Diurexan

Diurexan Tablets

Xipamide 20 mg

The tablets are white, round and biplanar with bisecting score on one side and debossed A on the other. They have a diameter of approximately 6 mm.

For oral use.

For treatment of hypertension, either alone or as an adjunct to treatment with anti-hypertensive drugs.

For use as a diuretic.

1. Treatment of hypertension

Dosage:

Adults: 1 tablet (20 mg) daily, as a single early morning dose. When using Diurexan 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'.

Diurexan is contra-indicated in severe electrolyte deficiency, precomatose states associated with liver cirrhosis, severe renal insufficiency, hypersensitivity to xipamide or to any of the excipients listed in section 6.1, untreated Addisons disease, hypercalcaemia, pre-existing hypovolaemia, symptomatic hyperuricaemia, pregnancy and lactation.

In patients with liver disease, therapy with thiazide diuretics and related substances may cause hepatic encephalopathy. In that case, treatment with Diurexan must be discontinued immediately.

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.

Some cases of photosensitivity have been reported during the use of thiazide diuretics (see section 4.8 Undesirable effects).

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 Diurexan.

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 patients 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 controll 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 show an increased tendency toward acute gouty arthritis.

Renal function and diuretics:

Thiazide and 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.

The following interactions have been reported for thiazide diuretics and related substances and may therefore be relevant for xipamide as well.

The antihypertensive effect of xipamide may be intensified by other diuretics, antihypertensive agents, beta-adrenergic blockers, nitrates, vasodilators, barbiturates, phenothiazines, tricyclic antidepressant agents or by the consumption of alcohol.

Concomitant use of Diurexan and loop diuretics increases the risk of disturbances in the electrolytes and fluid balance. Therefore, adequate monitoring is required.

The effects of antidiabetic agents, uricosuric substances, noradrenaline and adrenaline may be reduced.

The following combinations are

not

recommended:

Lithium:

In case of concomitant lithium therapy, the cardiotoxic and neurotoxic effects of lithium will be intensified. If diuretic treatment is essential close monitoring of the lithium level and adequate dosage adjustment are required.

Sultopride:

Increased risk of ventricular arrhythmias, especially torsade de pointes (hypokalaemia is a predisposing factor).

Perform clinical, electrolyte and electrocardiographic monitoring.

Particular precautions have to be taken for the following combinations:

Torsade de pointes-inducing substances (excluding Sultopride):

- class Ia antiarrhythmics (e. g. quinidine, hydrochinidine, disopyramide),

- class III antiarrhythmics (e. g. amiodarone, sotalol, dofetilide, ibutilide),

- specific antipsychotics: phenothiazine (e. g. chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamide (e. g. amisulpride, sulpiride, tiapride), butyrophenones, (e. g. droperidol, haloperidol),

- others: bepridil, cisapride, diphemanil, erythromycin i.v., halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine i.v.

Increased risk of ventricular arrhythmias, in particular torsade de pointes (promoted by hypokalaemia).

Testing for hypokalaemia should be carried out prior to therapy when considering combination therapy with Diurexan and any of the above.

Clinical control, control of plasma electrolytes and ECG monitoring should be considered.

Substances should be preferred which do not cause torsade de pointes in case of concomitant hypokalaemia.

Non-steroidal anti-inflammatory drugs (systemic) including selective COX 2 inhibitors, high dose salicylic acid (>3g/day):

Possible reduction of the antihypertensive effect of xipamide.

Risk of acute renal failure in case of dehydration (diminished glomerular filtration). A sufficient fluid supply has to be ensured, and renal function must be controlled at therapy start.

Intake of high salicylate doses may intensify the toxic effect of salicylate on the central nervous system.

ACE inhibitors:

Risk of a large drop in blood pressure and/or acute renal failure at therapy start with an ACE inhibitor in patients with pre-existing sodium deficiency (in particular with renal artery stenosis).

If sodium deficiency has been caused by a previous antihypertensive diuretic treatment, it is necessary to

- either withdraw the diuretic three days prior to therapy start with ACE inhibitors and then, if necessary, use a kaliuretic substance in addition.

- or start ACE inhibitor treatment with low dose with subsequent gradual dose increase.

In patients with cardiac decompensation, the initial ACE inhibitor dose should be very low, if possible after dose reduction of the concomitantly administered kaliuretic substance.

At any rate, renal function (determination of serum creatinine) must be monitored in the first weeks of an ACE inhibitor therapy.

Other substances with lowering effect on the serum potassium level:

- Amphotericin B (i.v.)

- Gluco- and mineralocorticoids (systemic)

- Tetracosactide

- Stimulating laxatives

- Kaliuretic diuretics (e.g. furosemide)

- ACTH

- Carbenoxolone

- Penicillin G

Increased risk of hypokalaemia (additive effect).

