·         Oedema due to heart or renal disease.

·         Oedema due to hepatic impairment usually in combination with a potassium-sparing diuretic.

·         Arterial hypertension

Posology

As with all other diuretics, therapy should be initiated with the lowest possible dose. This dose should be established according to the individual patient’s response to gain maximum therapeutic benefit while keeping side effects to a minimum. The daily dosage of ESIDREX can be administered as a single dose or in two divided doses, with or without food.

Oedemas

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

The maintenance dose is 25 to 50 mg/day or once every 2 days.

Hypertension

The current recommended dosages for high blood pressure are 12.5 or 25 mg/day.

For a given dose, the maximum effect is reached in 3 to 4 weeks. If the decrease in blood pressure proves inadequate with 25mg/day, combined treatment with another antihypertensive drug is recommended. Sodium and/or volume depletion should be corrected prior to the use of ESIDREX in combination with an ACE inhibitor, an angiotensin II receptor blocker or a direct renin inhibitor. Or the treatment should start under close medical supervision.

Specific populations

Renal impairment

Patients with mild to moderate renal impairment require no adjustment of the initial dose (see section 5.2).

ESIDREX is contraindicated in patients with anuria and with severe renal disease.

Hepatic impairment

Patients with mild to moderate hepatic impairment require no adjustment of the initial dose.

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

Method of administration

This drug is administered orally.

The scored tablets should be taken with water.

Special warnings

Patients with bilateral renal artery stenosis, unilateral stenosis with a single functional kidney, or with hypokalaemia, should not normally take this medicinal product.

Hydrochlorothiazide is a sulfonamide. The possibility of an allergic cross-reaction with other sulfonamides, including antimicrobials, remains hypothetical and has not been validated clinically.

Hepatic impairment

Thiazide diuretics, like other diuretics, may precipitate electrolyte imbalance, hepatic encephalopathy or hepatorenal syndrome when used to treat cirrhotic ascites. Hydrochlorothiazide should be used with caution, especially in patients with severe hepatic impairment.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) with an increase in the cumulative dose of hydrochlorothiazide (HCTZ) was observed in two epidemiological studies from the Danish Cancer Registry. The photosensitising effect of HCTZ could be a potential molecular mechanism of NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and be advised to regularly check their skin for any new lesions and promptly report any suspicious skin damage. Preventative measures include limited exposure to the sun and UV rays and, if exposed, patients should be advised about adequate protection to minimise the risk of skin cancer. Suspicious skin damage should be examined as soon as possible, including potential histological analysis of biopsies. The use of HCTZ may also need to be reconsidered in patients who have previously been diagnosed with NMSC (see also section 4.8).

Photosensitive reactions have been reported during the use of thiazide diuretics (see section 4.8).

If a photosensitive reaction occurs during treatment, it is recommended that the treatment be discontinued. If re-administration of the treatment is essential, areas of the body exposed to the sun or artificial UVA should be protected.

This drug can be used by patients with coeliac disease. Wheat starch may contain gluten, but only trace amounts, and is therefore considered safe for patients with coeliac disease.

This drug contains lactose. Patients with a galactose intolerance, Lapp lactase deficiency or glucose- galactose malabsorption syndrome (rare hereditary diseases) are advised against taking this drug.

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.

Precautions for use Electrolyte balance Natraemia

Serum sodium concentration should be checked before treatment is initiated, and at regular intervals thereafter.

Thiazide diuretics can precipitate hyponatraemia or exacerbate pre-existing hyponatraemia. In severely sodium depleted and/ or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of treatment with hydrochlorothiazide.

As the drop in serum sodium may initially be asymptomatic, regular monitoring is essential and should be even more frequent in at-risk populations: elderly subjects, particularly those with malnutrition, and patients with cirrhosis (see sections 4.8 and 4.9).

Patients with ascites due to liver cirrhosis and patients with oedema caused by nephrotic syndrome must be monitored particularly closely.

Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Thiazide diuretics should only be used after correction of any pre- existing sodium and/or volume depletion. Otherwise, treatment should be started under close medical supervision.

