Consumer medicine information

Amizide Tablets

Amiloride hydrochloride; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Amizide Tablets

Active ingredient

Amiloride hydrochloride; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Amizide Tablets.

What is in this leaflet

This leaflet answers some common questions about Amizide.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Amizide against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What Amizide is used for

Amizide is used for:

  • oedema, swelling of the ankles, feet and legs
  • ascites due to liver disease resulting in fluid accumulation in the stomach area
  • lower high blood pressure (hypertension).

Amizide contains a combination of two diuretics, amiloride hydrochloride and hydrochlorothiazide as the active ingredients. It helps reduce the amount of excess fluid in the body by increasing the amount of urine produced, while at the same time, minimizing potassium loss.

Amizide works by making your kidneys pass more water and salt whilst retaining potassium. This helps reduce high blood pressure and some forms of swelling, while at the same time helping to maintain normal levels of potassium in your blood.

Amizide may be taken alone or in combination with other medicines to treat your condition.

Your doctor may have prescribed Amizide for another reason. Ask your doctor if you have any questions about why Amizide has been prescribed for you.

Amizide is available only with a doctor's prescription. There is no evidence that Amizide is addictive.

Before you take Amizide

When you must not take it

Do not take Amizide if you are allergic to medicines containing either amiloride or hydrochlorothiazide or any of the ingredients listed at the end of this leaflet.

Do not take Amizide if you are allergic to medicines which contain sulfur (sulfonamides).

Hydrochlorothiazide, one of the active ingredients of Amizide, is a sulfur containing medicine. Therefore, if you are allergic to sulfur medicines, such as some antibiotics, you are likely to be allergic to Amizide. If you are not sure if you have an allergy to sulfonamide medicines, check with your doctor or pharmacist.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take Amizide if you have:

  • certain kidney problems
  • no production of urine
  • high potassium levels in your blood (hyperkalaemia), possibly due to a high potassium diet, taking potassium supplements, or other potassium-sparing medication.

Amizide helps maintain normal levels of potassium in your blood. If you are taking potassium tablets or supplements, other potassium-conserving medicines or a potassium rich diet, your potassium levels may increase too much.

Ask your doctor or pharmacist if you are not sure whether you are taking too much potassium.

Do not take Amizide if you are pregnant or intend to become pregnant unless you and your doctor have discussed the risks and benefits involved.

Like most diuretic medicines, Amizide is not recommended for use during pregnancy.

Do not take Amizide if you are breastfeeding or plan to breastfeed.

Amizide passes into breast milk and may affect your baby.

Do not take Amizide if the expiry date (Exp.) printed on the pack has passed.

Do not take Amizide if the packaging shows signs of tampering or the tablets do not look quite right.

Do not give Amizide to children.

The safety of Amizide in children has not been established.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • diabetes
  • kidney problems
  • liver problems
  • heart and lung problems
  • asthma
  • gout or hyperuricaemia
  • systemic lupus erythematosus
  • high cholesterol levels.

Your doctor may want to take special care if you have any of these conditions.

If you have not told your doctor about any of the above, tell them before you start taking Amizide.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by Amizide, or may affect how well it works. These include:

  • preparations which contain potassium
  • potassium conserving medicines
  • angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists, a group of medicines used to treat high blood pressure and some heart conditions
  • other medicines to treat high blood pressure
  • cyclosporin, tacrolimus, medicines used to suppress the immune system
  • lithium, a medicine used in the treatment of mood swings and some types of depression
  • non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, diclofenac, indomethacin, medicines used to relieve pain, swelling and other symptoms of inflammation including arthritis
  • barbiturates such as phenobarbitone, and carbamazepine, medicines used to treat epilepsy
  • strong pain killers such as codeine, morphine and dextropropoxyphene
  • insulin and tablets used to treat diabetes
  • steroid-based medicines such as prednisone, dexamethasone
  • adrenaline, a medicine used in emergency situations such as an anaphylactic reaction
  • cholestyramine, colestipol resins, medicines used to lower blood cholesterol levels
  • medicines used to relax muscles before and during surgery
  • medicines used in emergency situations such as adrenaline
  • alcohol

These medicines may be affected by Amizide or may affect how well it works. You may need to take different amounts of your medicine, or may need to take different medicines.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Amizide.

How to take Amizide

How much to take

The usual dose is one or two tablets daily.

Your doctor may advise you to take a different dose. This depends on your condition and whether or not you are taking any other medicines. Your initial dose will be maintained or adjusted until a satisfactory response is noted, but should not exceed 4 tablets per day.

Your doctor may increase your dose if necessary. No more than four tablets a day should be taken.

Follow all directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in this leaflet.

How to take Amizide

Swallow the tablets with a glass of water.

When to take Amizide

If you are taking Amizide once a day, take it in the morning, for example, at breakfast time.

Amizide takes about two hours to start working.

If you are taking more than one dose a day, take the last dose no later than 6 p.m, unless your doctor tells you otherwise.

Amizide may increase the amount of water (urine) you pass and also the number of times you go to the toilet. By taking the last dose no later than 6 p.m there may be less chance of your sleep being disturbed.

If you forget to take Amizide

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have any questions about this, check with your doctor or pharmacist.

How long to take Amizide for

It is important to take Amizide every day as it helps control your condition and lower the fluid build-up in your body.

Keep taking Amizide for as long as your doctor recommends.

