Xaqua 5 mg Tablets

Xaqua is indicated for the treatment of

Xaqua is also indicated for the treatment of mild and moderate hypertension, alone or in combination with other antihypertensive medicines of a different class.

Important note: Xaqua tablets bioavailability may be different from other metolazone preparations (see section 5.2). Therefore, the recommended doses (expressed in mg) can differ from other metolazone products. A dose adjustment may be necessary and individualised titration based on patient's response and tolerability is advised if switching from Xaqua tablets to another metolazone product, or vice versa.

Posology

Adults

Treatment of Oedema

Metolazone should generally be administered once daily

The tablet should always be taken at the same time in relation to food.

The following dosages should serve as guidelines:

Oedema related to congestive heart failure and kidney disease: 2.5-5 mg/day.

The therapy should be initiated with a dose of 2.5 mg/day and the dose must be adjusted according to the individual reaction of the patient. Once the desired therapeutic effect has been achieved, it may be advisable to reduce the maintenance dose if possible

Hypertension

The recommended initial dose in mild and moderate hypertension is 2.5 mg/day, and the dose must be adjusted according to the individual reaction of the patient. Once the desired therapeutic effect has been achieved, it may be advisable to reduce the maintenance dose.

Renal impairment

Metolazone should be used with caution in patients with severe impaired renal function. If azotemia and oliguria deteriorate during treatment of patients with severe renal disease, metolazone should be discontinued. (see section 4.3 and 4.4).

Hepatic impairment

Metolazone should be used with caution in patients with severe impaired hepatic function (see section 4.3 and 4.4)

Patient with electrolyte disturbances

Metolazone should be used with caution in patients with preexisting electrolyte disturbances. Careful monitoring of the fluid and electrolyte balance is required (see section 4.3 and 4.4)

Elderly

Metolazone should be used with caution in elderly patients (see section 4.4)

Pediatric population

The safety and efficacy of Xaqua in children aged under 18 years has not yet been established.

No data are available.

Hypersensitivity to the active substance, sulfonamides, thiazides or to any of the excipients listed in section 6.1.

Anuria

Hepatic coma or precomatose conditions.

severe disturbances of the electrolyte balance.

Renal impairment

Metolazone should be used with caution in patients with severe renal impairment. Renal function should be continuously monitored during thiazide therapy.

Hepatic impairment

In severe hepatic impairment, hypokalaemia caused by diuretics can precipitate encephalopathy. In patients with alcoholic cirrhosis there is an increased risk of hypomagnesaemia.

Elderly

Regular ongoing monitoring and blood tests are to be performed in elderly patients and patients who are on long term treatment with metolazone.

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Hyperkalaemia might occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Hypokalemia should be corrected by the addition of potassium-sparing diuretics, potassium supplements or potassium-containing salts substitutes to the regimen (see section 4.5).

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

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnaesemia.

Metabolic and endocrine effects

Thiazide diuretics tend to reduce glucose tolerance and raise serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but frank gout or overt diabetes may be precipitated in susceptible patients.

In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Primary adrenal insufficiency

Diuretics should be avoided for the treatment of hypertension if the patient has primary adrenal insufficiency, known as Addison's disease.

Gout attacks

Azotemia and hyperuricemia may occur during the administration of thiazide therapy. Infrequently, attacks of gout have been reported in persons with a history of gout

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.

Excipients

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

No formal interaction studies have been performed with Xaqua.

Loop Diuretics (e.g. furosemide)

Concurrent use of furosemide and presumably also of other loop diuretics may potentiate the effect of metolazone considerably and lead to serious disturbances of the electrolyte balance.

Curariform Drugs

Diuretic-induced hypokalaemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine). The most serious effect would be respiratory depression which could proceed to apnoea. Accordingly, it is advisable to discontinue metolazone tablets three days before elective surgery.

Cyclosporine

Concurrent administration of metolazone and cyclosporine may lead to an increase in serum creatinine.

Additional information on metolazone interactions when administered concurrently, the following medicinal products may interact with thiazide diuretics:

Alcohol, barbiturates and narcotics : potentiation of orthostatic hypotension may occur;

Antidiabetic medicinal products (oral agents and insulins) : dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4);

Corticosteroids, ACTH : electrolyte depletion, particularly hypokalaemia, may be increased;

Cardiac Glycosides: Hypokalaemia may increase the risk of digitalis toxicity with higher risk of severe arrhythmias. In case of concurrent administration with digitalis drugs the dosage may need to be adjusted (see section 4.4.).

