Hydrochlorothiazide 12.5 mg tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Hydrochlorothiazide 12.5 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 12.5 mg of hydrochlorothiazide

Excipient with known effect:

Each tablet contains 65.20 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

White, round, biconvex tablets with a diameter of 5.8 to 6.2 mm and a thickness of 3.0 to 3.6 mm

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hydrochlorothiazide tablets are indicated in adults for the treatment of:

• Oedema of cardiac or renal origin.
• Oedema of hepatic origin, usually in combination with a potassium-sparing diuretic.
• Arterial hypertension.

4.2 Posology and method of administration

Posology

For oral use.

As with all other diuretics, treatment should be started with the lowest possible dose. This dose should be adjusted based on the response of each individual patient to achieve the maximum therapeutic benefit while minimizing adverse effects. The daily dose of Hydrochlorothiazide can be given as a single dose or divided over two doses, with or without food.

Oedema

The starting dose is 50 to 100 mg/day, possibly 200 mg/day. The lowest effective dose should be identified by titration and only administered for limited periods.

The maintenance dose is 25 mg to 50 mg/day or every other day.

Arterial hypertension

The doses currently recommended in arterial hypertension are 12.5 or 25 mg/day.

For a given dose, the maximum effect is achieved within 3 to 4 weeks. If blood pressure is not sufficiently lowered with a dose of 25 mg/day, combined treatment with another antihypertensive drug is recommended. Sodium depletion and / or volume must be corrected before using hydrochlorothiazide in combination with an ACE inhibitor, an antagonist of angiotensin II or a direct renin inhibitor. Otherwise, treatment should be initiated under close medical supervision.

Special populations

Renal impairment

No adjustment to the starting dose is necessary in patients with mild to moderate renal impairment (see section 5.2).

Hydrochlorothiazide is contraindicated in patient with anuria and with severe renal impairment.

Hepatic impairment

No adjustment to the starting dose is necessary in patients with mild to moderate hepatic impairment (see section 5.2).

Hydrochlorothiazide should be used with caution in patients with severe hepatic impairment (see section 4.4).

Elderly (above 65 years of age)

In the treatment of elderly patients, attention should be paid to possible restrictions to renal function.

Severe cardiac decompensation

In patients with severe cardiac decompensation, resorption of hydrochlorothiazide may be clearly limited.

Paediatric population

There is no experience in children and adolescents. Therefore, hydrochlorothiazide should not be used in children and adolescents.

Method of administration

The tablet(s) should be taken with a sufficient quantity of liquid.

Duration of treatment

The duration of treatment is unlimited and depends on the type and severity of the disease. After long-term treatment, therapy with hydrochlorothiazide should be discontinued gradually.

4.3 Contraindications

• Hypersensitivity to hydrochlorothiazide or to any of the excipients listed in section 6.1.
• Anuria.
• Severe renal impairment (creatinine clearance less than 30 ml/min).

4.4 Special warnings and precautions for use

Special warnings

Hydrochlorothiazide is generally not recommended in patients with bilateral renal artery stenosis or a single functioning kidney or with hypokalaemia.

Hydrochlorothiazide is a sulfonamide. The possibility of cross-reactivity especially with other antibacterials including sulfonamides is theoretical and not clinically confirmed.

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

Hepatic impairment

Thiazides, like other diuretics may induce electrolyte imbalance, hepatic encephalopathy or hepatorenal syndrome when used to treat cirrhotic ascites. Hydrochlorothiazide should be used with caution particularly in patients with severe liver damage.

Photosensitivity reactions have been reported with the use of thiazide diuretics (see section 4.8).

If a photosensitivity reaction occurs treatment should be discontinued. If re-administration of treatment is essential, areas exposed to the sun or artificial UVA should be protected.

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine.

Precautions for use

Electrolyte imbalance

Serum sodium

Serum sodium levels should be monitored before treatment and at regular intervals thereafter.

Thiazide diuretics may lead to hyponatraemia or an exacerbation of pre-existing hyponatraemia. In subjects with a significant decrease in serum sodium and / or a significant volume depletion, as observed in patients receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of hydrochlorothiazide treatment.

A decrease in plasma sodium may initially be asymptomatic, regular monitoring is essential and needs to be more frequent in populations at risk such as the elderly, and even more in malnourished and cirrhotic patients (see sections 4.8 and 4.9).

Monitoring is especially important in patients with ascites as a result of liver cirrhosis and in patients with oedema as a result of nephrotic syndrome.