Kalaemia

Thiazide and related diuretics may precipitate new-onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving significant loss of potassium, for example, in salt-losing nephropathies or prerenal (cardiogenic) impairment of kidney function.

The risk of onset of hypokalaemia (<3.5 mmol/L) must be considered in certain at-risk populations: elderly and/or malnourished and/or polymedicated subjects, cirrhosis patients with oedema and ascites, and patients with coronary heart disease or heart failure. This is because, in these patients, hypokalaemia increases the cardiac toxicity of digitalis glycosides and the risk of heart rhythm disorders.

Patients with a prolonged QT interval on ECG are also at risk, whether this is congenital or drug-induced. Hypokalaemia (like bradycardia) predisposes such patients to the onset of severe heart rhythm disorders, notably torsades de pointes, which can be fatal, particularly in the presence of bradycardia.

Correction of hypokalaemia and any coexisting hypomagnesaemia is recommended prior to the initiation of thiazides.

The first plasma potassium measurement must be taken in the week after the treatment is introduced.

Thereafter, serum potassium concentrations should be carried out periodically. All patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium.

For chronic treatment, serum potassium concentrations should be checked at the start of treatment. Monitoring at weeks 3-4 may be considered depending on the risk factors. Regular monitoring is subsequently advised, particularly in at-risk patients.

Uric acid

Like other diuretics, ESIDREX can produce an increase in plasma concentrations of uric acid, due to the decrease in its urinary excretion, and thus contribute to the onset of hyperuricaemia or exacerbate pre-existing hyperuricaemia, potentially triggering episodes of gout in predisposed patients.

The dose must be adapted based on plasma concentrations of uric acid.

Metabolic effects

Serum calcium

Thiazide diuretics decrease urinary excretion of calcium and can result in a mild, temporary elevation in serum calcium in patients with no known calcium metabolism problems. ESIDREX must be used with caution in patients with hypercalcaemia and must not be administered until after any pre-existing hypercalcaemia has been corrected. ESIDREX must be withdrawn if patients develop hypercalcaemia during treatment. Serum calcium must be monitored regularly during treatment with thiazide diuretics. Marked hypercalcaemia may indicate hidden hyperparathyroidism. Thiazide diuretics must be withdrawn before investigating parathyroid function.

Blood glucose and serum lipids

Thiazide diuretics, including hydrochlorothiazide, may decrease glucose tolerance and raise serum levels of cholesterol and triglyceride. Patients with diabetes may require adaptation of their doses of insulin or oral glucose-lowering agents.

Renal function and diuretics

Thiazide diuretics are fully effective only in patients with normal or mildly impaired renal function (assessed for example by calculating creatinine clearance from serum creatinine level). In elderly subjects, creatinine clearance values must be adjusted based on the age, weight and sex of the patient, using the Cockcroft-Gault formula, for example:

CrCl = (140 - age) x weight/0.814 x serum creatinine With:

·         age expressed in years,

·         weight in kg,

·         serum creatinine in micromol/L.

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

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

This temporary functional renal impairment may exacerbate pre-existing renal impairment.

Acute myopia and secondary angle-closure glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in acute 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 hydrochlorothiazide as rapidly as possible. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamides or penicillin allergy.

Others

Combinations with anti-hypertensives

It is advisable to reduce the dose when used in combination with another antihypertensive, at least initially.

The anti-hypertensive effect of ACE inhibitors, angiotensin II antagonists or renin inhibitors is potentiated by treatments that increase plasma renin activity (diuretics).

Caution is advised when an ACE inhibitor, an angiotensin II antagonist, or a direct renin inhibitors is co- administered with ESIDREX, particularly in severely sodium-depleted and/or volume depleted patients.

Athletes

Athletes must be made aware that this product contains an active substance that may produce a positive reaction in an anti-doping test.

Other

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

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

Interactions may result from concomitant administration of ESIDREX with the following medicinal products.

+ Potassium-lowering medicinal products

Hypokalaemia is a contributing factor to the onset of heart rhythm disorders (notably torsades de pointes) and the increased toxicity of certain medicinal products, such as digoxin. As such, medicinal products that can result in hypokalemia are involved in a large number of interactions. These consist of potassium-lowering diuretics, used alone or in combination, stimulant laxatives, glucocorticoids, tetracosactide and amphotericin B (IV administration).

