TRITACE 1.25 MG

Israel - English - Ministry of Health

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Active ingredient:
RAMIPRIL
Available from:
SANOFI - AVENTIS ISRAEL LTD
ATC code:
C09AA
Pharmaceutical form:
TABLETS
Composition:
RAMIPRIL 1.25 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
SANOFI S.P.A., ITALY
Therapeutic group:
ACE INHIBITORS, PLAIN
Therapeutic indications:
Hypertension congestive heart failure reduction of mortality in patients after MI with left ventricular dysfunction. For reducing the risk of myocardial infarction stoke cardiovascular death or need for revascularization procedures in patients over 55 years or more who have clinical evidence of cardiovascular disease (previous MI unstable angina or multivessel CABG or multivessel PTCA) stroke or peripheral vascular disease. Also for reducing the risk of myocardial infarction stroke cardiovascular death or need for revascularization procedures in diabetic patients of 55 years or more who have one or more of the following clinical findings : hypertension (systolic blood pressure > 160 mmHg or diastolic pressure > 90 mmHg) high total cholesterol (>5.2 mmol/L) low HDL ( <0.9 mmol/L) current smoker known microalbuminuria clinical evidence of previous vascular disease. Prevention of progressive renal failure in patients with persistent proteinuria in excess of 1g/day.
Authorization number:
124 59 30412 00
Authorization date:
2012-01-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

26-02-2019

Tritace Comp 2.5/12.5

Tritace Comp 5/25

1. NAME OF THE MEDICINAL PRODUCT

Tritace Comp 2.5 mg/12.5 mg tablets

Tritace Comp 5 mg/25 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Tritace Comp 2.5 mg/12.5 mg

Each tablet contains 2.5 mg ramipril and 12.5 mg hydrochlorothiazide

Tritace Comp 5 mg/25 mg

Each tablet contains 5 mg ramipril and 25 mg hydrochlorothiazide

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet 2.5 mg/12.5 mg

White to almost white oblong tablet with score line, both sides embossed with HNV and

company logo. The tablet can be divided into equal halves.

Tablet 5 mg/25 mg

White to almost white oblong tablet with score line, both sides embossed with HNW and

company logo. The tablet can be divided into equal halves.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Essential hypertension.

Tritace comp is indicated in patients whose blood pressure cannot be adequately

lowered with ramipril alone.

4.2 Posology and method of administration

Posology

It is recommended that TRITACE COMP is taken once daily, at the same time of the

day, usually in the morning.

TRITACE COMP can be taken before, with or after meals, because food intake does not

modify its bioavailability (see section 5.2).

TRITACE COMP has to be swallowed with some liquid. The tablet must not be chewed

or crushed.

Adults

The dose should be individualised according to the patient profile (see section 4.4) and

blood pressure control. The administration of the fixed combination of ramipril and

hydrochlorothiazide is usually recommended after dosage titration with one of the

individual components.

TRITACE COMP should be started at the lowest possible dosage.

If necessary, the dose can be graduallly increased to achieve target blood pressure; the

maximum permitted doses are 10 mg of ramipril and 25 mg of hydrochlorothiazide daily.

Special populations

Patients treated with diuretics

Caution should be exercised in patients on diuretics, as hypotension may occur at the

start of therapy. Prior to initiating treatment with TRITACE COMP, a dose reduction or

discontinuation of the diuretic should be considered.

Should discontinuation not be possible, it is recommended that treatment be initiated

with the smallest possible dosage of 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.

Patients with renal impairment

TRITACE COMP is contraindicated in severe renal impairment due to the

hydrochlorothiazide component (creatinine clearance < 30 ml/min) (see section 4.3).

Patients with impairment of renal function may require reduced doses of TRITACE

COMP. Patients with creatinine clearance levels between 30 and 60 ml/min should only

be treated with the lowest fixed dose combination of ramipril and hydrochlorothiazide

after administration of ramipril alone. The maximum permitted doses are 5 mg of ramipril

and 25 mg of hydrochlorothiazide daily.

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment, treatment with TRITACE COMP

must be initiated only under close medical supervision and the maximum daily doses are

2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide.

TRITACE COMP is contraindicated in severe hepatic impairment (see section 4.3).

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual

because of greater chance of undesirable effects especially in very old and frail patients.