Isolated cases of hyponatremia have been observed accompanied by neurological symptoms (nausea, increasing disorientation, apathy). Thiazides should be only used after normalization of any existing sodium and / or volume depletion. Otherwise, treatment should be initiated under strict medical supervision.

Serum potassium

Thiazide diuretics can also lead to hypokalaemia or an exacerbation of a pre-existing hypokalaemia. Thiazides should be used with caution in patients with a disease that can cause a significant loss of potassium, such as kidney disease with loss of salts or kidney function disorders of prerenal origin (cardiogenic).

The risk of hypokalaemia onset (< 3.5 mmol/l) must be prevented in certain at-risk populations i.e. the elderly and / or malnourished and / or polymedicated patients, cirrhotic patients with oedema and ascites, patients with coronary heart disease or heart failure. Indeed, in these cases hypokalaemia increases the cardiac toxicity of digitalis and the risk of heart rhythm problems.

Patients with long QT interval on an ECG are also at risk, whether the origin is congenital or due to medication. Hypokalaemia (as with bradycardia) then acts as a factor inducing severe arrhythmias, in particular torsades de pointes, potentially fatal, especially in the presence of bradycardia.

Treatment with thiazide diuretics should only be started after correction of hypokalaemia and concurrently occurring existing hypomagnesemia.

Serum potassium concentration should be determined during the week following the initiation of treatment.

Thereafter, regular monitoring of serum potassium is recommended. The electrolyte balance, particularly that of potassium, should be monitored in all patients receiving thiazide diuretics.

With long term treatment, serum potassium concentration should be determined at start of treatment. A control at 3-4 weeks may be considered depending on risk factors. Then regular checks should be recommended especially in patients at risk.

Uric acid

As with other diuretics, hydrochlorothiazide can increase serum uric acid concentration, due to the reduction in its excretion in urine, and consequently promote hyperuricemia or the aggravation of an existing hyperuricemia. This can trigger attacks of gout in susceptible patients.

The dose should be adjusted according to serum levels of uric acid.

Metabolic effects

Serum calcium

Thiazide diuretics reduce the urinary excretion of calcium and can cause a slight, transient increase in serum calcium levels in the absence of known calcium metabolism disorders. Hydrochlorothiazide should be used with caution in patients with hypercalcemia and should be administered only after correction of any pre-existing hypercalcemia. Hydrochlorothiazide should be discontinued if hypercalcemia occurs during treatment. Serum calcium levels should be monitored regularly during treatment with thiazide diuretics. Marked hypercalcemia may be a sign of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out parathyroid function tests.

Serum glucose and lipid levels

Thiazide diuretics, including hydrochlorothiazide, can decrease glucose tolerance and raise serum levels of cholesterol and triglycerides. In diabetic patient dosage adjustments of insulin or oral hypoglycaemic agents may be required.

Renal function and diuretics

Thiazide diuretics are only fully effective when renal function is normal or only slightly impaired (evaluated, for example by calculating the creatinine clearance from serum creatinine). In the elderly, the creatinine clearance value should be adjusted by patient age, weight and sex, according to the Cockroft formula, for example: CrCl = (140 - age) x weight / 0.814 x serum creatinine

with:

• the age in years,
• weight in kg
• creatinine in micromol/l.

This formula is valid for the elderly male and should be corrected for women by multiplying the result by 0.85.

Hypovolemia, secondary to the loss of water and sodium induced by the diuretic at the start of treatment, leads to a reduction in glomerular filtration. This can result in an increase in blood urea and creatinine.

This transitory renal function impairment may worsen pre-existing renal impairment.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic response, resulting in choroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma. Symptoms include an acute onset of decreased visual acuity or acute ocular pain and typically occur within a few hours up to weeks after the start of treatment. Untreated angle glaucoma may lead to permanent loss of vision. The primary treatment is to discontinue hydrochlorothiazide as soon as possible. Risk factors for developing acute angle-closure glaucoma include a history of sulphonamide or penicillin allergy.

Other

Antihypertensive combinations

It is advised to reduce the dose when combined with other antihypertensives, at least initially.

The antihypertensive effect of ACE inhibitors, angiotensin II antagonists or renin inhibitors is potentiated by treatment that increases plasma renin activity (diuretics).

Caution is advised when an ACE inhibitor, an angiotensin II antagonist or a direct renin inhibitor is administered concomitantly with hydrochlorothiazide, particularly in patients with severe sodium and / or volume depletion.

