Information for healthcare professionals Metolazon Galepharm

The German version is legally binding (german).

Composition

Active substances

Metolazonum.

Excipients

Lactosum monohydricum 53 mg, Cellulosum microcristallinum, Carmellosum natricum conexum, Natrii steraylis fumaras, corresp. max 0.63 mg Natrium.

Pharmaceutical form and active substance quantity per unit

Divisible tablets containing 5 mg of metolazone.

Indications/Uses

• Oedema accompanying renal disease, including nephrotic syndrome and conditions with impaired renal function.
• Oedema accompanying heart failure.

Dosage/Administration

Important note: Metolazon Galepharm tablets bioavailability may be different from the bioavailability of other metolazone preparations (see «Pharmacokinetics»). 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 Metolazon Galepharm tablets to another metolazone product, or vice versa.

In general, metolazone should be administered once a day. The tablet should always be taken at the same time in relation to a meal, e.g. always with breakfast.

The following dosages serve as guidelines for Metolazon Galepharm:

Adults

Oedema in renal disease and heart failure: 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.

In patients with paroxysmal nocturnal dyspnoea, sustained diuresis can be ensured for 24 hours at a dosage within the upper end of the dose range stated.

Special dosage instructions

Patients with renal impairment

Metolazone should be used with caution in patients with severe impaired renal function (see section «contradiction» and «warnings and precautions»).

Patients with hepatic impairment

Metolazone should be used with caution in patients with severe hepatic insufficiency (see section «contradiction» and «warnings and precautions»).

Patients 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 «contradiction» and «warnings and precautions»).

Elderly

Metolazone should be used with caution in elderly patients (see section «warnings and precautions»).

Children and adolescents

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

Contraindications

• Hypersensitivity to the active substance (metolazone), sulfonamides, thiazides or to any of the excipients.
• Anuria.
• Hepatic coma or pre-comatose conditions.
• Severe disturbances of the electrolyte balance.

Warnings and precautions

Renal impairment

Metolazone should be used with caution in patients with severe impaired renal function. Renal function should be monitored regularly. If azotemia and oliguria deteriorate during treatment of patients with severe renal disease, metolazone should be discontinued.

Hepatic impairment

In severe hepatic insufficiency, diuretic-induced hypokalaemia may cause encephalopathy.

Electrolyte imbalance

The fluid and electrolyte balance should be (as with other diuretics) carefully monitored during treatment with Metolazon Galepharm. Determination of serum and urine electrolytes is important, especially in cases of severe vomiting, severe diarrhoea or parenteral fluid intake. 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. Monitoring of serum electrolytes is particularly indicated in elderly patients, in patients with ascites due to liver cirrhosis or with oedema due to nephrotic syndrome. In the latter condition, metolazone may only be used under strict surveillance in patients with normal serum potassium levels and without signs of volume depletion or severe hypoalbuminaemia.

The risk of electrolyte disturbances is increased when high metolazone doses are administered.

Rarely, severe hyponatraemia/hypokalaemia may occur immediately after the start of treatment.

The risk of hypokalemia 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, diuretics, ACTH or digitalis or with signs of coronary heart disease, unless they are being given an ACE inhibitor at the same time. As well as in patients treated with a high dose beta-adrenergic agonist and in all cases where the serum potassium concentration is below 3.0 mmol/L.

The clinical signs of potassium deficiency of hypokalaemia are e.g. muscle weakness, paresis or ECG changes.

In all cases of combination treatment, maintenance or normalisation of the potassium balance must be carefully monitored. Hypokalaemia should be corrected by the addition of potassium-sparing diuretics, potassium supplements or potassium-containing salts substitutes to the regimen (e.g. KCl oral), or metolazone should be discontinued.

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.

Hyponatraemia can occur at any time during long-term therapy and can be life-threatening in rare cases. Hyponatraemia is associated with neurological symptoms (nausea, weakness, increasing disorientation, apathy).

Hypochloraemic alkalosis (hypochloraemia) may occur and cases of hypomagnesaemia have also been reported.

Diuretics (thiazides) similar to metolazone 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. The therapy with metolazone should be discontinued before carrying out tests for parathyroid function.

