Zidaflo Tablets

Oedema due to sodium and water retention: Paradoxically, hydrochlorothiazide appears to have an antidiuretic effect on patients with diabetes insipidus and may be of value in the management of the disease.

Essential hypertension: Preferably in combination with reduced doses of specific anti-hypertensive medicines.

Posology

If a single dose of ZIDAFLO 12,5 mg is indicated, the dose should preferably be taken in the morning in order to minimise the effect of increased frequency of urination during sleep. ZIDAFLO 12,5 mg should be taken with or after meals to minimise stomach upset.

Adults - For the treatment of oedema: An initial dose of 25 to 100 mg is usually given, and later reduced to a smaller maintenance dose, often given on alternative days. An initial dose of up to 200 mg may be necessary in some patients, but larger doses have no additional effect.

Adults u2013 For the treatment of mild to moderate hypertension: 12,5 mg daily.

Adults - As an adjunct in the treatment of hypertension: 25 u2013 100 mg daily in conjunction with a reduced dose of the hypotensive medicine. The dosage should not be higher than necessary to achieve the desired effect. Prolonged treatment may result in potassium ion loss. Potassium supplements may be necessary.

Paediatric population: 2,5 mg per kg body mass daily in two divided doses.

Method of administration: The tablet should be taken orally.

• Hypersensitivity to the hydrochlorothiazide or to any of the excipients listed in section 6.1.
• Patients with anuria or severe renal insufficiency (creatinine clearance < 30 mL/min).
• Patients with severe hepatic impairment.
• Patients with Addisonu2019s disease.
• Patients with pre-existing hypercalcaemia.
• The second and third trimesters of pregnancy and during lactation (see section 4.6).
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

Hepatic impairment: ZIDAFLO should be used with caution in patients with impaired hepatic function since they may increase the risk of hepatic encephalopathy. Patients with hepatic cirrhosis are particularly at risk from hypokalaemia.

Metabolic and endocrine effects: Thiazide treatment as in ZIDAFLO can alter glucose tolerance. In diabetic patients it may be necessary to adjust the dose of insulin or oral hypoglycaemic. During the administration of thiazides, latent diabetes mellitus may occur.

Cholesterol and triglyceride levels: Increases in cholesterol and triglyceride levels have been associated with treatment with thiazide diuretics. Hydrochlorothiazide should be administered with caution to patients with gout or hyperuricemia, since the medicine reduces uric acid clearance. Cases of gout attacks have been reported at the start of a hydrochlorothiazide treatment. The dosage will be adapted based on the plasma concentrations of uric acid.

Renal impairment: Hydrochlorothiazide should be used with caution in patients with renal dysfunction because the hypovolemia produced by the medicine can trigger uremia, thus further reducing renal function.

Hyperuricaemia: Hyperuricaemia may occur or ZIDAFLO may precipitate attacks of acute gout in susceptible patients.

Electrolyte imbalance: All patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid. As in any patient who is receiving a diuretic treatment, a periodic determination of serum electrolytes should be made at appropriate intervals. The warning signs of an imbalance of fluids or electrolytes are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, pain or muscle cramps, muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disorders, such as nausea or vomiting. Patients with serious electrolyte imbalances such as hyponatremia or hypokalaemia should correct such imbalances before starting a diuretic treatment with hydrochlorothiazide. Otherwise, these medicines can cause serious dysrhythmias, hypotension and seizures. The elderly, malnourished, polymedicated, cirrhotic and patients with heart failure are more likely to develop such reactions.

Hypercalcaemia: ZIDAFLO may increase plasma calcium concentrations and should be used with caution in patients with hypercalcemia. High hypercalcaemia may indicate hidden hyperparathyroidism. Thiazide treatment should be discontinued before performing parathyroid function tests.

Hypomagnesaemia: It has been observed that thiazides increase urinary excretion of magnesium, which can lead to hypomagnesaemia.

Hypokalaemia: Hypokalaemia may develop, especially with brisk diuresis, in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH) also known as corticotropin, of after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalaemia. Hypokalaemia may cause cardiac dysrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalaemia may be avoided or treated by use of potassium sparing diuretics or potassium supplements such as foods with a high potassium content.

Chloride deficit: Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Hyponatremia: Dilutional hyponatremia may occur in oedematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Systemic lupus erythematosus (SLE): There is a possibility that ZIDAFLO may exacerbate or activate systemic lupus erythematosus in susceptible patients.