Anti-doping test

Hydrochlorothiazide could produce a positive analytical result in an anti-doping test.

Other

Lupus erythematosus: exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics, including hydrochlorothiazide.

Hypersensitivity reactions to hydrochlorothiazide are more likely to occur in patients with allergies and asthma.

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 minimize 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).

4.5 Interaction with other medicinal products and other forms of interaction

When administered concomitantly, the following drugs may cause an interaction with Hydrochlorothiazide:

Medicines that affect serum potassium levels

Hypokalaemia is a predisposing factor for heart rhythm disorders (torsades de pointes, in particular) and for increasing the toxicity of certain drugs, such as digoxin. Therefore, medicines that can cause hypokalaemia are involved in many interactions. These are potassium lowering diuretics, alone or combined; stimulant laxatives; glucocorticoids; the tetracosactide and amphotericin B (IV route).

Medicines that affect serum sodium levels

Certain drugs are frequently involved in causing hyponatremia. These are diuretics, desmopressin, serotonin reuptake inhibiting antidepressants, carbamazepine and oxcarbazepine. The combination of these drugs increase the risk of hyponatremia.

Concomitant use not recommended:

Lithium:

Increased serum lithium levels with signs of lithium overdose, as in a salt-free diet (decreased urinary excretion of lithium).

If this combination proves essential, serum lithium levels should be closely monitored and the lithium dose should be adjusted.

Concomitant use requiring caution:

Acetylsalicylic acid

For anti-inflammatory doses of acetylsalicylic acid (≥1 g per dose and / or ≥3 g daily) or for analgesic or antipyretic doses (≥500 mg per dose and / or <3 g per day): Acute renal failure in dehydrated patients with decreased glomerular filtration secondary to decreased renal prostaglandin synthesis. In addition, reduction of the antihypertensive effect.

Hydrate the patient and monitor renal function at start of treatment.

Non-steroidal anti-inflammatory drugs

Acute renal failure in at risk patients (elderly and / or dehydrated) due to reduced glomerular filtration (inhibition of vasodilatory prostaglandins due to non-steroidal anti-inflammatory drugs). In addition, reduction of the antihypertensive effect.

Hydrate the patient and monitor renal function at start of treatment.

Carbamazepine

Risk of symptomatic hyponatraemia. Clinical and biological monitoring. If possible, use another class of diuretic.

Chelating resins

Chelating resins can decrease intestinal absorption and the effectiveness of other medicines taken simultaneously. In general, the resin should be taken at a time distant from that of the other medicines, with an interval of more than 2 hours, if possible.

Digitalis

Hypokalaemia increases the toxic effects of digitalis.

Correct any hypokalaemia beforehand and perform clinical, electrolyte and electrocardiographic monitoring.

Potassium-sparing diuretics (alone or in combination)

This reasonable combination, useful for some patients, does not rule out the occurrence of hypokalaemia or, particularly in renal failure and diabetes, of hyperkalaemia.

Monitor serum potassium, possibly ECG and, if necessary, reconsider the treatment.

Angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonist

Risk of sudden hypotension and / or acute renal failure when starting or increasing the dose of an ACE inhibitor or an angiotensin II antagonist when there is pre-existing sodium depletion.

In arterial hypertension, when prior diuretic treatment lead to salt depletion, you must:

• either stop the diuretic before starting treatment with the angiotensin II antagonist or AEC, and reintroduce a potassium lowering diuretic later if necessary;
• or give lower initial doses of the angiotensin II antagonist or ACE and gradually increase the dosage.

In patients with congestive heart failure being treated with diuretics, start with a very low dose of ACE inhibitor or angiotensin II antagonist, possibly after lowering the dose of the concomitant potassium lowering diuretic.

In all cases, renal function (serum creatinine) should be monitored during the first weeks of treatment with ACE inhibitors or angiotensin II antagonists.

Medicines that may cause torsades de pointes (amiodarone, amisulpride, arsenic, artenimol, chloroquine, chlorpromazine, citalopram, cyamemazine, diphemanil, disopyramide, dofetilide, dolasetron, domperidone, dronedarone, droperidol, erythromycin, escitalopram, flupentixol, fluphenazine, halofantrine, haloperidol, hydroquinidine, hydroxyzine, ibutilide, levofloxacin, levomepromazine, lumefantrine, mequitazine, methadone, mizolastine, moxifloxacin, pentamidine, pimozide, pipamperone, piperaquine, pipotiazine, prucalopride, quinidine, sotalol, spiramycin, sulpiride, sultopride, tiapride, toremifene, vandetanib, vincamine, zuclopenthixol)

Increased risk of ventricular arrhythmias, especially torsades de pointes.

