Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use
Hyperkalaemia has been observed in patients receiving amiloride hydrochloride, either alone or with other diuretics, particularly in the aged and in diabetics. It has been 
reported in seriously ill hospital patients with hepatic cirrhosis or congestive heart failure with renal impairment, or were undergoing vigorous diuretic therapy.

Such patients should be carefully observed for clinical, laboratory and ECG evidence of hyperkalaemia (not always associated with an abnormal ECG). Some deaths have been reported in this group of patients.

Due to the risk of hyperkalemia, use with caution and monitor serum potassium levels frequently, if concomitant use with any other medicinal product known to cause elevated potassium levels is indicated.

Treatment of hyperkalaemia: Should hyperkalaemia develop, discontinue Kaluril treatment immediately and, if necessary, take active measures taken to reduce the serum potassium to normal.

Impaired renal function: Renal function should be monitored carefully for serum electrolytes and blood urea levels, as should seriously ill patients, such as those with hepatic cirrhosis with ascites and metabolic alkalosis or those with resistant oedema who are also taking diuretics because the use of Kaluril in impaired renal function may result in the rapid development of hyperkalaemia. Thiazide diuretics become ineffective when creatinine clearance falls below 30 ml/min.

Electrolyte imbalance and blood urea increases: Although the likelihood of electrolyte imbalance is reduced with Kaluril, careful check should be kept for such signs of fluid and electrolyte imbalance as hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia, particularly in the elderly and in patients receiving long-term therapy. It is particularly important to make serum and urine electrolyte determinations when the patient is vomiting excessively or receiving parenteral fluids.

Warning signs or symptoms of fluid or electrolyte imbalance include: dryness of the mouth, weakness, lethargy, drowsiness, restlessness, seizures, confusion, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastro-intestinal disturbances such as nausea and vomiting (see also 4.8 Undesirable Effects, Electrolyte Imbalance).
Hypokalaemia may develop, especially as a result of brisk diuresis, after prolonged therapy or when severe cirrhosis is present. Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability). A potassium chloride supplement is recommended in these circumstances, however, neither potassium supplements nor a potassium-rich diet should be used with Kaluril except under careful monitoring in severe and/or refractory cases of hypokalaemia. Potassium conserving therapy should be initiated with caution in severely ill patients in whom metabolic or respiratory acidosis may occur, e.g. patients with decompensated diabetes or cardiopulmonary disease. Shifts in acid base balance alter the balance of extracellular/intracellular potassium. The development of acidosis may be associated with rapid increases in serum potassium. Potassium replacement or conservation is also likely to be necessary in patients at risk from the cardiac effects of hypokalaemia such as those with severe heart disease, those taking cardiac glycosides preparations or high doses of diuretics and in patients with severe liver disease.
Potassium supplements should not be given in renal insufficiency complicated by hyperkalaemia. Potassium supplementation alone may not be sufficient to correct hypokalaemia in patients who are also deficient in magnesium. Magnesium depletion 
has also been implicated as a risk factor for arrhythmias.

Some patients may be particularly susceptible to hyponatraemia, including the elderly and those with severe heart failure who are very oedematous, particularly with large doses of thiazides in conjunction with restricted salt in the diet. Diuretic-induced hyponatraemia is usually mild and asymptomatic. It may become severe and symptomatic in a few patients who will then require immediate attention and appropriate treatment.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Therapy should be discontinued before carrying out tests for parathyroid function.

In seriously ill patients, reversible increases in blood urea have been reported accompanying vigorous diuresis, hepatic cirrhosis, ascites and metabolic alkalosis or those with resistant oedema. Serum electrolyte and blood urea levels should be carefully monitored in these patients. Kaluril should be used with caution in patients with renal impairment. Special care should be taken to avoid cumulative or toxic effects due to a reduced excretion of its components (see 4.3 Contraindications).

Uraemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing uraemia and oliguria develop during treatment, Kaluril should be discontinued.

Hepatic disease: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease (see 4.3 'Contraindications'), since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. As a result of associated aldosteronism, oral diuretic therapy is more frequently accompanied by adverse reactions in patients with hepatic cirrhosis and ascites because these patients are intolerant of acute shifts in electrolyte balance (which may precipitate hepatic coma) and because they often have pre-existing hypokalaemia (see 4.8 Undesirable Effects).

Metabolic: Hyperuricaemia may occur, or gout may be precipitated or aggravated in certain patients receiving thiazides (see 4.8 Undesirable Effects, Metabolic subsection).
Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated by therapy with Kaluril (see 4.3 'Contraindications'). Dosage adjustment of antidiabetic agents, including insulin, may be required.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

To minimise the risk of hyperkalaemia in diabetic or suspected diabetic patients, the status of renal function should be determined before initiating therapy with Kaluril.
Therapy should be discontinued at least three days before giving a glucose tolerance test. Potassium-conserving therapy should be initiated only with caution in severely ill patients in whom metabolic or respiratory acidosis may occur, e.g., patients with cardiopulmonary disease or patients with inadequately controlled diabetes.

Shifts in acid-base balance alter the balance of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in plasma potassium.


Sensitivity reactions: The possibility that thiazides may activate or exacerbate systemic lupus erythematosus has been reported.

Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. Caution is required in patients with severe asthma, as hypokalaemia associated with beta 2 -agonist therapy can be potentiated by concurrent use of diuretics.

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 minimise 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).

Choroidal effusion, acute myopia and secondary angle-closure glaucoma: Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, 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 drug intake 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.

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, Kaluril should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Excipients with known effect
Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Sunset yellow FCF
This medicine contains Sunset yellow FCF, which may cause allergic reactions.

Effects on Driving

4.7     Effects on ability to drive and use machines
Patients may experience side-effects such as headache, visual disturbances, weakness, fatigue, dizziness, stupor and vertigo. Should any of these occur, the patient should be cautioned not to drive or operate machinery.