+ Sodium-lowering medicinal products

Certain medicinal products are more commonly involved in the onset of hyponatraemia. These consist of diuretics, desmopressin, selective serotonin reuptake inhibitor antidepressants, carbamazepine and oxcarbazepine. Using these medicinal products in combination increases the risk of hyponatraemia.

Combinations to avoid

+ Lithium

Increased serum lithium with signs of lithium overdose, such as with a low sodium diet (decreased renal excretion of lithium).

If the combination cannot be avoided, carefully monitor serum lithium and adapt the lithium dose.

Combinations subject toprecautions for use

+ Acetylsalicylic acid

When using acetylsalicylic acid as an anti-inflammatory (≥ 1 g per dose and/or ≥ 3 g per day) or for pain relief or to treat fever (≥ 500 mg per dose and/or < 3 g per day):

Acute kidney injury in patients with dehydration, due to reduced glomerular filtration rate secondary to reduced renal prostaglandin synthesis. The antihypertensive effect is also reduced.

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

+ Nonsteroidal anti-inflammatories

Acute kidney injury in at-risk (elderly and/or dehydrated) patients due to reduced glomerular filtration rate (inhibition of prostaglandin-mediated vasodilation by nonsteroidal anti-inflammatories). The antihypertensive effect is also reduced.

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

+ Carbamazepine

Risk of symptomatic hyponatraemia. Clinical and laboratory monitoring required. If possible, use a different class of diuretics.

+ Ion-exchange resins

Taking ion-exchange resins can reduce the intestinal absorption and, potentially, efficacy of other medicinal products taken concomitantly. Ion-exchange resins should generally be taken separately from other medicinal products, with an interval of more than 2 hours between them if possible.

+ Digitalis glycosides

Hypokalaemia predisposing patients to the toxic effects of digitalis glycosides.

Correct any hypokalaemia before starting treatment, and put the patient on clinical, electrolyte and electrocardiogram monitoring.

+ Potassium-sparing diuretics (alone or in combination)

Although the logical combination is useful for some patients, the onset of hypokalaemia or hyperkalaemia, particularly in patients with renal impairment or diabetes, cannot be ruled out.

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

+ Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers

Risk of sudden hypotension and/or acute kidney injury when introducing or increasing the dose of treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in patients with pre-existing salt and water depletion.

In patients with hypertension for whom previous diuretic treatment resulted in salt and water depletion, it is necessary to:

·         either withdraw the diuretic before beginning treatment with the angiotensin II receptor blocker or ACE inhibitor, and reintroduce a potassium-lowering diuretic if subsequently required;

·         or administer a reduced dose of the angiotensin II receptor blocker or ACE inhibitor to begin with and gradually increase the dose.

In patients with congestive heart failure on diuretic therapy, begin the ACE inhibitor or angiotensin II receptor blocker on a very low dose, if needed after reducing the dose of the potassium-lowering diuretic used in combination.

In all cases, monitor renal function (serum creatinine) in the first few weeks of treatment with an ACE inhibitor or angiotensin II receptor blocker

+ Medicinal products that may cause torsades de pointes (amiodarone, amisulpride, arsenic-based agents, 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, particularly torsades de pointes.

Correct any hypokalaemia before administering the product and put the patient on clinical, electrolyte and electrocardiogram monitoring.

+ Other potassium-lowering agents

Increased risk of hypokalaemia. Monitor serum potassium with correction if needed.

+ Iodinated contrast products

In patients with diuretic-induced dehydration, increased risk of functional acute kidney injury, particularly if iodinated contrast products are used at high doses.

Rehydrate before administering the iodinated contrast product.

Combinations to take into consideration

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

Increased hypotensive effect. Increased risk of orthostatic hypotension.

+ Antihypertensive alpha-blockers

Increased hypotensive effect. Increased risk of orthostatic hypotension.