Paediatric population

TRITACE COMP is not recommended for use in children and adolescents below 18

years of age due to insufficient data on safety and efficacy.

Method of administration

Oral use.

4.3 Contraindications

Hypersensitivity to the active substance or to any other ACE (Angiotensin Converting

Enzyme) inhibitor, hydrochlorothiazide, other thiazide diuretics, sulfonamides or any

of the excipients listed in section 6.1.

History of angioedema (hereditary, idiopathic or due to previous angioedema with

ACE inhibitors or AIIRAs)

Concomitant use with sacubitril/valsartan therapy (see sections 4.4 and 4.5).

Extracorporeal treatments leading to contact of blood with negatively charged

surfaces (see section 4.5)

Significant bilateral renal artery stenosis or renal artery stenosis in a single

functioning kidney

and 3

trimester of pregnancy (see sections 4.4 and 4.6)

Lactation (see section 4.6)

Severe impairment of renal function with a creatinine clearance below 30 ml/min in

undialysed patients

Clinically relevant electrolyte disturbances which may worsen following treatment

with TRITACE COMP (see section 4.4)

Severe impairment of liver function

Hepatic encephalopathy

The concomitant use of TRITACE COMP with aliskiren-containing products is

contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60

ml/min/1.73 m

) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Special populations

Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor

Antagonists (AIIRAs) should not be initiated during pregnancy. Unless

continued ACE inhibitor/ AIIRAs 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/ AIIRAs should

be stopped immediately, and, if appropriate, alternative therapy should be

started (see sections 4.3 and 4.6).

Patients at particular risk of hypotension

- Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system 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 or a concomitant diuretic is given for the first

time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and

medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow

impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including

patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that

produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion

before initiating treatment (in patients with heart failure, however, such corrective action

must be carefully weighed out against the risk of volume overload).

- Patients at risk of cardiac or cerebral ischaemia in case of acute hypotension The initial

phase of treatment requires special medical supervision.

Primary Hyperaldosteronism

The combination ramipril + hydrochlorothiazide does not represent a treatment of choice

for primary hyperaldosteronism. If ramipril + hydrochlorothiazide is used in a patient with

primary hyperaldosteronism, then careful monitoring of plasma potassium level is

required.

Elderly

See section 4.2

Patients with liver disease

Electrolyte disturbances due to diuretic therapy including hydrochlorothiazide may cause

hepatic encephalopathy in patients with liver disease.

Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as

ramipril should be discontinued where possible one day before surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted

especially in the initial weeks of treatment. Particularly careful monitoring is required in

patients with renal impairment (see section 4.2). There is a risk of impairment of renal

function, particularly in patients with congestive heart failure or after renal transplant or

with renovascular disease including patients with haemodynamically relevant unilateral

renal artery stenosis.

Renal impairment

In patients with renal disease, thiazides may precipitate uraemia. Cumulative effects of

the active substance may develop in patients with impaired renal function. If progressive

renal impairment becomes evident, as indicated by a rising non-protein nitrogen, careful

reappraisal of therapy is necessary, with consideration given to discontinuing diuretic

therapy (see section 4.3).

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes

should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide,

can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia and

hypochloraemic alkalosis). Although hypokalaemia may develop with the use of thiazide

diuretics, concurrent therapy with ramipril may reduce diuretic-induced hypokalaemia.

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients

experiencing rapid diuresis, in patients who are receiving inadequate electrolytes and in

patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

The first measurement of plasma potassium levels should be carried out during the first

week following the start of treatment. If low potassium levels are detected, correction is

required.

Dilutional hyponatraemia may occur. Reduction in sodium levels can be initially

asymptomatic and regular testing is therefore essential. Testing should be more frequent

in elderly and cirrhotic patients.

Thiazides have been shown to increase the urinary excretion of magnesium, which may

result in hypomagnesaemia.

Electrolyte Monitoring: Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors

including TRITACE COMP. Patients at risk for development of hyperkalaemia include

those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those

using potassium salts, potassium retaining diuretics and other plasma potassium

increasing active substances or conditions such as dehydration, acute cardiac

decompensation, metabolic acidosis. If concomitant use of the above mentioned agents

is deemed appropriate, regular monitoring of serum potassium is recommended (see

section 4.5).