Control and, if necessary, correction of the potassium plasma level has to be followed in particular in patients treated with cardiac glycosides.

Baclofen:

Intensification of the antihypertensive effect.

A sufficient fluid supply has to be ensured, and renal function must be controlled at therapy start.

Cardiac glycosides:

Hypokalaemia and/or hypomagnesaemia intensifying the toxic side effects of digitalis glycosides: control of potassium plasma level and ECG monitoring, if necessary adjustment of therapy.

Aminoglycosides (parenteral):

Increased risk of ototoxicity and nephrotoxicity of aminoglycosides (functional renal insufficiency related to diuretic-induced dehydration).

Concomitant treatment is possible with monitoring of the state of hydration and renal and cochleovestibular functions and possible plasma concentrations of the aminoglycoside.

Phenytoin (by extrapolation from fosphenytoin):

Up to 50% reduction of the diuretic effect.

Higher doses of diuretic may be necessary.

Carbamazepine:

Risk of symptomatic hyponatraemia.

Potassium-sparing diuretics (amiloride, spironolactone, triamterene):

Even though this combination may be appropriate for certain patients, hypokalaemia or hyperkalaemia may occur (particularly in patients with renal insufficiency or diabetes); control of potassium plasma level and ECG, if necessary adjustment of therapy.

Metformin:

Increased risk of a metformin-induced lactic acidosis due to a possible functional renal insufficiency in connection with diuretic therapy particularly with loop diuretics.

Therefore, metformin must not be used if serum creatinine exceeds 15 mg/l (135 μmol/l) in men and 12 mg/l (110 μmol/l) in women.

Iodine-containing contrast media:

The use of iodine-containing contrast media (particularly in high doses) increases the risk of acute renal failure in diuretic caused dehydration.

Rehydration prior to administration of the iodine-containing contrast medium.

Furthermore, the following combinations may cause interactions:

Tricyclic antidepressants (imipramine-type), neuroleptics:

Antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Amifostine:

Enhanced antihypertensive effect.

Urological alpha-blockers (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin) and alphablocking antihypertensives:

Enhanced antihypertensive effect. Risk of severe orthostatic hypotension.

Platinum salts:

Risk of additive ototoxic and nephrotoxic effects.

Calcium (salts):

Risk of hypercalcaemia by reduced calcium excretion in urine.

Cyclosporine, tacrolimus:

Even with normal water- and sodium balance risk of increased creatinine levels in the serum without change in the circulating cyclosporine levels.

Corticoids, tetracosactide (systemic):

Reduction of the antihypertensive effect (water- and sodium retention by corticoids).

Cytostatics (e.g. cyclophosphamide, fluorouracil, methotrexate):

Risk of increased bone marrow toxicity, particularly a reduction in granulocytes.

Quinidine:

Excretion may be reduced.

Curare-like muscle relaxants:

Intensified and prolonged effect.

Colestipol and cholestyramine:

Absorption of xipamide is presumably reduced.

Pregnancy:

There is no experience with the use of xipamide during pregnancy. In animal studies, reproduction toxic effects occurred (see section 5.3).

Thiazide diuretics pass the placenta and may lead to electrolyte changes, hypoglycaemia as well as to haemolytic anaemia and thrombocytopenia in the unborn or newborn child. There is no data available on the transplacental passage of xipamide.

Due to their pharmacological properties, diuretics like xipamide are contraindicated during pregnancy in principle. Moreover, diuretics are not to be used under any circumstances for treatment of pregnancy-related oedemas and physiological oedemas, particularly since with these substances foetoplacental ischaemia may occur with the risk of foetal growth disturbances.

Thiazides and related diuretics should not be used to treat hypertension. They may cause neonatal thrombocytopenia, bone marrow suppression, jaundice, electrolyte disturbances, and hypoglycaemia; placental perfusion may also be reduced. Stimulation of labour, uterine inertia, and meconium staining have also been reported.

Breast-feeding

Since it is unknown whether xipamide passes into human breast milk, Diurexan-is contraindicated during lactation period.

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.

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.

Cases of choroidal effusion with visual field defect have been reported after the use of thiazide and thiazide-like diuretics.

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 or search for MHRA Yellow card in the Google Play or Apple App Store.

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.

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.

Not relevant.

Maize starch EP, Mannitol BP, Cellulose powder EP, Colloidal silicon dioxide EP, Magnesium stearate EP, Purified Water EP.

None known.

5 years.

None.

Aluminium - PVC Blister strip holds 14 tablets Ten blister strips in folded cardboard box.

Not relevant.

Mylan Products Ltd, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom

PL 46302/0127

30 June 02

March 2023