Gout attacks

As with other diuretics, azotaemia and hyperuricaemia may occur during the administration of metolazone. In rare cases, 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.

Lupus erythematosus

Sulfonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus.

Porphyria

Although not reported with Metolazon Galepharm, thiazides have been associated with acute attacks of porphyria. Caution is required when Metolazon are used in porphyric patients.

Glucose metabolism

Metolazone has only a slight effect on glucose metabolism. Metolazon may increase blood glucose levels and may cause glycosuria and hyperglycaemia in patients with diabetes mellitus or latent diabetes. The blood glucose level shouldtherefore be checked on a regular basis (see «Interactions»).

Pediatric population

No experience is available on the use of metolazone in patients under 18 years of age.

Laboratory values

Although this has not been reported for metolazone, thiazides and thiazide-like diuretics have been reported to adversely affect the plasma-lipid profile by increasing VLDL or LDL cholesterol and triglycerides. The clinical relevance of these observations is unclear.

Excipients

Metolazone Galepharm tablets contain 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».

Interactions

Adrenergic and cholinergic system

Although no such observations were made with metolazone, there have been reports for related diuretics, which claim that these medicinal products cause increased responsiveness to tubocurarine (not authorised in Switzerland) and reduced arterial reactivity to noradrenaline. Diuretic-induced hypokalaemia may enhance neuromuscular blocking effects of curariform drugs. The most serious effect would be respiratory depression which could proceed to apnoea. The dosage of these medicinal products must therefore be carefully adjusted in patients treated with metolazone and who need to undergo a surgical procedure.

Antihypertensives

Caution is advised when metolazone is co-administered with antihypertensive agents, especially in the initial phase of treatment, due to the risk of hypotension. The dosage must be adjusted as necessary. Deterioration of renal function has been reported with concomitant administration of ACE inhibitors, angiotensin II antagonists and aldosterone antagonists.

Alcohol, barbiturates, or narcotics

Orthostatic hypotension may occur with metolazone; it is potentiated by alcohol, barbiturates and narcotics.

Diuretics (e.g. Loop diuretics, as Furosemid)

Concomitant use of furosemide and presumably other loop diuretics can significantly potentiate the effect of metolazone and lead to serious disturbances of the electrolyte balance (see section «warnings and precautions»).

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 «Warnings and precautions»).

Antiarrhythmic drugs (e.g. Sotalol)

When sotalol is co-administered with a potassium-depleting diuretic (e.g. furosemide, hydrochlorothiazide) or other medicinal products leading to the loss of potassium or magnesium, there is an increased risk of hypokalaemically-induced cardiac arrhythmias (syncope, prolong the QT interval).

Corticosteroids and ACTH

Corticosteroids and ACTH may increase the risk of hypokalaemia and exacerbate electrolyte and fluid retention.

NSAIDs and salicylates

Salicylates and other non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the diuretic and natriuretic effects of metolazone in some patients. Deterioration of renal function has been reported with concomitant administration of NSAIDs.

Antigout medicinal products

Dosage adjustments of antigout medicinal products may be necessary as thiazide diuretics may raise the level of serum uric acid (see section «Warnings and precautions»). Increase in dosage of probenecid or sulfinpyrazone may be necessary (not authorised in Switzerland). 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) are prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Lithium

The concurrent use of lithium and thiazides may increase lithium serum levels leading to intoxication. In patients on lithium therapy and receiving metolazone at the same time, the lithium level must be monitored.).

Antidiabetic drugs (including insulin)

The dosage of insulin or oral antidiabetics must be adjusted as necessary (see section «Warnings and precautions»). It has also been reported that the hypoglycaemic effect of sulphonylureas may be potentiated by concomitant administration of metolazone.

Cyclosporin

Concomitant administration of metolazone and ciclosporin may lead to an increase in serum creatinine.

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. It has been reported that metolazone can increase the effect of warfarin (not authorised in Switzerland). A prolongation of bleeding time has been reported with concomitant use of metolazone and warfarin (not authorised in Switzerland).

CYP3A4 substrates

It is not known whether metolazone might affect the plasma concentrations of co-administered medicinal products due to inhibition or induction of metabolising enzymes such as cytochrome (CYP) P450. Therefore, caution must be exercised when co-administering CYP450 substrates with a narrow therapeutic index.