Electrolyte Monitoring: Hyponatremia

Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent

hyponatremia has been observed in some patients treated with ramipril. It is

recommended that serum sodium levels be monitored regularly in the elderly and in

other patients at risk of hyponatremia.

Hepatic Encephalopathy

Electrolyte disturbances due to diuretic therapy including hydrochlorothiazide may cause

hepatic encephalopathy in patients with liver disease. Treatment should be immediately

discontinued in case of hepatic encephalopathy.

Hypercalcaemia

Hydrochlorothiazide stimulates renal calcium reabsorption and may cause

hypercalcaemia. It may interfere with test for parathyroid function.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril

(see section 4.8). This risk of angioedema (e.g. swelling of the airways or tongue, with or

without respiratory impairment)

may be increased in patients taking concomitant

medications which may cause angioedema such as mTOR (mammalian target of

rapamycin) inhibitors (e.g. temsirolimus, everolimus, sirolimus), vildagliptin or neprilysin

(NEP) inhibitors (such as racecadotril). The combination of ramipril with

sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see

sections 4.3 and 4.5).

In case of angioedema TRITACE COMP must be discontinued. Emergency therapy

should be instituted promptly. Patient should be kept under observation for at least 12 to

24 hours and discharged after complete resolution of the

symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors

including TRITACE COMP (see section 4.8). These patients presented with abdominal

pain (with or without nausea or vomiting).

The intestinal angioedema symptoms resolved after stopping the ACE inhibitor.

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom

and other allergens are increased under ACE inhibition. A temporary discontinuation of

TRITACE COMP should be considered prior to desensitization

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis have been rarely seen and bone marrow depression has

also been reported. It is recommended to monitor the white blood cell count to permit

detection of a possible leucopoenia. 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), and all those treated with

other medicinal products that can cause changes in the blood picture (see sections 4.5

and 4.8).

Acute Myopia and Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in

acute transient myopia and acute angle-closure glaucoma. Symptoms include acute

onset of decreased visual acuity or ocular pain and typically occur within hours to weeks

of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision

loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible.

Prompt medical or surgical treatments may need to be considered if the intraocular

pressure remains uncontrolled. Risk factors for developing acute angle-closure

glaucoma may include a history of sulfonamide or penicillin allergy.

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black

patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in

black people than in non black patients, possibly because of a higher prevalence of

hypertension with low renin level in the black hypertensive population.

Athletes

Hydrochlorothiazide may produce a positive analytic result in the anti-doping test.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments

of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may

become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels have been associated with thiazide

diuretic therapy. Hyperuricaemia may occur or frank gout may be precipitated in certain

patients receiving thiazide therapy.

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.

Other

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial

asthma. The possibility of exacerbation or activation of systemic lupus erythematosus

has been reported.

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.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC)

and squamous cell carcinoma (SCC)] with increasing cumulative dose of

hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies

based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could

act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly

check their skin for any new lesions and promptly report any suspicious skin lesions.

Possible preventive measures such as limited exposure to sunlight and UV rays and, in

case of exposure, adequate protection should be advised to the patients in order to

minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined

potentially including histological examinations of biopsies. The use of HCTZ may also

need to be reconsidered in patients who have experienced previous NMSC (see also

section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

Clinical trial data has shown that dual blockade of the renin-angiotensin-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)

Contra-indicated combinations

The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this

increases the risk of angioedema (see sections 4.3 and 4.4). Treatment with ramipril

must not be started until 36 hours after taking the last dose of sacubitril/valsartan.

Sacubitril/valsartan must not be started until 36 hours after the last dose of TRITACE

COMP.

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 sulphate due to

increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is

required, consideration should be given to using a different type of dialysis membrane or

a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium

increasing active substances (including Angiotensin II antagonists, trimethoprim and in

fixed dose combination with sulfamethoxazole, tacrolimus, ciclosporin): Hyperkalaemia

may occur; therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood

pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake,

baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk

of hypotension is to be anticipated (see section 4.2 for diuretics).

Vasopressor sympathomimetics and other substances (epinephrine) that may reduce

the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.