Lithium: Lithium generally should not be given with ZIDAFLO (see section 4.5).

Acute myopia and secondary angle-closure glaucoma: ZIDAFLO, a sulphonamide, can cause 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 medicine initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue ZIDAFLO 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 sulphonamide or penicillin allergy.

Post-sympathectomy: The antihypertensive effects of ZIDAFLO may be enhanced in the post-sympathectomy patient.

Anti-doping test: The hydrochlorothiazide contained in ZIDAFLO could give a positive test result.

Hypersensitivity reactions: Sensitivity reactions may occur in patients with and without a history of allergy or bronchial asthma. ZIDAFLO may exacerbate or activate systemic lupus erythematosus. Cases of pancreatitis have been reported in patients treated with hydrochlorothiazide as in ZIDAFLO, so ZIDAFLO should be administered with caution to patients with a history of pancreatitis.

When ZIDAFLO is administered with other diuretics or antihypertensives, additive effects are observed, which is used to increase its effectiveness. However, orthostatic hypotension may also occur, so it is necessary to adjust the doses appropriately to the needs of each patient. People over 65 may have a greater sensitivity to the diuretic effects of ZIDAFLO. Elderly patients are particularly susceptible to electrolyte imbalance.

Non-melanoma skin cancer: An increased risk of non-melanoma skin cancer (NSCLC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] has been observed with exposure to increasing cumulative doses of hydrochlorothiazide (HCTZ) in two epidemiological studies. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC. Patients taking ZIDAFLO should be informed of the risk of NMSC and advised to regularly check their skin for new lesions and promptly report any suspicious skin lesions. Possible preventative measures such as limited exposure to sunlight and UV rays and, in the case of exposure, adequate protection should be advised to the patients to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. ZIDAFLO should not be used by patients who have had previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin or lip (see section 4.3).

Excipients: lactose intolerance: ZIDAFLO contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take ZIDAFLO.

Antidiabetic medicines (oral medicines or insulin): Thiazide diuretics, as in ZIDAFLO reduce insulin sensitivity increasing glucose intolerance and hyperglycaemia. Therefore, diabetic patients who start a hydrochlorothiazide treatment, as in ZIDAFLO should carefully monitor their blood glucose levels and properly adjust the doses of antidiabetics.

Baclofen: Baclofen increased antihypertensive effect. Blood pressure and renal function should be monitored and the dosage of the antihypertensive will be adapted.

Other Antihypertensives: Concomitant use with ZIDAFLO produces an additive effect, increasing the hypotensive effect.

IECAs: Possible potentiation of toxicity with the presence of hypokalemia.

Cholestyramine and colestipol resins: The absorption of hydrochlorothiazide decreases or is delayed in the presence of ion exchange resins. Single doses of cholestyramine or colestipol fix hydrochlorothiazide, as in ZIDAFLO and reduce its gastrointestinal absorption up to 85 % and 43 %, respectively. It is recommended to administer thiazides at least 4 hours before cholestyramine. The same goes for colestipol, although to a lesser extent, so it is recommended to administer thiazides at least 2 hours before.

Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH), beta2-agonists or carbenoxolone or stimulant laxatives: ZIDAFLO may intensify electrolyte disturbance, especially hypokalemia. Concomitant use of hydrochlorothiazide with amiloride, spironolactone or triamterene may reduce the risk of hypokalemia, due to its potassium-sparing effects. The use of these medicines may be an alternative to potassium supplements that are recommended for patients treated with diuretics. The risk of hydrochlorothiazide-induced hypokalemia is higher if it is administered concomitantly with other medicines that also reduce plasma potassium levels such as corticosteroids (corticotropin, amphotericin B), beta 2-agonists such as salbutamol or carbenoxolone. In these cases it is recommended to monitor potassium levels and cardiac function, adding if necessary potassium supplements.

Pressing amines (for example, epinephrine / adrenaline): ZIDAFLO may decrease the response to pressor amines, such as (norepinephrine /noradrenaline) but not enough to prevent its use.

Non-depolarizing muscle relaxants (eg, tubocurarine): ZIDAFLO may enhance the neuromuscular blocking action of competitive muscle relaxants such as turbocurarine.

Lithium: Concomitant administration of ZIDAFLO and lithium is not generally recommended since the association may lead to toxic blood concentrations of lithium. Although diuretics are sometimes used to counteract the polyuria caused by lithium, plasma levels must be monitored and doses adjusted (reduce lithium dose to 50 %) when combined with the diuretic.

