Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands drive, Woodmead 2191
AMILORETIC is contraindicated in:
Hyperkalaemia has been observed in patients receiving amiloride hydrochloride, either alone or with other diuretics, particularly in the aged or in hospital patients with hepatic cirrhosis or congestive heart failure with renal involvement, who were seriously ill, or were undergoing vigorous diuretic therapy. Such patients should be carefully observed for clinical, laboratory, and ECG evidence of hyperkalaemia (not always associated with an abnormal ECG). It should be given with care to patients likely to develop acidosis.
Neither potassium supplements nor a potassium-rich diet should be used with AMILORETIC except under careful monitoring in severe and/or refractory cases of hypokalaemia.
Some deaths have been reported in this group of patients.
Should hyperkalaemia develop, discontinue treatment immediately and, if necessary, take active measures to reduce the plasma potassium to normal.
Although the likelihood of electrolyte imbalance is reduced by AMILORETIC, careful check should be kept for such signs of fluid and electrolyte imbalance as hyponatraemia, hypochloremic alkalosis, hypokalaemia and hypomagnesaemia. It is particularly important to make serum and urine electrolyte determinations when the patient is vomiting excessively or receiving parenteral fluids.
Hypomagnesaemia has also occurred. There is some evidence to suggest that electrolyte imbalances during long-term treatment with thiazides may be associated with an increased incidence of cardiac arrhythmias. Adverse changes in plasma lipids have also been noted, but their clinical significance is unclear.
Warning signs or symptoms of fluid or electrolyte imbalance include: dryness of the mouth, weakness, lethargy, drowsiness, restlessness, seizures, confusion, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastro-intestinal disturbances such as nausea and vomiting.
Hypokalaemia may develop, especially as a result of brisk diuresis, after prolonged therapy or when severe cirrhosis is present. Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Diuretic-induced hyponatraemia is usually mild and asymptomatic. It may become severe and symptomatic in a few patients with severe congestive heart failure who are very oedematous, particularly with large doses in conjunction with restricted salt in the diet.
AMILORETIC may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Therapy should be discontinued before carrying out tests for parathyroid function.
When creatinine clearance falls below 30 ml/min, thiazide diuretics are ineffective. Patients with increases in blood urea over 5 mmol/l, with serum creatinine levels over 130 micromol/L, or with whole blood urea values over 10 mmol/l, or with diabetes mellitus should not receive AMILORETIC without careful, frequent monitoring of serum electrolytes and blood urea nitrogen levels. Potassium retention in the presence of renal impairment is accentuated by the addition of an antikaliuretic medicine and may result in the rapid development of hyperkalaemia.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the medicine may develop in patients with impaired renal function. If increasing azotaemia and oliguria develop during treatment of renal disease, AMILORETIC should be discontinued. Blood-urea-nitrogen should be estimated periodically.
Hyperuricaemia may occur, or gout may be precipitated or aggravated, in certain patients receiving thiazides. Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated by therapy with AMILORETIC (see section 4.3). Dosage adjustment of antidiabetic medicines, including insulin, may be required.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
To minimise the risk of hyperkalaemia in diabetic or suspected diabetic patients, the status of renal function should be determined before initiating therapy with AMILORETIC. Therapy should be discontinued at least three days before giving a glucose tolerance test. Potassium-conserving therapy should be initiated only with caution in severely ill patients in whom metabolic or respiratory acidosis may occur, e.g., patients with cardiopulmonary disease or patients with inadequately controlled diabetes. Serum electrolytes should be estimated periodically.
Shifts in acid-base balance alter the balance of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in plasma potassium.
The possibility that thiazides may activate or exacerbate systemic lupus erythematosus in susceptible patients has been reported.
An increased risk of non-melanoma skin cancer (NMSC) basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide 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 hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC. (See also section 4.8).
Choroidal effusion, acute myopia and secondary angle-closure glaucoma:
Sulfonamide or sulfonamide derivative medicines can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angleclosure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of medicine initiation. Untreated acute angleclosure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue medicine 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.
AMILORETIC is contraindicated in children under 18 years because safety and efficacy have not been established.
Lactose warning: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicine.
Sunset yellow FCF Lake (C.I. No. 15895)
May cause allergic reactions.
Lithium generally should not be given with thiazide diuretics since the association may lead to toxic blood concentrations of lithium. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the prescribing information for lithium preparations before use of such preparations.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of antihypertensive medicines, including the diuretic, natriuretic and antihypertensive effects of diuretics.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory medicines, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
Concomitant administration of NSAIDs and potassium-sparing medicines, including amiloride HCl, may cause hyperkalaemia, particularly in elderly patients. Therefore, when amiloride HCl is used concomitantly with NSAIDs, serum potassium levels should be carefully monitored.
When amiloride hydrochloride is administered concomitantly with an angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist, trilostane, ciclosporin or tacrolimus, the risk of hyperkalaemia may be increased. Therefore, if concomitant use of these medicines is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
When given concurrently, the following medicines may interact with thiazide diuretics:
Co-administration may potentiate orthostatic hypotension.