Furthermore, the effect of the vasopressor sympathomimetics may be attenuated by

hydrochlorothiazide.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other

substances that may change the blood cell count: Increased likelihood of haematological

reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore

lithium toxicity may be increased. Lithium levels must be monitored. Concomitant use of

thiazide diuretics may increase the risk of lithium toxicity and enhance the already

increased risk of lithium toxicity with ACE inhibitors. The combination of ramipril and

hydrochlorothiazide with lithium is therefore not recommended.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur.

Hydrochlorothiazide may attenuate the effect of antidiabetic medicines. Particularly close

blood glucose monitoring is therefore recommended in the initial phase of co-

administration.

Nonsteroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the

antihypertensive effect of TRITACE COMP is to be anticipated. Furthermore,

concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of

worsening of renal function and to an increase in kalaemia.

Oral anticoagulants: Anticoagulant effect may be decreased due to concomitant use of

hydrochlorothiazide.

Corticosteroids, ACTH, amphotericin B, carbenoxolone, large amounts of liquorice,

laxatives (in case of a prolonged use), and other kaliuretic or plasma potassium

decreasing agents: Increased risk of hypokalaemia.

Digitalis preparations, active substances known to prolong the QT interval and

antiarrhythmics: Their proarrhythmic toxicity may be increased or their antiarrhythmic

effect decreased in the presence of electrolyte disturbances (e.g. hypokalaemia,

hypomagnesaemia).

Methyldopa: Haemolysis possible.

Colestyramine or other enterally administered ion exchangers: Reduced absorption of

hydrochlorothiazide. Sulphonamide diuretics should be taken at least one hour before or

four to six hours after these medications.

Curare-type muscle relaxants: Possible intensification and prolongation of the muscular

relaxing effect.

Calcium salts and plasma calcium increasing medicinal products: Rise in serum calcium

concentration is to be anticipated in case of concomitant administration of

hydrochlorothiazide; therefore close monitoring of serum calcium is required.

Carbamazepine: Risk of hyponatraemia due to additive effect with hydrochlorothiazide.

Iodine containing contrast media: In case of dehydration induced by diuretics including

hydrochlorothiazide, there is increased risk of acute renal impairment, in particular when

use of important doses of iodine containing contrast media.

Penicillin: Hydrochlorothiazide is excreted in the distal tubulus, and reduces excretion of

penicillin.

Quinine: Hydrochlorothiazide reduces quinine excretion.

Heparin: Rise in serum potassium concentration possible.

mTOR inhibitors or vildagliptin:

An increased risk of angioedema is possible in patients

taking concomitant medications such as mTOR inhibitors (e.g. temsirolimus, everolimus,

sirolimus) or vildagliptin. Caution should be used when starting therapy (see section 4.4).

Neprilysin (NEP) inhibitors: An increased risk of angioedema has been reported with

concomitant use of ACE inhibitors and NEP inhibitor such as racecadotril (see section

4.4)

Sacubitril/valsartan

The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this

increases the risk of angioedema.

4.6 Fertility, pregnancy and lactation

Pregnancy

TRITACE COMP is not recommended during the first trimester of pregnancy (see

section 4.4) and contraindicated during the second and third trimesters of pregnancy

(see section 4.3).

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 inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the

second and third trimesters is known to induce human fetotoxicity (decreased renal

function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal

failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should

exposure to ACE inhibitor have occurred from the second trimester of pregnancy,

ultrasound check of renal function and skull is recommended. Newborns whose mothers

have taken ACE inhibitors should be closely observed for hypotension, oliguria and

hyperkalaemia (see also sections 4.3 and 4.4).

Hydrochlorothiazide, in cases of prolonged exposure during the third trimester of

pregnancy, may cause a foeto-placental ischaemia and risk of growth retardation.

Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been

reported in case of exposure near term. Hydrochlorothiazide can reduce plasma volume

as well as the uteroplacental blood flow.

Breast-feeding

TRITACE COMP is contraindicated during breast-feeding.

Ramipril and hydrochlorothiazide are excreted in breast milk to such an extent that

effects on the suckling child are likely if therapeutic doses of ramipril and

hydrochlorothiazide are administered to breast-feeding women. Insufficient information is

available regarding the use of ramipril during breast-feeding and alternative treatments

with better established safety profiles during breast-feeding are preferable, especially

while nursing a newborn or preterm infant. Hydrochlorothiazide is excreted in human

milk. Thiazides during breast-feeding by lactating mothers have been associated with a

decrease or even suppression of lactation. Hypersensitivity to sulphonamide-derived

active substances, hypokalaemia and nuclear icterus might occur. Because of the

potential for serious reactions in nursing infants from both active substances, a decision

should be made whether to discontinue nursing or to discontinue therapy taking account

of the importance of this therapy to the mother.

