There is no specific antidote to xipamide. Acute intoxications express themselves especially with disturbances in the electrolytes and fluid balance (hyponatraemia, hypokalaemia). Clinical symptoms such as nausea, vomiting, drop in blood pressure, convulsions, dizziness, somnolence, confusional state, polyuria or oliguria and anuria (due to hypovolaemia) may occur.
Emergency procedures: detoxification by administering activated charcoal; subsequently restoration of a normal water and electrolytes balance in a specialized centre.
Gastric lavage or induced emesis may prevent further absorption. General measures should be aimed at the maintenance of blood pressure, restoration of blood volume and correction of electrolyte imbalance with appropriate intravenous infusion as required.
Aquaphoril is contra-indicated in severe electrolyte deficiency, precomatose states associated with liver cirrhosis, severe renal insufficiency, hypersensitivity to xipamide, untreated Addisons disease, hypercalcaemia, pre-existing hypovolaemia, symptomatic hyperuricaemia, pregnancy and lactation.
None known.
With thiazide diuretics and drugs related to these including xipamide, the following undesirable effects may occur. Regarding clinical and chemical parameters the majority of undesirable effects are dose-dependent
In case of excessive diuresis, haemoconcentration may occur as a result of hypovolaemia as well as convulsions, somnolence, confusional state and circulatory collapse in rare cases.
Rarely, anaphylactoid reactions may occur.
A latent diabetes mellitus may manifest. In patients with diabetes mellitus, glucose levels may be increased.
With high dosages the risk of thrombosis and embolism is increased, particularly with previous existing venous disorders.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/l0), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (> 1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports, not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Very rare: Thrombocytopenia, leukopenia, agranulocytosis, aplastic anaemia (discontinuation of therapy)
Metabolism and nutrition disorders
Rare: Hyperlipidaemia
Psychiatric disorders
Common: Lethargy, anxiety, agitation
Nervous system disorders
Common: Headache, dizziness, dry mouth, fatigue, sweating
Eye disorders
Rare: Minor visual disturbances, aggravation of existing myopia (discontinuation of therapy)
Cardiac disorders
Common: Palpitation
Vascular disorders
Common: Orthostatic hypotension
Gastrointestinal disorders
Common: Upper abdominal discomfort, cramping abdominal pain, diarrhoea, constipation
Rare: Haemorrhagic pancreatitis (discontinuation of therapy)
Hepatobiliary disorders
Rare: Acute cholecystitis in case or pre-existing cholelithiasis (discontinuation of therapy)
Very rare: Jaundice (icterus)
Skin and subcutaneous tissue disorders
Uncommon: Photosensitivity reactions
Rare: Allergic skin reactions (pruritus, erythema, urticarial) (discontinuation of therapy)
Musculoskeletal and connective tissue disorders
Common: Muscle spasms/cramps
Renal and urinary disorders
Very common: Hypokalaemia which may become apparent with symptoms such as nausea, vomiting, ECG changes, increased sensitivity to glycosides, arrhythmia or hypotonia of the skeletal muscles.
Common: Disturbances in the electrolytes and water balance, such as dehydration, hyponatraemia, hypomagnesaemia, hypochloremic alkalosis. Reversible increase in nitrogenous, urinary excreted substances (urea, creatinine), particularly at the beginning of treatment. Increase in serum uric acid level and triggering acute gouty arthritis in predisposed patients.
Very rare: Acute interstitial nephritis.
Therapy should be discontinued in case of:
- therapy-resistant disorder in the electrolytes balance
- orthostatic regulatory disorders
- hypersensitivity reactions
- distinct gastrointestinal complaints
- central nervous disturbances
- pancreatitis
- changes in blood count (anaemia, leukopaenia, thrombocytopenia)
- acute cholecystitis
- occurrence of vasculitis
- aggravation of existing myopia
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard
Not relevant.
For treatment of hypertension, either alone or as an adjunct to treatment with anti-hypertensive drugs.
For use as a diuretic.
Xipamide is an anti-hypertensive diuretic which can be characterised pharmacologically neither as a thiazide nor as a specific loop diuretic. Although structurally similar to chlorthalidone, it has a markedly different pharmacological profile with its main diuretic effect exerted at the distal section of the nephron.
As a diuretic, xipamide has been shown to be as effective as frusemide in terms of daily urine output, but has a more gradual and prolonged action.
Following single oral administration of 20 mg xipamide, peak plasma concentrations of up to 3 µg/ml occur within 1 hour. Absolute bioavailability after oral administration is about 73%.
Xipamide is highly bound to plasma protein and has a volume of distributions of about 10 litres. After oral or i.v. administration, the apparent elimination t½ is of the order of 5-8 h. About 90% of an oral or i.v. dose is excreted in the urine with 50% of the dose eliminated in urine unchanged and a further 30% as the 0-0 glucuronide.
In patients with liver disease, therapy with thiazide diuretics and related substances may cause hepatic encephalopathy. In that case, treatment with Aquaphoril must be discontinued immediately.