Nonsteroidal anti-inflammatory drugs (indomethacin): Inhibition of renal synthesis of prostaglandins produced by nonsteroidal anti-inflammatory drugs may reduce the diuretic, natriuretic and antihypertensive effects of ZIDAFLO. It can also increase the risk of kidney failure, by reducing renal blood flow. Careful monitoring of these patients is recommended to check for any change in the effectiveness of diuretic treatment or any symptoms of renal impairment and if necessary hydrate the patient.

Calcium salts: An increase in serum calcium levels may occur due to a decrease in urinary excretion, when administered concomitantly with thiazide diuretics as in ZIDAFLO, which may cause hypercalcemia.

Cardiac glycosides: Increases the possibility of digitalis toxicity (digoxin), associated with thiazide-induced hypokalemia.

Medicines associated with Torsades de pointes (sultopride): Due to the risk of hypokalemia, caution should be used when administering ZIDAFLO with medicines associated with torsades de pointes, e.g., some antiarrhythmics (eg: quinidine, hydroquinidine, disopyridine, amiodarone, sotalol, dofetilide, ibutilide), some antipsychotics (eg, thioridazine, clopromazine, levomepromazine, sulpiride, haloperidol) and other medications known to induce Torsades de Pointes (eg: Ketanserin, mizolastin, vincamine, cisapride, erythromycin iv).

Carbamazepine: The concomitant use of carbamazepine and hydrochlorothiazide as in ZIDAFLO has been associated with the risk of symptomatic hyponatremia. The level of electrolytes should be controlled during this concomitant administration. If possible, another class of diuretic should be administered.

Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricemia and gouty complications.

Tetracyclines: The concomitant administration of tetracyclines and thiazide diuretics increases the risk of increased urea induced by tetracyclines. This interaction is probably not applicable to doxycycline.

Anticholinergic medicines (eg atropine, biperidene): The bioavailability of thiazide diuretics may increase with anticholinergic medicines, due to a decrease in gastrointestinal motility and the rate of stomach emptying.

Medicines used for the treatment of gout (probenecid, sulfinpyrazone and allopurinol): A dosage adjustment of uricosuric medication may be necessary since hydrochlorothiazide as in ZIDAFLO may raise the level of serum uric acid. It may be necessary to increase the dose of probenecid or sulfinpyrazone. Concomitant administration of thiazide diuretics, including ZIDAFLO, may increase the incidence of allopurinol hypersensitivity reactions.

Beta blockers and diazoxide: The concomitant use of thiazide diuretics, including hydrochlorothiazide as in ZIDAFLO, with beta blockers may increase the risk of hyperglycemia. Thiazide diuretics, including ZIDAFLO, may increase the hyperglycemic effect of diazoxide.

Methyldopa: Isolated cases of hemolytic anemia have been reported in patients who received concomitant treatment with hydrochlorothiazide as in ZIDAFLO and methyldopa.

Amantadine: Thiazides, including ZIDAFLO, may increase the risk of adverse effects due to amantadine due to decreased tubular secretion.

Cytotoxic medicines (eg cyclophosphamide, methotrexate): Thiazides, including ZIDAFLO, can reduce renal excretion of cytotoxic medicines and enhance their myelosuppressive effects.

Salicylates: In case of high doses of salicylates, ZIDAFLO may potentiate the toxic effect of salicylates on the central nervous system. They can also produce hypokalemia.

Antihypertensive medicines, alcohol, barbiturates, narcotics or antidepressants and opioids: ZIDAFLO may enhance the effect of other antihypertensive medicines, while postural hypotension associated with this therapy may be enhanced by concomitant ingestion of alcohol, barbiturates, or opioids. Diuretic therapy with ZIDAFLO should be discontinued for 2 to 3 days prior to initiation of therapy with an ACE-inhibitor, to reduce the likelihood of first dose hypotension.

Other interactions: Thiazide diuretics, including ZIDAFLO may increase the photosensitizing effects of some medicines such as griseofulvin, phenothiazines, sulfonamides and sulfonylureas, tetracyclines, retinoids and medicines used in photodynamic therapy.

Laboratory tests: ZIDAFLO may cause analytical interference in the diagnosis of the bentiromide test. ZIDAFLO may decrease serum Protein Bound Iodine (PBI) levels without signs of thyroid disturbance. Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function. Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals.