4.7 Effects on ability to drive and use machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as

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).

This can happen especially at the start of treatment, or when changing over from other

preparations. After the first dose or subsequent increases in dose it is not advisable to

drive or operate machinery for several hours.

4.8 Undesirable effects

Summary of safety profile

The safety profile of ramipril + hydrochlorothiazide includes adverse reactions occurring

in the context of hypotension and/or fluid depletion due to increased diuresis. The

ramipril active substance may induce persistent dry cough, while the hydrochlorothiazide

active substance may lead to worsening of glucose, lipid and uric acid metabolism. The

two active substances have inverse effects on plasma potassium. Serious adverse

reactions include angioedema or anaphylactic reaction, renal or hepatic impairment,

pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Tabulated list of adverse reactions

Adverse reactions frequency is defined using the following convention:

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).

Within each frequency grouping, undesirable effects are presented in order of

decreasing seriousness.

Common

Uncommon

Very rare

Not known

Neoplasms

benign,

malignant and

unspecified

(incl cysts and

polyps)

Non-melanoma

skin cancer*

(Basal cell

carcinoma and

Squamous cell

carcinoma)

Non-melanoma

skin cancer: Based

on available data

from

epidemiological

studies, cumulative

dose-dependent

association

between HCTZ

and NMSC has

been observed

(see also sections

4.4 and 5.1).

Blood and

lymphatic

system

disorders

White blood cell

count

decreased, red

blood cell count

Bone marrow

failure,

neutropenia

including

decreased,

haemoglobin

decreased,

haemolytic

anaemia,

platelet count

decreased

agranulocytosis,

pancytopenia,

eosinophilia,

haemoconcentratio

n in the context of

fluid depletion

Immune system

disorders

Anaphylactic or

anaphylactoid

reactions to either

ramipril or

anaphylactic

reaction to

hydrochlorothiazid

e, antinuclear

antibody increased

Endocrine

disorders

Syndrome of

inappropriate

antidiuretic

hormone

secretion (SIADH)

