Special Warning : אזהרת שימוש

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.

Acute Respiratory Toxicity
Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension.
If diagnosis of ARDS is suspected, Tritace comp should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

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).

Choroidal effusion, acute Myopia and Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in Choroidal effusion with visual field defect, 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).


Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects on Driving

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.