Correct any hypokalaemia before administering the medicine and perform clinical, electrolyte and electrocardiographic monitoring.

Other potassium-lowering medicines

Increased risk of hypokalaemia. Monitoring of serum potassium with correction if required.

Iodine Contrast Media

In cases of dehydration caused by diuretics there is a greater risk of acute renal function impairment, especially with high doses of iodinated contrast media.

Rehydration before administration of the iodinated product.

Combinations to be taken into account

Alpha-blockers for urological problems (alfuzosin, doxazosin, prazosin, silodosin, tamsulosin, terazosin)

Hypotensive effect increased. Greater risk of orthostatic hypotension.

Alpha-blocker antihypertensives

Hypotensive effect. Greater risk of orthostatic hypotension.

Medicines causing orthostatic hypotension

Besides antihypertensives, many other drugs can cause orthostatic hypotension. Especially nitrates, phosphodiesterase type 5 inhibitors, alpha blockers for urological problems, of tricyclic antidepressants and phenothiazines, dopamine agonists, levodopa, baclofen, amifostine.

Increased risk of hypotension, especially orthostatic hypotension.

Calcium

Risk of hypercalcaemia due to reduced urinary calcium excretion.

Cyclosporin

Risk of increased creatinine without changes in ciclosporin blood levels, even in the absence of sodium depletion. Also risk of hyperuricaemia and gout-type complications.

Nitrate derivatives

Increased risk of hypotension, especially orthostatic hypotension.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are insufficient data on the use of hydrochlorothiazide during pregnancy, especially during the first trimester of pregnancy. Studies in animals are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters of pregnancy may impair foetal-placental perfusion and cause foetal and neonatal jaundice, electrolyte imbalance and thrombocytopenia.

Hydrochlorothiazide must not be used in women with pregnancy oedema, hypertension or preeclampsia because there is also a risk of reduced plasma volume and placental hypoperfusion, while the progress of the clinical picture is not affected by this medicine.

Hydrochlorothiazide should not be used for the treatment of essential hypertension in pregnant women except in rare cases where no other treatment could be used.

Breast-feeding

Hydrochlorothiazide is excreted in breast milk in small amounts. The use of thiazides in high doses intensifies diuresis and my inhibit milk production.

The use of hydrochlorothiazide during breast-feeding is not recommended. If hydrochlorothiazide is indicated, the doses should be as low as possible.

Fertility

There are no human fertility data for hydrochlorothiazide.

In animal studies, hydrochlorothiazide had no effect on fertility and conception (see section 5.3).

4.7 Effects on ability to drive and use machines

Hydrochlorothiazide has minor or moderate influence on the ability to drive and use machines.

This has to be considered especially at the beginning of therapy or when dosage is increased, when the medication is changed or when taken in combination with alcohol.

4.8 Undesirable effects

The adverse reactions below are classified where appropriate by system organ class and frequency according to the following convention:

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

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

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.

4.9 Overdose

Symptoms

Symptoms of acute and chronic overdose depend on the extent of fluid and electrolyte loss.

In obvious cases of fluid and electrolyte loss overdose may lead to thirst, weakness, dizziness, vomiting, muscle pain and muscle cramps (e.g. calf cramps), headache, tachycardia, hypotension and orthostatic hypotension. Dehydration and hypovolaemia can result in haemoconcentration, convulsions, lethargy, confusion, collapse and acute renal failure. Electrolyte disturbances with arrhythmias may occur.

Hypokalaemia may result in fatigue, muscle weakness, paraesthesia, paresis, apathy, meteorism, and constipation or arrhythmias. Severe potassium loss may result in paralytic ileus or unconsciousness and hypokalaemic coma.

Management

Hydrochlorothiazide treatment must be stopped immediately when symptoms of overdose occur.

After a recent overdose, attempts can be made to reduce systemic hydrochlorothiazide absorption by primary elimination of the drug (induced emesis, gastric lavage) or by reducing resorption (activated charcoal).

Vital signs should be monitored. In addition, water- and electrolyte balance as well as acid-base metabolism and blood sugar should be checked regularly. Clinical urine analysis should be performed. Deviations from normal values should be corrected.