+ Medicinal products causing orthostatic hypotension

Other than antihypertensives, numerous medicinal products may cause orthostatic hypotension. They include in particular nitrovasodilators, phosphodiesterase type 5 inhibitors, alpha-blockers for urological purposes, tricyclic antidepressants and phenothiazine antipsychotics, dopamine agonists, levodopa, baclofen, amifostine, etc.

Increased risk of hypotension, in particular orthostatic hypotension.

+ Calcium

Risk of hypercalcaemia due to reduced urinary excretion of calcium.

+ Ciclosporin

Risk of increased serum creatinine with no change in blood concentrations of ciclosporin, even in the absence of salt and water depletion. Also risk of hyperuricaemia and complications such as gout.

+ Nitrovasodilators and related products

Increased risk of hypotension, in particular orthostatic hypotension.

Pregnancy

There are limited data on the use of hydrochlorothiazide during pregnancy, particularly during the first trimester. The animal studies are inadequate.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, using it during the second and third trimesters of pregnancy may reduce foetoplacental circulation and produce fetal and neonatal effects such as jaundice, electrolyte imbalance and thrombocytopenia.

Hydrochlorothiazide must not be used in patients with gestational oedema, gestational hypertension or pre-eclampsia due to the risk of reduced plasma volume and placental hypoperfusion, with no beneficial effect on the disease course.

Hydrochlorothiazide must not be used to treat essential hypertension in pregnant women, other than in exceptional cases where no other treatment can be used.

Breastfeeding

Hydrochlorothiazide is excreted in human milk in low quantities. High-dose thiazide diuretics resulting in significant urine output may inhibit lactation.

The use of ESIDREX in breast-feeding women is not recommended. If ESIDREX is used in breast- feeding women, this must remain at the lowest possible dose.

Fertility

There are no human fertility data for ESIDREX.

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

Not relevant.

Adverse reactions (Table 1) are ranked by frequency, starting with the most frequent according to the following convention: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000) and unknown (cannot be estimated based on available data).

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

**Cases of choroidal effusion with visual field defect have been reported after the use of thiazide

and thiazide-like diuretics. If cases are to be reported for these substances in the future, the appropriate procedure should be used to update the product information accordingly.

Reporting of suspected adverse reactions

It is important to declare any suspected adverse effects after drug authorization. This ensures ongoing monitoring of the drug’s risk/benefit ratio. Healthcare professionals should report any suspected adverse reactions via the national reporting system: Please report adverse drug events to:

The National Pharmacovigilance Centre (NPC):

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration due to excessive urination. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalaemia can cause muscle spasms and/or exacerbate the cardiac arrhythmias associated with concomitant use of digitalis glucosides and some antiarrhythmic medicinal products.

Treatment consists of restoring the water-electrolyte balance, hyponatraemia must be corrected gradually. Cardiovascular monitoring should be put in place depending on the patient’s clinical status.

Pharmacotherapeutic class: CORTICAL DILUTING SEGMENT DIURETICS ATC code: C03AA03.

Mechanism of action

Hydrochlorothiazide, the active substance in ESIDREX is a benzothiadiazide diuretic.

Thiazide diuretics act primarily on the distal renal tubule (early convoluted part), inhibiting the reabsorption of sodium chloride (by blocking the NaCl cotransporter).

The enhanced delivery of Na+ and water to the cortical collecting tubule and/or the increased flow rate leads to increased secretion and excretion of K+ and H+. The inhibition of NaCl reabsorption also results in indirect stimulation of Ca2+reabsorption.

The diuretic and natriuretic effect appears within 1 to 2 hours after oral administration of hydrochlorothiazide.

Maximum activity is reached after 4 to 6 hours and may persist for 10 to 12 hours.

Thiazide-induced diuresis initially leads to decreases in plasma volume, cardiac output, and systemic blood pressure. The renin-angiotensin-aldosterone system may become activated. With continuous administration, the hypotensive effect is maintained, probably due to a fall in total peripheral vascular resistance; cardiac output returns to pre-treatment values, plasma volume remains somewhat reduced, and plasma renin activity may be elevated.

