas the loss of potassium which accompanies the action of hydrochlorothiazide is
attenuated through the use of ramipril.
Mode of action
Ramipril: Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme
dipepitdylcarboxypeptidase I (synonyms: angiotensin – converting enzyme, kininase II).
In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active
vasodilatator bradykinin.

Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to
vasodilatation.
Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a
reduction in aldosterone secretion. The increase in bradykinin activity probably
contributes to the cardioprotective and endothelioprotective effects observed in animal
experiments. It has not yet been established to what extent this is also responsible for
certain unwanted effects (e.g. tickling cough).
ACE inhibitors are effective even in patients with low-renin hypertension. The average
response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean)
hypertensive patients (usually a low-renin hypertensive population) than in non-black
patients.
Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. It inhibits the
reabsorption of sodium and chloride in the distal tubule. The increase renal excretion of
these ions is accompanied by increased urine output (due to osmotic binding of water).
Potassium and magnesium excretion are increased, uric acid excretion is decrease. High
doses lead to increased excretion of bicarbonates, and long-term treatment decreases the
excretion of calcium.
Possible mechanisms of the antihypertensive action of Hydrochlorothiazide could be: the
modified sodium balance, the reduction in extracellular water and plasma volume, a
change in renal vascular resistance as well as a reduced response to norepinephrine and
angiotensin II.
Pharmacodynamic characteristics
Ramipril: administration of ramipiril causes a marked reduction in peripheral arterial
resistance. Generally, these are no major changes in renal plasma flow and glomerular
filtration rate.
Administration of ramipril to patients with hypertension leads to a reduction in supine
and standing blood pressure without a compensatory rise in heart rate.
In most patients the onset of the antihypertensive effect of a single dose becomes
apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually
reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose
usually lasts for 24 hours.
The maximum antihypertensive effect of continued treatment with ramipril is generally
apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained
under long term therapy lasting 2 years.
Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound
increase in blood pressure.

Hydrochlorothiazide: Electrolyte and water excretion starts approx. 2 hours after
administration, reaches its peak after 3 to 6 hours and lasts from 6 to 12 hours.
The onest of the antihypertensive effect occurs after 3 to 4 days and can last up to one
week after discontinuation of therapy.
16. PHARMACOKINETICS
Ramiprill: The prodrug ramipril undergoes an extensive hepatic first pass metabolisim,
which is essential for the formation of the sole active metabolite ramiprilat (hydrolysis,
which occurs principally in the liver). In addition to this activation into ramiprilat,
ramipril is glucuronized and transformed into ramipril diketopiperazine (ester).
Ramiprilat is glucuronized as well and transformed into ramiprilat diketopiperazine
(acid).
As a result of this activation/metabolization of the prodrug, approx 20% of orally
administered ramipril is bioavailable.
The bioavailability of ramiprilat after oral administration of 2.5 and 5mg. Ramipril is
approx. 45% compared with its availability after intravenous administration of the same
doses.
Following oral administration of 10mg. Of radioactive labelled ramipiril, approx. 40% of
total radioactivity is excreted in faeces and approx. 60% in urine. After intravenous
administration of ramipril, approx. 50 to 60% of the doses have been detected in urine (as
ramipril and metabolites); aprox. 50% were eliminated apparently by non-renal routes.
Following intravenous administration of ramiprilat approx. 70% of the substance and its
metabolites have been found in urine – indicating non-renal ramiprilat elimination of
approx. 30% . After oral administration of 5mg ramipril in patients with drainage of the
bile ducts, approx. the same amount of ramipril and its metabolites was excreted in urine
and bile during the first 24 hours.
Approx. 80 to 90% of the metabolites in urine and bile have been identified as ramiprilat
of ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazine represented
approx. 10 to 20% of the total amount, whereas unmetabolized ramipril accounted for
approx. 2%.
Studies in lactating animals have shown that ramipril passes into the milk.
Ramipril is rapidly absorbed after oral administration. As measured by the recovery of
radioactivity in the urine, which represent only one of the elimination routes, absorption
of ramipril is at least 56% .Administration of ramipril at the same time as food has no
relevant effect on absorption.
Peak plasma concentrations of ramipril are reached within 1 hour after oral
administration. The elimination half-life of ramipril is approx. 1 hour. Peak plasma
concentrations of ramipirilat are reached 2 to 4 hours after oral administration of ramipril.
Plasma concentrations of ramiprilat decline in a polyphasic manner. The initial
distribution and elimination phase has a half-life of approx. 3 hours. It is followed by an