Iodine contrast medium: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine products. Patients should be rehydrated before administration.

The safety of ZIDAFLO in pregnancy and lactation has not been established.

Pregnancy: There is limited experience on the use of hydrochlorothiazide as in ZIDAFLO during pregnancy.

Breastfeeding: Hydrochlorothiazide is excreted in breast milk and is not recommended for use in breastfeeding.

Fertility: No data are available.

ZIDAFLO can cause headache and dizziness, drowsiness and visual disturbance. Patients should not drive, use machinery, or perform any tasks that require concentration until they are certain that ZIDAFLO does not adversely affect their ability to do so.

Adverse effects of ZIDAFLO are rare (< 10 %) and are generally dose-related, and can be minimized by establishing the minimum effective dose, particularly in arterial hypertension.

a) Tabulated list of adverse reactions

The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with hydrochlorothiazide.

System Organ Class Frequency Frequent Less Frequent Not known Infections and infestations Sialadenitis Neoplasm benign, malignant and unspecified (including cysts and polyps) Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) Blood and lymphatic system disorders Aplastic anaemia, haemolytic anaemia, leukopenia, purpura, Agranulocytosis, neutropenia, bone marrow thrombocytopenia, blood dyscrasias depression Immune system disorders Hypersensitivity reactions Anaphylactic reactions, purpura Metabolism and nutrition disorders Electrolyte imbalances, Hypochloraemic alkalosis, hyponatraemia (may occur in patients with severe heart failure who are very oedematous, particularly with large doses in conjunction with restricted salt in the diet), and hypokalaemia (intensifies the effect of digitalis on cardiac muscle and administration of digitalis or its glycosides may have to be temporarily suspended) Metabolic disturbances especially at high doses, hyperglycaemia and carbohydrate intolerance in diabetic and other susceptible patients, asymptomatic hyperuricaemia and precipitate attacks of gout in some patients, hypomagnesaemia, anorexia hypokalaemia, electrolyte imbalance (hyponatraemia, hypochloraemia, metabolic alkalosis, hypercalcaemia and hypokalaemia), increased cholesterol and triglycerides. Psychiatric disorders Restlessness Agitation, depression, sleep disorders. Nervous system disorders Lethargy, drowsiness, seizures Loss of appetite, paraesthesia, dizziness, vertigo, headache, weakness, restlessness. Light-headedness Eye disorders xhantopsia (yellow vision) Transient blurred vision, choroidal effusion Ear and labyrinth disorders Vertigo Cardiac disorders allergic myocarditis, vasculitis Cardiac dysrhythmias Vascular disorders Postural hypotension (aggravated by barbiturates, alcohol or narcotics) Necrotising angiitis (vasculitis, cutaneous vasculitis) Respiratory, thoracic and mediastinal disorders Respiratory disorders including pneumonitis, pulmonary oedema. Respiratory distress Gastrointestinal disorders Gastrointestinal disturbances, dry mouth Gastric irritation, nausea, vomiting, constipation, diarrhoea, intestinal ulceration has occurred following the administration of tablets containing thiazides with an enteric-coated core of potassium chloride, pancreatitis, cramping Hepatobiliary disorders Intrahepatic cholestatic jaundice. Skin and subcutaneous tissue disorders Photosensitivity reactions, rash, Erythema multiforme including Stevens-Johnson Syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria Musculoskeletal and connective tissue disorders Muscle pain and cramps Muscle spasm Renal and urinary disorders Oliguria Renal function disorders, interstitial nephritis, polyuria, polaquiuria, glycosuria, urinary excretion of calcium is reduced Renal failure, renal dysfunction, interstitial nephritis Reproductive system and breast disorders Impotence General disorders and administration site conditions Thirst, weakness Fever

b) Description of selected adverse reactions: Eye disorders: 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 ZIDAFLO is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms: ZIDAFLO can produce acute renal failure either from overdosage, producing saline depletion and hypovolaemia or, occasionally, as a result of a hypersensitivity reaction. The most frequent signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac dysrhythmias.

Treatment: In massive overdosage, treatment should be symptomatic, supportive and directed at fluid and electrolyte replacement. In cases of recent ingestion emesis or gastric lavage should be carried out. Dehydration, electrolyte imbalance, hepatic coma and hypotension should be corrected by established procedures. If required, give oxygen or artificial respiration for respiratory impairment. The degree to which ZIDAFLO is removed by haemodialysis has not been established.