Hypertension

With chronic administration, the anti-hypertensive effect of ESIDREX is dose dependent in most patients, for doses ranging from 12.5 mg/day up to 50-75 mg/day.

The therapeutic effect of thiazide diuretics plateaus beyond a certain dose, while the undesirable effects continue to increase: if the treatment is ineffective, increasing the dose beyond the recommended posology is of no benefit, and is often poorly tolerated (see section 4.2).

In patients with nephrogenic diabetes insipidus, hydrochlorothiazide reduces urinary volume and increases urinary osmolality.

Non-melanoma skin cancer

Based on available data from epidemiological studies, a dose-dependent cumulative association between HCTZ and NMSC has been observed.

One trial included a population of 71,533 cases of BCC and 8,629 cases of SCC matched to 1,430,833 and 172,462 controls in the population, respectively. High use of HCTZ (cumulative dose ≥50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval: 1.23-1.35) for BCC and 3.98 (95% confidence interval: 3.68-4.31) for SCC. A clear relationship between the cumulative dose-response relationship was observed for BCC and SCC.

Another trial showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip cancer were matched to 63,067 controls in the population, using a risk-based sampling strategy. A cumulative dose-response relationship has  been demonstrated with an adjusted OR  of  2.1    (95%

confidence interval: 1.7-2.6) up to an OR of 3.9 (3.0-4.9) for high use (~25000 mg) and an OR of 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

Absorption

Following oral administration, hydrochlorothiazide is rapidly absorbed (Tmax of around 2 hours). The increase in mean AUC is linear and dose-proportional within the therapeutic window.

Food intake has a limited clinical impact on absorption of hydrochlorothiazide. Following oral administration, the absolute bioavailability of hydrochlorothiazide is 70%.

In patients with congestive heart failure, absorption of hydrochlorothiazide is reduced.

Continuous administration does not affect the metabolism of hydrochlorothiazide. After 3 months of treatment with a daily dose of 50 mg of hydrochlorothiazide, absorption, elimination or excretion are similar to what is observed during short-term treatments.

Distribution

Hydrochlorothiazide accumulates in erythrocytes, reaching a peak concentration 4 hours after oral administration. After 10 hours, the concentration in erythrocytes is approximately 3 times higher than that of plasma. Binding to plasma proteins to the extent of approximately 40-70% has been reported, and the apparent volume of distribution has been estimated at 4-8 L/kg.

The half-life varies significantly from one subject to another: it is between 6 and 25 hours.

Elimination

Hydrochlorothiazide is largely unchanged when it leaves the plasma, with a half-life of approximately 6 to 15 h 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 2-amino-4-chloro-m-benzenedisulfonamide hydrolyzate (ABCS). Up to 24% of an oral dose is found in faeces and a negligible amount is excreted in the bile.

In patients with renal impairment or heart failure, the renal clearance of hydrochlorothiazide is reduced, and its elimination half-life is increased. This is also the case in elderly subjects, in whom an increase in the maximum plasma concentration is also observed.

The mutagenic potential was assessed in a series of in vitro and in vivo test systems. While some positive results were obtained in vitro, all in vivo tests were negative.

Hydrochlorothiazide showed no carcinogenic activity in rats. In mice, hepatocellular carcinoma was observed in males receiving a high dose with an incidence not greater than that usually seen in the control animals.

Hydrochlorothiazide is not teratogenic and has no effects on fertility and conception. No teratogenic potential was revealed in 3 animal species receiving doses at least 10 times higher than the recommended human doses, of the order of 1 mg/kg. A decrease in weight gain in suckling rat pups was attributed to the high dose (15 times the human dose) and diuretic effects of hydrochlorothiazide, with subsequent effects on milk production (see section 4.6).

Lactose monohydrate, wheat starch, talc, colloidal anhydrous silica, magnesium stearate.

Not relevant.

Store in the original package away from moisture.

Store in the original package away from light.

20 scored tablets within blisters (PVC/PE/PVDC/Aluminium).

30 scored tablets within blisters (PVC/PE/PVDC/Aluminium).

90 scored tablets within blisters (PVC/PE/PVDC/Aluminium).

Not all pack sizes may be marketed.

No specific requirements

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