Metabolism and

nutrition

disorders

Diabetes

mellitus

inadequate

control,

glucose

tolerance

decreased,

blood glucose

increased,

blood uric acid

increased,

gout

aggravated,

blood

cholesterol

and/or

triglycerides

increased due

hydrochlorothi

azide

Anorexia,

decreased

appetite

Blood

potassium

decreased,

thirst due to

hydrochlorothia

zide

Blood

potassium

increased due

to ramipril

Blood sodium

decreased

Glycosuria,

metabolic

alkalosis,

hypochloraemia,

hypomagnesaemia

, hypercalcaemia,

dehydration due to

hydrochlorothiazid

Psychiatric

disorders

Depressed

mood, apathy,

anxiety,

nervousness,

sleep disorders

including

somnolence

Confusional state,

restlessness,

disturbance in

attention

Nervous system

Headache,

Vertigo,

Cerebral

disorders

dizziness

paraesthesia,

tremor, balance

disorder,

burning

sensation,

dysgeusia,

ageusia

ischaemia

including

ischaemic stroke

and transient

ischaemic attack,

psychomotor skills

impaired, parosmia

Eye disorders

Visual

disturbance

including

blurred vision,

conjunctivitis

Xanthopsia,

lacrimation

decreased due to

hydrochlorothiazid

e; Secondary

acute angle-

closure glaucoma

and/or acute

myopia due to

hydrochlorothiazid

Ear and

labyrinth

disorders

Tinnitus

Hearing impaired

Cardiac

disorders

Myocardial

ischaemia

including

angina pectoris,

tachycardia,

arrhythmia,

palpitations,

oedema

peripheral

Myocardial

infarction

Vascular

disorders

Hypotension,

orthostatic

blood pressure

decreased,

syncope,

flushing

Thrombosis in the

context of severe

fluid depletion,

vascular stenosis,

hypoperfusion,

Raynaud’s

phenomenon,

vasculitis

Respiratory,

thoracic and

mediastinal

disorders

Non-productive

tickling cough,

bronchitis

Sinusitis,

dyspnoea,

nasal

congestion

Bronchospasm

including asthma

aggravated

Alveolitis allergic,

non cardiogenic

pulmonary

oedema due to

hydrochlorothiazid

Gastrointestinal

disorders

Gastrointestinal

inflammation,

Vomiting,

aphtous

Pancreatitis (cases

of fatal outcome

digestive

disturbances,

abdominal

discomfort,

dyspepsia,

gastritis,

nausea,

constipation

Gingivitis due to

hydrochlorothia

zide

stomatitis,

glossitis,

diarrhoea,

abdominal

pain upper,

dry mouth

have been very

exceptionally

reported with ACE

inhibitors),

pancreatic

enzymes

increased, small

bowel angioedema

Sialoadenitis due

hydrochlorothiazid

Hepatobiliary

disorders

Cholestatic or

cytolytic

hepatitis (fatal

outcome has

been very

exceptional),

hepatic enzyme

and/or bilirubin

conjugated

increased

Calculous

cholecystitis

due to

hydrochlorothia

zide

Acute hepatic

failure, jaundice

cholestatic,

hepatocellular

damage

Skin and

subcutaneous

tissue disorders

Angioedema:

very

exceptionally,

the airway

obstruction

resulting from

angioedema

may have a

fatal outcome;

dermatitis

psoriasiform,

hyperhidrosis,

rash, in

particular

maculo-papular,

pruritus,

alopecia

Toxic epidermal

necrolysis,

Stevens-Johnson

syndrome,

erythema

multiforme,

pemphigus,

psoriasis

aggravated,

exfoliative

dermatitis,

photosensitivity

reaction,

onycholysis,

pemphigoid or

lichenoid

exanthema or

enanthema,

urticaria

Systemic lupus

erythematosus due

hydrochlorothiazid

Musculoskeletal

and connective

tissue disorders

Myalgia

Arthralgia, muscle

spasms

Muscular

weakness,

musculoskeletal

stiffness, tetany

due to

hydrochlorothiazid

Renal and

urinary

disorders

Renal

impairment

including renal

failure acute,

urine output

increased,

blood urea

increased,

blood

creatinine

increased

Worsening of a

pre-existing

proteinuria

Interstitial nephritis

due to

hydrochlorothiazid

Reproductive

system and

breast disorders

Transient

erectile

impotence

Libido decreased,

gynaecomastia

General

disorders and

administration

site conditions

Fatigue,

asthenia

Chest pain,

pyrexia

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.

Any suspected adverse events should be reported to the Ministry of Health according to

the National Regulation by using an online form

https://sideeffects.health.gov.il/

4.9 Overdose

Symptoms

Symptoms associated with overdosage of ACE inhibitors may include excessive

peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte

disturbances, renal failure, cardiac arrhythmia, impairment of consciousness including

coma, cerebral convulsions, pareses, and paralytic ileus.

In predisposed patients (e.g. prostatic hyperplasia) hydrochlorothiazide overdose may

induce acute urinary retention.

Management

The patient should be closely monitored and the treatment should be symptomatic and

supportive. Suggested measures include primary detoxification (gastric lavage,

administration of adsorbents) and measures to restore haemodynamic stability, including

administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide)

administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the

general circulation by haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors and diuretics, ramipril and diuretics

code C09BA05

Mechanism of action

Ramipril

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme

dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II).

In plasma and tissue, this enzyme catalyses the conversion of angiotensin I to the active

vasoconstrictor substance angiotensin II, as well as the breakdown of the active

vasodilator 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 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. The mechanism of antihypertensive effect of

thiazide diuretics is not fully known. It inhibits the reabsorption of sodium and chloride in

the distal tubule. The increased 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 decreased. 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 effects

Ramipril

Administration of ramipril causes a marked reduction in peripheral arterial resistance.

Generally, there 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

With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at

about 4 hours, while the action persists for approximately 6 to 12 hours.

The onset of the antihypertensive effect occurs after 3 to 4 days and can last up to one

week after discontinuation of therapy.

The blood-pressure-lowering effect is accompanied by slight increases in the filtration

fraction, renal vascular resistance and plasma renin activity.