intermediate phase (half-life approx. 15 hours) and a terminal phase with very low
plasma ramiprilat concentrations and half-life of approx. 4 to 5 days.
This terminal phase is due to the slow dissociation of ramiprilat from the close but
saturable binding to ACE.
Despite this long terminal phase, a single daily dose of 2.5mg. ramipril of more yields
steady state plasma concentrations of ramiprilat after approx. 4 days. The “effective”
half-life, which is relevant for dosage, is 13 to 17 hours under multiple-dose conditions.
After intravenous administration the systematic distribution volume of ramipril is approx.
90 liters, and the relative systemic distribution volume of ramiprilat is approx. 500 liters.
In-vitro studies have shown an overall inhibitory constant of ramiprilat of 7 pmol/l and a
dissociation half-life of ramiprilat from ACE of 10.7 hours, which indicates high potency.
The protein-binding of ramipril and ramiprilat is approx. 73% and approx. 56%
respectively.
In healthy subjects aged between 65 and 76 years ramipril and ramiprilat kinetics are
similar to those in healthy young Subjects.
Renal excretion of ramiprilat is reduced in patients with impaired renal function, and
renal ramiprilat clearance is proportionally related to creatinine clearance. This results in
elevated plasma concentrations of ramiprilat, which decrease more slowly than in persons
with normal renal function.
When high doses (10mg.) of ramipril are administered, impairment of hepatic function
retards the activation of ramipril into ramiprilat, resulting in increased ramipril plasma
levels, and slows down the elimination of ramiprilat.
As in healthy persons and patients with hypertension, there was also no relevant
accumulation of ramipril and ramipirlat after oral administration of 5mg. ramipril once
daily over two weeks in patients with congestive heart failure.
Hydrochlorothiazide: Approx. 70% of hydrochlorothiazide is absorbed after oral
administration; the bioavailability of hydrochlorothiazide after oral administration is
approx. 70%
Peak plasma concentrations of 70 ng/ml were reached 1.5 to 4 hours after oral
administration of 12.5mg. of hydrochlorothiazide, peak concentrations of 142 ng/ml 2 to
5 hours after oral administration of 25mg. Hydrochlorothiazide, and peak concentrations
of 260 ng/ml 2 to 4 hours after oral intake of 50mg.
Hydrochlorothiazide. Approx. 40% hydrochlorothiazide is bound to plasma proteins.
Hydrochlorothiazide is excreted almost quantitatively (more than 95%) by renal route

in unchanged form. After oral administration of a single dose, 50 to 70% is excreted
within 24 hours. Detectable amounts of the substance appear in the urine as early as 60
minutes after intake.
The elimination half-life is 5 to 6 hours. In renal insufficiency excretion is reduced and
the half-life prolonged. Renal clearance of hydrochlorothiazide correlates closely with
creatinine clearance. In patients with glomerular filtration rates less than 10 ml/min only
10% of the administered dose was found in the urine. More recent studies indicate that
some of the drug is excreted via non-renal routes (bile).
Hydrochlorothiazide passes into breast milk in small quantities.
No relevant changes in the pharmacokinetics of hydrochlorothiazide have been noted in
liver cirrhosis. Studies on pharmacokinetics in patients with heart failure are not
available.
Ramipril + hydrochlorothiazide: Concurrent administration of ramipril and
hydrochlorothiazide has no influence on the bioavailability of the single components.
The fixed dose combination tablet of 5mg. Ramipril and 25mg. Hydrochlorothiazide and
the free combination of 5mg. Ramipril and 25 mg. Hydrochlorothiazide capsules may be
considered bioequivalent.
17. NON-CLINICAL SAFTEY DATA
Acute toxicity:
Ramipril: as it has an LD50 in excess of 10,000 mg/kg Body weight in mice and rats and
above 1000 mg/kg body weight in beagle hounds, oral administration of ramipril has
been found to be devoid of acute toxicity.
Hydrochlorothiazide: In studies on acute toxicity in mice, the LD50 (after oral
administration) was in excess of 10,000 mg/kg body weight and 884 mg/kg body weight
after intravenous administration.
In rats the acute LD50 oral administration was in excess of 10,000 mg/kg body weight,
and after intraperitoneal administration it was 3130 mg/kg body weight.
In rabbits the acute LD50 after intravenous administration was 461 mg/kg body weight
and in dogs it was approx. 1000 mg/kg body weight. Dogs tolerated 2000 mg/kg body
weight or more after oral administration without showing any signs of toxicity.
Ramipril + Hydrochlorothiazide: The oral LD50 in rats and mice is in excess of 10,000
m./kg body weight , i.e., the combination ramipril + Hydrochlorothiazide