Pregnancy, lactation

Pregnancy

There are clear indications of risks to the human foetus. Metolazone may reduce the placental blood flow and passes the placental barrier. Thiazide diuretics and related diuretics may pass over to the foetus and cause electrolyte imbalance. The use of thiazide diuretics and related diuretics during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Metolazone must therefore not be administered during pregnancy unless clearly necessary.

Lactation

Thiazides and thiazide-like diuretics may be excreted in breast milk and suppress lactation. Metolazone should therefore not be used by breastfeeding mothers unless clearly necessary.

Effects on ability to drive and use machines

No studies are available on the effect of metolazone on the ability to drive and use machines.

Treatment with metolazone may lead to fatigue, drowsiness or dizziness, which may affect the ability to drive and/or operate machinery.

Undesirable effects

Undesirable effects associated with metolazone are listed within the system organ classes using the following frequencies: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Reporting suspected adverse reactions after authorisation of the medicinal product is very important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions online via the ElViS portal (Electronic Vigilance System). You can obtain information about this at www.swissmedic.ch.

Overdose

Symptoms

Overdosing may lead to dehydration and electrolyte disturbances (primarily hyponatraemia, but also loss of potassium and magnesium). Symptomes include thirst, nausea, vomiting, disorientation, somnolence, headache, muscle cramps, arterial hypotension and arrhythmias (in severe cases of hypokalaemia).

Treatment

Within the first hour following ingestion, absorption can be reduced by the administration of medicinal charcoal (1 g/kg body weight). Thereafter, priority should be given to adequate hydration and correction of electrolyte disturbances.

Properties/Effects

ATC code

C03BA08

Mechanism of action

Metolazone is a sulfonamide diuretic with a mechanism of action similar to the one of thiazides. Metolazone decreases sodium reabsorption along the renal tubules but it is acting mostly in the distal convoluted tubule. The enhancement of sodium excretion results also to an increased loss of chloride and water.

Pharmacodynamics

At the optimal therapeutic dosage, metolazone achieves approximately the same diuretic activity as thiazide-type diuretics. Because metolazone works primarily in the distal convoluted tubule, it has little effect on glomerular filtration rate (GFR) and can be used in patients with a reduced GFR. Metolazone can also stimulate diuresis in patients with a very low GFR (less than 20 mL/min).
Diuresis usually sets in within the first hour after administration and lasts for 12 24 hours depending on the dosage. The peak effect is reached after approximately 2 hours.

At the antihypertensive dosage, the effect is observed as early as 3 4 days after the start of therapy. The optimal effect is reached after 3 4 weeks.

Clinical efficacy

No clinical studies have been conducted with Metolazon Galepharm. The clinical efficacy of metolazone is extensively documented in the literature.

Pharmacokinetics

Absorption

Metolazone is almost completely absorbed in the digestive tract. The peak plasma concentration is reached on average after 2 hours. The rate and extent of absorption are formulation dependent. The effect of concomitant food intake on the bioavailability of Metolazon Galepharm has not been studied. To minimise variability for the individual patient, the tablet should always be taken at the same time with regard to a meal, e.g. always with breakfast.

Distribution

The apparent volume of distribution is 113 L/kg; the substance is 95% bound to red blood cells and to plasma proteins. Metolazone crosses the placenta and is excreted in breast milk.

Metabolism

Metolazone undergoes virtually no metabolism; the metabolites produced have been shown to be non toxic.

Elimination

80‑95% of the administered dose is excreted renally with a half-life of 8‑10 houres in unchanged form. The remaining moiety appears in the faeces. Since metolazone clearance is parallel to creatinine clearance, excretion is delayed in the presence of renal insufficiency.

Preclinical data

There are no relevant data available for use.

Other information

Shelf life

Do not use this medicine after the expiry date («EXP») stated on the pack.

Special precautions for storage

Do not store above 30 °C.

Store in the original packaging, in order to protect the contents from light.

Keep out of the reach of children.

Authorisation number

56468 (Swissmedic).

Packs

Metolazon Galepharm, divisible tablets: packs of 20 and 100 tablets (B).

Marketing authorisation holder

Galepharm AG, Zürich.

Date of revision of the text

July 2023.