Clinical efficacy and safety

Concomitant administration of ramipril-hydrochlorothiazide

In clinical trials, the combination led to greater reductions in blood pressure than when

either of the products was administered alone. Presumably through blockade of the

renin-angiotensin-aldosterone system, co-administration of ramipril to

hydrochlorothiazide tends to reverse the potassium loss associated with these diuretics.

Combination of an ACE-inhibitor with a thiazide diuretic produces a synergistic effect

and also lessens the risk of hypokalaemia provoked by the diuretic alone.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in

combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans

Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-

inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or

cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-

organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus

and diabetic nephropathy. These studies have shown no significant beneficial effect on

renal

and/or

cardiovascular

outcomes

mortality,

while

increased

risk

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

adverse

events

serious

adverse

events

interest

(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in

the aliskiren group than in the placebo group.

Non-melanoma skin cancer:

Based on available data from epidemiological studies, cumulative dose-dependent

association between HCTZ and NMSC has been observed. One study included a

population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to

1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥ 50,000 mg

cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC

and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship

was observed for both BCC and SCC. Another study showed a possible association

between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched

with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-

response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6)

increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the

highest cumulative dose (~100,000 mg) (see also section 4.4).

5.2 Pharmacokinetic properties

Ramipril

Absorption

Following oral administration ramipril is rapidly absorbed from the gastrointestinal tract;

peak plasma concentrations of ramipril are reached within one hour. Based on urinary

recovery, the extent of absorption is at least 56 % and is not significantly influenced by

the presence of food in the gastrointestinal tract. The bioavailability of the active

metabolite ramiprilat after oral administration of 2.5 mg and 5 mg ramipril is 45 %.

Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril are

reached 2-4 hours after ramipril intake. Steady-state plasma concentrations of ramiprilat

after once daily dosing with the usual doses of ramipril are reached by about the fourth

day of treatment.

Distribution

The serum protein binding of ramipril is about 73 % and that of ramiprilat about 56 %.

Biotransformation

Ramipril is almost completely metabolised to ramiprilat, and to the diketopiperazine

ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.

Elimination

Excretion of the metabolites is primarily renal. Plasma concentrations of ramiprilat

decline in a polyphasic manner. Because of its potent, saturable binding to ACE and

slow dissociation from the enzyme, ramiprilat shows a prolonged terminal elimination

phase at very low plasma concentrations. After multiple once-daily doses of ramipril, the

effective half-life of ramiprilat concentrations was 13-17 hours for the 5-10 mg doses and

longer for the lower 1.25-2.5 mg doses. This difference is related to the saturable

capacity of the enzyme to bind ramiprilat. A single oral dose of ramipril produced an

undetectable level of ramipril and its metabolites in breast milk. However, the effect of

multiple doses is not known.

Patients with renal impairment (see section 4.2).

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

subjects with normal renal function.

Patients with liver impairment (see section 4.2).

In patients with impaired liver function, the metabolism of ramipril to ramiprilat was

delayed due to diminished activity of hepatic esterases, and plasma ramipril levels in

these patients were increased. Peak concentrations of ramiprilat in these patients,

however, are not different from those seen in subjects with normal hepatic function.

Hydrochlorothiazide

Absorption

Following oral administration about 70 % of hydrochlorothiazide is absorbed from the

gastrointestinal tract. Peak plasma concentrations of hydrochlorothiazide are reached

within 1.5 to 5 hours.

Distribution

The plasma protein binding of hydrochlorothiazide is 40 %.

Biotransformation

Hydrochlorothiazide undergoes negligible hepatic metabolism.

Elimination

Hydrochlorothiazide is eliminated almost completely (> 95 %) in an unchanged form

through the kidneys; 50 to 70 % of a single oral dose is eliminated within 24 hours. The

elimination half-life is 5 to 6 hours.

Patients with renal impairment (see section 4.2)

Renal excretion of hydrochlorothiazide is reduced in patients with impaired renal

function, and renal hydrochlorothiazide clearance is proportionally related to creatinine

clearance. This results in elevated plasma concentrations of hydrochlorothiazide, which

decrease more slowly than in subjects with normal renal function.

Patients with liver impairment (see section 4.2)

In patients with hepatic cirrhosis the pharmacokinetics of hydrochlorothiazide has not

changed significantly. The pharmacokinetics of hydrochlorothiazide has not been studied

in patients with cardiac failure.