(1:5) is totally devoid of acute toxicity. This is consistent with the results of acute
toxicity. This is consistent with the results of acute toxicity testing of the single
components.
Chronic toxicity
Ramipril: Studies involving chronic administration have been conducted in rats, dogs and
monkeys. In rats, daily doses of the order of 40 mg/kg body weight lead to shifts in
plasma electrolytes and to anaemia. At daily doses of 3.2 mg/kg body weight or higher
there was some evidence of changes in renal morphology (distal tubular atrophy).
However, these effects can be explained in pharmacodynamic terms and are characteristic
of the substance class. Daily doses of 2 mg/kg body weight have been tolerated by rats
without toxic effects. Tubular atrophy is encountered in rats, but not in dogs and
monkeys.
As an expression of the pharmacodynamic activity of ramipril (a sign of increased renin
production as a reaction to reduced angiotensin II formation) ,pronounced enlargement of
the juxtaglomerular apparatus has been noted in the dog and monkey – especially at daily
doses of 250 mg/kg body weight or higher. Indication of plasma electrolyte shifts and
changes in blood picture have also been found in the dog and monkey. Dogs and
monkeys tolerated daily doses of 2.5 mg/kg body weight and 8 mg/kg body weight
respectively without harmful effects.
Hydrochlorothiazide: Subchronic (subacute) oral toxicity studies in rats with 500, 1000
and 2000 mg/kg per body weight daily (five days a week over a total period of three
weeks) yielded no signs of a toxic drug effect: such fatalities as occurred were attributed
to pneumonia.
In studies conducted in dogs receiving 250, 500 and 1000 mg/kg per body weight daily
over a period of eight weeks, no serious effects of the drug were noted with the exception
of an imbalance in electrolytes.
Chronic toxicity studies in rats receiving oral doses of up to 2000 mg/kg per body weight
daily five days a week over a period of 26 weeks revealed no signs of a toxic drug effect
and no alterations attributable to the drug were noted during the drug were noted during
the post-mortem investigations.
Dogs received doses of 125,250 and 500 mg/kg per body weight daily over a period of 26
weeks (in the 500 mg. group, however, the medication was interrupted after the 7 th .
weeks for 11 weeks).
A slight reduction in plasma potassium occurred. Further, in the course of the
macroscopic investigation, small quantities of yellow crystalline precipitates were found
in the bladders of 2 of the 12 dogs. Histomorphological investigations revealed no
disturbances attributable to the drug.
Ramipril + Hydrochlorothiazide: with the exception of disturbances in electrolyte
balance, studies conducted in rats and monkeys yielded no conspicuous findings.

Reproduction toxicology
Ramipril: Reproduction toxicology studies in the rat, rabbit and monkey did not disclose
any teratogenic properties.
Fertility was not impaired either in male or in female rats.
The administration of ramipril to female rats during the fetal period and lactation
produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at
doses of 50 mg/kg body weight or higher.
When ACE inhibitors have been administered to women in the second and third trimester
of pregnancy, there have been reports of harmful effects on the fetus and newborn child,
including – sometimes in conjunction with oligohydramnios (presumably as an
expression of impaired fetal renal function) – craniofacial deformities, pulmonary
hypoplasias, fetal limb contractures, hypotension, anuria reversible and irreversible renal
failure as well as death. Prematurity, intrauterine growth retardation and persistence of
Botallo’s duct have also been reported in humans, although it is uncertain whether these
phenomena are a consequence of exposure to ACE inhibitors.
Hydrochlorothiazide: In animal studies, hydrochlorothiazide crosses the placenta.
Studies conducted in mice, rats and rabbits yielede no indication of teratogenic effect.
Experience is available in humans on the use of the drug in more than 7,500 pregnant
women. Of these, 107 had taken hydrochlorothiazide during the first trimester.
It is suspected that neonatal thrombopenia may develop following administration of
Hydrochlorothiazide in the second half of pregnancy.
It is possible that disturbances in electrolyte balance in pregnant women may effect the
fetus.
Ramipril + Hydrochlorothiazide: in studies on embryotoxicity, the combination was
administered during the sensitive phase of organogenesis: to rats in daily doses of 1, 10,
150, 600 or 2400 mg/kg body weight, and to rabbits in daily doses of 0.96, 2.40 or 6.00
mg/kg body weight.
Hydrochlorothiazide has been studies in a similar way alone at daily doses of 125,500 or
2000 mg/kg body weight in rats, and at a daily dose of 2 mg/kg body weight in rabbits;
these doses corresponded to the proportions of hydrochlorothiazide contained in the high
doses of the combination.
The studies in rats shows that dams tolerated the combination administered at dose levels
of 1 mg/kg and 10mg/km body weight without complications. Doses of 150 mg/kg body