Antiarrhythmic Drugs (e.g. Sotalol)

Hypokalaemia associated with thiazide therapy may increase the risk of sotalol-induced arrhythmia (syncope, prolonged QT interval)

Non-steroidal anti-inflammatory drugs : the administration of a non-steroidal anti-inflammatory drug may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;

Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not sufficiently to preclude their therapeutic use.

Antigout medicinal products : dosage adjustments of antigout medicinal products may be necessary as thiazide diuretics may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol;

Calcium salts : thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;

Lithium : Concurrent use of lithium and thiazides may reduce lithium clearance leading to intoxication. (see section 4.4).

Other antihypertensive drugs

Concomitant administration of Xaqua and other antihypertensive drugs may result in hypotension. Particular caution is required in the initial phase. Dosage adjustments of other antihypertensives may be necessary.

Cross-reactivity with other drugs

Cross reactions may occur in patients who are allergic to sulfonamides or thiazides.

Anticoagulants

Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary.

Methenamine

Efficacy may be decreased due to urinary alkalizing effect of metolazone.

Pregnancy

Thiazide diuretics and related diuretics may pass over to the foetus and cause electrolyte imbalance. Cases of neonatal thrombocytopenia have been reported. Therefore, metolazone must not be administered during the last trimester of pregnancy unless absolutely necessary, and then with the lowest recommended dose.

Breast-feeding

Metolazone passes over to the breast milk in such an amount that there is a risk for the baby child even at therapeutic doses. Inhibition of lactation has been observed in treatment with diuretics.

Metazolane may cause adverse reactions affecting the ability to drive a vehicle and/or to operate machines, such as dizziness and fatigue.

Within each System Organ Class, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Description of selected adverse reactions:

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

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.

Symptoms: Overdosing may lead to dehydration and electrolyte disturbances (primarily hyponatraemia, but also loss of potassium and magnesium), and as a consequence the patient may experience thirst, nausea, vomiting, disorientation, somnolence, headache, muscle cramps, arterial hypotension, and in severe cases dysrhythmia (hypokalaemia).

Treatment: Within the first hour of ingestion the absorption may be reduced by administration of medicinal charcoal (1 g/kg body weight). Thereafter priority should be given to establish adequate hydration and re- establishment of the electrolyte balance.

Pharmacotherapeutic group: Sulfonamides, plain, ATC code: C03BA08

Mechanism of action

Metolazone obstructs the re-absorption of sodium in the ascending branch of the loop of Henle and in the proximal tubules, which leads to excretion of approximately equivalent amounts of sodium and chloride.

At the optimal therapeutic dosage metolazone leads to approximately the same diuretic activity as diuretic of the thiazide-type. However, it may also stimulate the diuresis in patients with a very low glomerular filtration rate (less than 20 ml/min).

The diuresis starts within the first hour after administration and will continue for 12-24 hours depending on the dose. The maximum effect will be achieved after approximately 2 hours.

Thiazides also reduce carbonic anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small and does not appreciably alter the acid base balance or the pH of the urine.

Comparative bioavailability studies have shown that the bioavailability of Xaqua may differ significantly (up to approximately 2-fold) from Metenix. Bioavailability has not been compared to any other metolazone products (see section 4.2). Therefore, once the appropriate dose has been identified for a patient with a certain product, this product cannot readily be exchanged with another product.

Absorption

Metolazone is rapidly absorbed in the digestive tract. The maximal plasma concentration is on average reached after 2 hours. The rate and extent of absorption are formulation dependent. The effect of concomitant food on the bioavailability of Xaqua has not been evaluated. In order, to minimise variability for the individual patient, the tablet should always be taken at the same in relation to food (see section 4.2).

Distribution

The apparent volume of distribution is estimated approximately 113 litres; 95 % of the substance is bound to red blood cells and to plasma proteins. Metolazone crosses the placenta and passes into breast milk.

Metabolism and Elimination

Metabolism of metolazone appears to be minimal. Most of the absorbed drug is excreted in urine, mainly unchanged. The elimination half-life of metolazone is reported to be 8-10 hours. In case of impaired kidney function the excretion is delayed, as the clearance of metolazone is directly related to renal function (creatinine clearance).

No data is available.

Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate

Not Applicable

3 years.

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.

Blister of PVC-PVDC and aluminum foil with 20, 60 or 100 tablets. Not all pack sizes may be marketed.

No special requirements

Any unused product or waste material should be disposed of in accordance with local requirements.