Ramipril and Hydrochlorothiazide

The concurrent administration of ramipril and hydrochlorothiazide does not affect their

bioavailability. The combination product can be considered as bioequivalent to products

containing the individual components.

5.3 Preclinical safety data

In rats and mice the combination of ramipril and hydrochlorothiazide has no acute toxic

activity up to 10,000 mg/kg. Repeated doses administration studies performed in rats

and monkeys revealed only disturbances in electrolytes balance.

No studies on mutagenicity and carcinogenicity have been performed with the

combination as studies with individual components showed no risk.

Reproduction studies in rats and rabbits revealed that the combination is somewhat

more toxic than either of the single components but none of the studies revealed a

teratogenic effect of the combination.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pregelatinized starch, microcrystalline cellulose, hydroxypropylmethylcellulose and

sodium stearyl fumarate.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4 Special precautions for storage

Store below 25°C.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

2.5 mg/12.5 mg: packs of 14, 28 tablets in PVC/Alu blisters

5 mg/25 mg: packs of 14, 28 tablets in PVC/Alu blisters

Not all pack sizes may be marketed.

7. MANUFACTURER

Sanofi S.P.A., Italy

8. MARKETING AUTHORISATION HOLDER

Sanofi - aventis Israel Ltd., POB 8090 NETANYA 4250499

Revised on June 2020.

וא יפונאס

ןואג ינב 'חר ,לארשי סיטנ

ופ קראפ , .ד.ת ,גל

8090

םורד הינתנ ,

42504

לט

09-8633700

סקפ

09-8851444

רבמצד

2019

:רישכתה םש

Tritace 1.25 mg tablets

Tritace 2.5 mg tablets

Tritace 5 mg tablets

ה/אפור ,ה/דבכנ ת/חקור

תרבח יפונאס

עידוהל תשקבמ מ"עב לארשי סיטנווא ןולעב ןוכדע לע

אפורל

םירישכתה לש

.ןודנבש

ליעפ רמוח

המאתהב הליכמ הילבט לכ

1.25 / 2.5 / 5 mg

Ramipril

היוותה תרשואמ

:

Hypertension congestive heart failure reduction of mortality in patients after MI with left ventricular

dysfunction.

For reducing the risk of myocardial infarction stroke cardiovascular death or need for

revascularization procedures in patients over 55 years or more who have clinical evidence of

cardiovascular disease (previous MI unstable angina or multivessel CABG or multivessel PTCA)

stroke or peripheral vascular disease.

Also for reducing the risk of myocardial infarction stroke cardiovascular death or need for

revascularization procedures in diabetic patients of 55 years or more who have one or more of

the following clinical findings :

hypertension (systolic blood pressure > 160 mmHg or diastolic pressure > 90 mmHg) high total

cholesterol (>5.2 mmol/L) low HDL ( <0.9 mmol/L) current smoker known microalbuminuria

clinical evidence of previous vascular disease.

Prevention of progressive renal failure in patients with persistent proteinuria in excess of 1g/day.

.ןוכדע השענ םהב םיפיעסה יתת קר םיטרופמ וז העדוהב

ןלהל ףסונש עדימ קוריב ןמוסמ

וא יפונאס

ןואג ינב 'חר ,לארשי סיטנ

ופ קראפ , .ד.ת ,גל

8090

םורד הינתנ ,

42504

לט

09-8633700

סקפ

09-8851444

ןוכדעה :אפורל ןולעב

4.4 Special warnings and precautions for use

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see

section 4.8).

This risk of angioedema (e.g. swelling of the airways or tongue, with or

without respiratory impairment) may be increased in patients taking concomitant

medications which may cause angioedema such as mTOR (mammalian target of

rapamycin) inhibitors (e.g. temsirolimus, everolimus, sirolimus) vildagliptin or neprilysin

(NEP) inhibitors (such as racecadotril)

ולעה

ןכדועמה אפורל

תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל חלשנ

לבקל ןתינ

םושירה לעבל היינפ ידי לע ספדומ

יפונאס

ןואג ינב 'חר ,מ"עב לארשי סיטנווא

וא הינתנ :ןופלטב

09-8633700

:תואירבה דרשמ רתאל רושיקה ןלהל

https://data.health.gov.il/drugs/index.html#!/byDrug

,הכרבב

יפונאס

מ"עב לארשי סיטנווא

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