weight and above showed toxic effects on dams and led to reduced food intake and
weight development. Heart and liver weights were reduced. Clinical symptoms of
toxicity and deaths occurred at dose levels of 2400 mg/kg body weight.
At dose levels of 150 mg/kg body weight and above, urine excretion increased and after
2400 mg/kg body weight kidney weights were slightly increased. These effects are
attributable to the pharmacodynamic action of hydrochlorothiazide.
1 mg/kg body weight does not impair the development of the embryo. Doses of
10 mg/kg body weight and above led to a slight retardation in development of the fetus,
which manifested itself in delayed skeletal ossification and, at dose levels of
150 mg/kg body weight and above, in reduced body weight and reduced body length.
Placenta weight was also reduced.
Morphological investigations conducted in fetuses revealed increased occurrences of
dilatation of the renal pelvis and the ureter as well as waved thickened ribs at dose levels
of 150 mg/kg body weight and above and, at levels of 600 mg/kg body weight and
above, bent and shortened scapula and bones of the limbs.
The studies with hydrochlorothiazide alone confirm that the retardation of fetal growth is
attributable to the diuretic. The other findings point to a joint effect of the two single
components in the combination.
Administration of the combination in rabbits at dose levels of 0.96mg/kg body weight led
to a slight reduction in food intake and stagnation in body weight. However , it had no
adverse effect on the intrauterine development in the progeny.
Following administration at dose levels of 2.40 and 6.00mg/kg body weight , the dams
reduced their intake of food and water and lost weight; furthermore ,deaths and
spontaneous abortions occurred at these dose levels and living fetuses showed slightly
retarded growth at birth. No signs of external anomalies or of anomalies affecting internal
organs and skeleton of the fetuses were detected which could be attributed to
administration of the combination.
Hydrochlorothiazide alone administered at daily doses of 2 mg/kg body weight was
tolerated by the dams and their fetuses.
The two studies in rats and rabbits revealed that the combination is somewhere more
toxic than either of the single components, but none of the studies revealed any signs of a
teratogenic effect of the combination or of hydrochlorothiazide.
Studies were conducted in rats to determine the peri-and postanal toxicity of the
combination doses of 10 and 60 mg/kg body weight daily were given orally during the
last third of pregnancy and during the 3 weeks of lactation. At doses of
10 mg/kg body weight, the drug neither had an adverse effect on the dams’general
condition, the course of pregnancy of parturition , nor did it lead to a disturbance of
intrauterine and postnatal development of the progeny.

After administration of 60 mg/kg body weight, the dams reduced food intake slightly, and
the pups showed slightly reduced weights at birth and during the first week thereafter. In
the subsequent period, the postnatal development of the pups turned up no conspicuous
findings. The incidence of dilatation of the renal pelvis (such as has been noted following
higher doses of ramipril) was not increased.
Studies on possible impairment of fertility and reproductive capability were not
conducted with the combination, since no toxic effect was to be excepted on the basis of
results in the single components.
Immunotoxicology
Ramipril: toxicology studies have yielded no indication that ramipril possesses any
immunotoxic effects.
Mutagenicity
Ramipril: Extensive mutagenicity testing using several test systems has yielded no
indication that ramipril possesses mutagenic or genotoxic properties.
Hydrochlorothiazide: there is limited evidence of genotoxicity of hydrochlorothiazide
In virto. It may be deduced from in vivo data that the substance is not mutagenic.
Ramipril + Hydrochlorothiazide: mutagenicity studies were not conducted with the
combination since the results of tests with each component alone have shown no
evidence of any such risk.
Carcinogenicity:
Ramipril: Long –term studies in rat and mouse have yielded to indication of any
tumorigenic effect.
Renal tubules with oxyphilic cells and tubules with oxyphilic cellular hyperplasia in rats
are regarded as respone to functional alterations and morphological changes, and not as a
neoplastic or pre-neoplastic respone.
Hydrochlorothiazide: A carcinogenicity study with hydrochlorothiazide in mice yielded
equivocal evidence of carcinogenic activity in male animals at high doses (in the form of
an increased incidence of hepatocellular neoplasis). There was no evidence of
carcinogenicity in female mice. A study with hydrochlorothiazide in male and female rats
also yielded no evidence of carcinogenic potential.
Summarizing these findings, it may be assumed that hydrochlorothiazide lacks any
neoplastic potential.

Ramipril + hydrochlorothiazide: carcinogenicity studies were not conducted with the
combination since the results of test with each component alone have shown no evidence
of any such risk.
Manufacturer: Aventis Pharma Germany.
Importer: Aventis Pharma Ltd., P.O.B. 8090, Netanya 42170.