Oral and parenteral antidiabetic medicines may require adjustment of dosage with concurrent use. AMIROLETIC can act synergistically with chlorpropamide to increase the risk of hyponatraemia.
Other antihypertensive medicines may have an additive effect. Therefore, the dosage of these medicines, especially adrenergic-blockers, may need to be reduced when AMILORETIC is added to the regimen. Diuretic therapy 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.
Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastro-intestinal tract by up to 85% and 43%, respectively. When cholestyramine is given 4 hours after the hydrochlorothiazide, the absorption of hydrochlorothiazide is reduced by 30% to 35%.
Corticosteroids, corticotrophin, carbenoxolone.or ACTH may intensify any thiazide-induced electrolyte depletion, particularly hypokalaemia.
Pressor amines such as epinephrine (adrenaline) may show decreased arterial responsiveness when used with AMILORETIC but this reaction is not enough to preclude their therapeutic usefulness.
Non-depolarising muscle relaxants such as tubocurarine may possibly interact with AMILORETIC to increase muscle relaxation.
Because thiazides may affect calcium metabolism, AMILORETIC may interfere with tests for parathyroid function; serum concentrations of protein-bound iodine may increase without signs of thyroid disturbance.
Safety in pregnancy, lactation and childhood has not been established.
The routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated, because they may be associated with hypovolaemia, increased blood viscosity, and decreased placental perfusion. Diuretics do not prevent the development of toxaemia of pregnancy and there is no satisfactory evidence that they are useful for its treatment.
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta.
Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, neonatal jaundice, disturbance of electrolyte balance, bone marrow depression and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Although it is not known whether amiloride hydrochloride is excreted in human milk, it is known that hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of AMILORIDE during breast feeding is not recommended. If AMILORIDE is used during breast-feeding, doses should be kept as low as possible.
No data are available.
AMILORETIC has moderate influence on the ability to drive and use machines. Since adverse reactions such as weakness, fatigue, dizziness, stupor and vertigo have been reported in patients receiving AMILORETIC patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that AMILORETIC does not adversely affect their ability to do so (see section 4.4 and/or 4.8).
| System organ class | Frequent | Less frequent | Frequency unknown (cannot be estimated from the available data) |
|---|---|---|---|
| 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 the lymphatic system disorders | Granulocyt openia | Blood dyscrasias, thrombocytopenia, leucopenia, aplastic and haemolytic anaemia, neutropenia, purpura | |
| Immune system disorders | Photosensitivity, skin rashes | ||
| Metabolism and nutrition disorders | Increase in blood-urea-nitrogen, hyperkalaemia, elevated plasma potassium levels (above 5.5 mmol/l), electrolyte imbalance, hyponatraemia, gout, dehydration, symptomatic hyponatraemia, glycosuria, hyperglycaemia, hyperuricaemia | ||
| Psychiatric disorders | Minor psychiatric, insomnia, nervousness, mental confusion, depression, sleepiness, Encephalopathy, decreased libido, somnolence restlessness. | ||
| Nervous system disorders | Paraesthesia,dizziness, headache, vertigo, stupor | ||
| Eye disorders | Visual changes, yellow vision, transient blurred vision, xanthopsia, choroidal effusion | ||
| Ear and labyrinth disorders | Tinnitus, increased intra-ocular pressure | ||
| Cardiac disorders | Orthostatic hypotension heart block, palpitation | ||
| Vascular disorders | Necrotising angiitis (vasculitis, cutaneous vasculitis) | ||
| Respiratory, thoracic and mediastinal disorders | Pulmonary oedema, pneumonitis, dyspnoea, cough, respiratory distress | ||
| Gastrointestinal disorders | Anorexia, gastric irritation nausea, vomiting, abdominal pain, diarrhea, constipation, thirst, dry mouth gastrointestinal bleeding, appetite changes, abdominal fullness, flatulence, hiccups. activation of probable pre-existing peptic ulcer, dyspepsia | ||
| Hepato-biliary disorders | Cholestatic jaundice, pancreatitis, abnormal liver function | ||
| Skin and subcutaneous tissue disorders | Skin rash, pruritus, flushing, diaphoresis, alopecia, urticaria, toxic epidermal necrolysis | ||
| Musculoskeletal and connective tissue disorders | Muscle cramps, leg ache, joint pain, neck/shoulder ache, pain in extremities | ||
| Renal and urinary disorders | Renal dysfunction including renal failure, incontinence, nocturia, dysuria, polyuria, urinary frequency, bladder spasm, interstitial nephritis. | ||
| Reproductive system and breast disorders | Impotence | ||
| General disorders and administrative site conditions | Weakness, fever |
Cases of choroidal effusion with visual field defect have been reported after the use of thiazide and thiazide-like diuretics.
Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer has been observed.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to: SAHPRA: https://www.sahpra.org.za/health-products-vigilance/
Aspen Pharmacare: E-mail: Drugsafety@aspenpharma.com, Tel: 0800 118 088
Not applicable.
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