Therapeutic measures

• in cases of hypovolaemia: volume substitution
• in cases of hypokalaemia: potassium substitution
• in cases of collapse: Trendelenburg position, shock therapy, if necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: thiazide diuretics, ATC code: C03A A03

Mechanism of action

Hydrochlorothiazide is a benzothiadiazine diuretic.

Thiazide diuretics exert their action primarily from the distal part of the renal tubule by inhibiting NaCl reabsorption (by means of antagonism of the NaCl transporter).

The increased amount of Na⁺ and water in the collecting duct and / or the increased filtration rate lead to an increased secretion and excretion of K⁺ and H⁺.

Inhibiting NaCl reabsorption also causes indirect stimulation of Ca²⁺ reabsorption.

The diuretic and natriuretic effect becomes noticeable 1-2 hours after oral administration of hydrochlorothiazide, reaching its peak after 4-6 hours, and can last for 10-12 hours.

Thiazide-induced diuresis initially leads to a decrease in plasma volume, cardiac output and systemic blood pressure. The renin-angiotensin-aldosterone system may be activated. The hypotensive effect is maintained when the medicine is continued, probably as a result of the decrease in peripheral resistance; the cardiac output returns to the baseline level, the plasma volume remains somewhat lower and plasma renin activity may be increased.

Hydrochlorothiazide is not effective in patients with chronic renal impairment (creatinine clearance < 30 ml/min and / or serum-creatinine greater than 1.8 mg/100 ml).

Hypertension

With long-term use, the antihypertensive effect of hydrochlorothiazide is dose dependent, in most patients, between 12.5 and 50-75 mg/day.

The therapeutic effect of hydrochlorothiazide remains steady beyond a certain dose, whilst adverse effects continue to increase. If treatment is ineffective, increasing the dose above the recommended dose is poorly tolerated and, from a therapeutic point of view, is rarely necessary (see section 4.2).

In nephrogenic diabetes insipidus, hydrochlorothiazide decreases the urine volume and increases the osmolality of the urine.

Non-melanoma skin cancer

Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

5.2 Pharmacokinetic properties

Absorption

After oral administration hydrochlorothiazide is absorbed rapidly (T_max about 2 hours). The increase in mean AUC is linear and dose proportional within the therapeutic range.

Variations in absorption as a result of fasting or food intake are of limited clinical significance. After oral administration, the absolute bioavailability of hydrochlorothiazide is 70%.

The absorption of hydrochlorothiazide is reduced in patients who suffer from heart failure.

Continuous administration does not alter the metabolism of hydrochlorothiazide. After 3 months treatment with a daily dose of 50 mg of hydrochlorothiazide, absorption, elimination or excretion are similar to those seen during short-term treatment.

Distribution

Hydrochlorothiazide accumulates in the erythrocytes and reaches a maximum concentration about 4 hours after oral administration. After 10 hours the concentration in the erythrocytes is roughly threefold higher than in plasma. A binding to the plasma proteins of about 40-70% has been reported and the apparent distribution volume may be estimated at 4-8 l/kg.

The half-life is highly variable from one subject to another and is between 6 and 25 hours.

Biotransformation and elimination

Hydrochlorothiazide is eliminated from plasma mainly as unchanged drug, with a half-life of about 6 to 15 hours in the terminal elimination phase. Within 72 hours, 60 to 80% of a single oral dose is excreted in the urine, 95% in unchanged form, and 4% as the hydrolysate 2-amino-4-chloro-m-benzenedisulfonamide (ABCS). Up to 24% of the oral dose is excreted in the faeces and a negligible amount is eliminated via the bile.

In patients with renal impairment and heart failure the urinary excretion rate is decreased, and elimination half-life is increased. The same occurs in the elderly, with a further increase in the maximum plasma concentration.

5.3 Preclinical safety data

Although equivocal evidence for a genotoxic or carcinogenic effect was found in some experimental models, the extensive human experience with hydrochlorothiazide has failed to show an association between its use and an increase in neoplasms.

Hydrochlorothiazide was not teratogenic and had no effects on fertility and conception of mice and rats.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Maize starch

Talc

Colloidal anhydrous silica

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

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

6.5 Nature and contents of container

Aluminium/PVC foil blisters.

A pack contains 20, 30, 50 or 100 tablets with a leaflet in a cardboard box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

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

7 MARKETING AUTHORISATION HOLDER

Aspire Pharma Limited

Unit 4, Rotherbrook Court,

Bedford Road,

Petersfield,

GU32 3QG,

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 35533/0304

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

05/08/2026

10 DATE OF REVISION OF THE TEXT

05/08/2026