Some cases of photosensitivity have been reported during the use of thiazide diuretics.
If a photosensitivity reaction occurs during the treatment, Xipamide should be discontinued. If a re-administration of the treatment cannot be avoided, the skin area exposed to sunlight or artificial UVA should be protected.
In case of chronic abuse of diuretic agents, a pseudo Bartter's may occur.
Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption or sucrose -isomaltose intolerance should not take Aquaphoril.
As with all antihypertensive agents, care should be taken in patients with severe coronary or cerebral arteriosclerosis.
An increased risk of developing urinary retention may arise in patients with prostatic hypertrophy.
Precautions for use of the drug:
Water- and electrolyte balance:
Sodium plasma level:
The sodium plasma level has to be controlled prior to start of therapy and in regular intervals during treatment. In principle, a hyponatraemia with very serious complications may occur with any diuretic treatment. Since a decrease in the sodium plasma level may at first take an asymptomatic course, a regular control is indispensable; elderly patient and patients with liver cirrhosis have to be closely monitored (cf. undesirable effects and overdose).
Potassium level:
As with other diuretics, hypokalaemia may occur during long-term therapy with xipamide. The serum electrolytes (in particular potassium, sodium, calcium), bicarbonate, creatinine, urea, uric acid and blood sugar should be controlled regularly. Potassium substitution may become necessary, particularly in elderly patients with insufficient potassium intake.
The drop in the potassium level up to hypokalaemia represents the main risk of a treatment with thiazide diuretics and closely related drugs. The occurrence of a hypokalaemia (potassium plasma level < 3.4 mmol/l) has to be avoided in particular in case of a larger fluid loss (e.g. due to vomiting, diarrhoea, or intensive sweating) and in risk groups, i.e. in elderly and/or undernutritioned patients and/or patients on multidrug treatment as well as in patients with liver cirrhosis and formation of oedemas or ascites, moreover in patients with coronary heart disease and those with cardiac insufficiency. In this patient group, a hypokalaemia will also increase cardiotoxicity of cardiac glycosides and the risk of cardiac dysrhythmia.
Hypovolaemia or dehydration as well as major electrolyte disturbances or disturbances in the acid-base balance have to be adjusted. This may require a temporary discontinuation of treatment with xipamide.
Persons with congenital or iatrogenic acquired prolonged QT interval rank among the group of high-risk patients too. The presence of hypokalaemia and bradycardia will then promote the occurrence of severe arrhythmia, in particular the possible lethal torsade de pointes (polymorphic ventricular tachycardia).
All above mentioned cases, require frequent controlled of the potassium level, starting the first control during the first week after beginning of therapy. A hypokalaemia has to be adjusted.
Calcium plasma level:
Treatment with thiazide diuretics and related drugs may cause a decreased calcium excretion in urine and to a minor temporary increase in the calcium plasma level. A manifest hypercalcaemia may have possibly occurred due to a previous undiscovered hyperparathryroidism.
Prior to a possible examination of the parathyroid gland function, xipamide therapy has to be discontinued.
Blood-sugar level:
Especially in diabetic patients with concomitant hypokalaemia the blood sugar level has to be monitored closely.
Uric acid level:
Patients with hyperuricaemia may should an increased tendency toward acute gouty arthritis.
Renal function and diuretics:
Thiazide ad related substances are only fully effective with normal or at most slightly impaired renal function (creatinine serum level <25 mg/l or <220 μmol/l in adults). In elderly patients, this serum creatinine value has to be adjusted according to age, weight and sex of the respective patient.
Hypovolaemia caused by diuretic-related water- and sodium loss at therapy start results in a decrease in glomerular filtration. This may cause a rise in blood urea nitrogen (BUN) and serum creatinine. This temporary functional renal insufficiency remains without any consequences in renal healthy persons, but may aggravate a pre-existing renal insufficiency.
In case of a therapy-resistant decompensation in the electrolytes balance, therapy should be discontinued.
Xipamide may cause dizziness and electrolyte disturbances which may affect the patient's concentration or alertness, and may affect their ability to safely drive or operate machinery. This particularly applies at initiation of treatment or changes to the dose. If affected, patients should not drive or operate machinery.
1. Treatment of hypertension
Dosage:
Adults: 1 tablet (20 mg) daily, as a single early morning dose. When using Aquaphoril in combination with other antihypertensive therapy, the same dose of 20 mg as a single early morning dose should be maintained.
Children: No dose recommended.
Elderly: See 'Precautions'.
2. Use as a diuretic
Dosage:
Adults: In the initial phase of treatment the usual dose is 2 tablets (40 mg) daily in a single early morning dose. Depending on the patient's response, the dose may be lowered to 1 tablet daily when sufficient control of oedema has been achieved. Higher doses, up to 4 tablets daily (80 mg), may be employed in resistant cases.
Children: No dose recommended.
Elderly: See 'Precautions'.
Not relevant.