If you take too much Amizide (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Amizide. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much Amizide, you may feel thirsty, tired, confused, dizzy, nausea, vomiting, have muscle cramps and a very fast heart rate.

While you are taking Amizide

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking Amizide.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Amizide.

If you become pregnant while taking Amizide, tell your doctor immediately.

Tell your doctor if you have any of the following dehydration symptoms:

  • excessive vomiting or diarrhoea
  • dry mouth, thirst
  • weakness, tiredness, drowsiness
  • muscle pain or cramps
  • fast heart beat
  • passing less urine than normal.

You may be dehydrated from losing too much water if you experience any of these symptoms.

If you plan to have surgery, including dental surgery, which needs a general anaesthetic, tell your doctor or dentist that you are taking Amizide.

If you have to have any blood tests, tell your doctor that you are taking Amizide.

Amizide may affect the results of some tests.

Visit your doctor regularly so they can check on your progress.

Your doctor may want to check your blood pressure and potassium levels regularly to make sure Amizide is working properly for you.

Things you must not do

Do not stop taking Amizide, or change the dose, without checking with your doctor.

Do not use Amizide to treat any other conditions unless your doctor tells you to.

Do not give Amizide to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how Amizide affects you.

Amizide may cause drowsiness, dizziness or lightheadedness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous. Make sure you know how you react to it before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or lightheaded.

Be careful getting up from a sitting or lying position.

Dizziness, lightheadedness or fainting may occur, especially when you get up quickly. Getting up slowly may help. If this problem gets worse or continues, talk to your doctor.

Be careful when drinking alcohol or taking strong pain killers while taking Amizide.

Combining Amizide with alcohol or strong pain killers can make you more dizzy or lightheaded.

Be aware of foods or drinks that have a high potassium content.

Amizide helps to maintain normal potassium levels in your body. However, if you eat foods or have drinks that are high in potassium this may lead to an increase of potassium in your body. Too much potassium can be harmful, therefore it is important to discuss your diet with your doctor or pharmacist.

Monitor your blood sugar levels carefully if you are a diabetic.

Amizide may change how well your diabetes is controlled. Your doses of diabetic medicines, including insulin, may need to change.

Things that would be helpful for your blood pressure

Some self-help measures suggested below may help your blood pressure.

Talk to your doctor or pharmacist about these measures and for more information.

  • Alcohol: your doctor may advise you to limit your alcohol intake.
  • Diet: eat a healthy diet which includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar.
  • Exercise: regular exercise helps to reduce blood pressure. Try regular walking, swimming, cycling or games such as tennis and golf. Before starting any exercise, ask your doctor about the best kind of programme for you.
  • Salt: your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake you should avoid using salt in cooking or at the table.
  • Smoking: your doctor may advise you to stop smoking or at least cut down.
  • Weight: your doctor may suggest losing some weight to help lower your blood pressure. Some people may need a dietician's help to lose weight.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Amizide.

Like all other medicines, Amizide may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • dizziness or light-headedness
  • drowsiness, lack of energy, weakness
  • restlessness
  • nausea, vomiting, change in appetite
  • diarrhoea or constipation
  • stomach discomfort or fullness
  • passing wind
  • bad taste in the mouth, visual disturbances, such as blurred vision or yellow vision
  • passing less urine than normal.

Tell your doctor as soon as possible if you notice any of the following:

  • very dry mouth or unusual thirst
  • severe dizziness, spinning sensation
  • fainting
  • muscle pain or cramps, swollen or painful joints
  • numbness or tingling in the hands or feet
  • irregular or very fast heart beat
  • chest pain
  • mental confusion
  • pain when passing urine, loss of control of your bladder or bowels
  • yellowing of the skin or eyes (jaundice)
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bruising or bleeding more easily than normal, nose bleeds
  • changes in heart beat

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • rash, itching or hives
  • severe skin reactions which starts with painful red areas, then large blisters and ends with peeling of layers of skin. This is accompanied by fever and chills, aching muscles and generally feeling unwell.
  • swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • fits or seizures
  • vomiting blood or material that looks like coffee grounds
  • bleeding from the back passage, black, sticky bowel motions (stools) or bloody diarrhoea.

These are serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

After taking Amizide

Storage

Keep Amizide where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in the bottle until it is time to take them.

If you take the tablets out of the bottle they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store Amizide or any other medicine in the bathroom or near a sink.

Do not leave Amizide in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking Amizide, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Amizide is a round, off-white, scored tablet marked H|A on one side and a on the reverse.

Each pack contains 50 tablets.

Ingredients

Amizide contains two active ingredients:

  • hydrochlorothiazide 50 mg
  • amiloride hydrochloride 5 mg.

The tablets also contain:

  • lactose
  • starch - wheat
  • povidone
  • sodium starch glycollate
  • magnesium stearate.

Manufacturer

Amizide is made in Australia  by:
Alphapharm Pty Limited
(ABN 93 002 359 739)
Level 1, 30 The Bond
30 - 34 Hickson Road
Millers Point NSW 2000
Phone: (02) 9298 3999
www.alphapharm.com.au

Australian registration numbers:
Amizide - Aust R 17702

This leaflet was prepared on
19 August 2013.

Amizide_cmi\aug13/00

BRAND INFORMATION

Brand name

Amizide Tablets

Active ingredient

Amiloride hydrochloride; Hydrochlorothiazide

Schedule

S4

 

Name of the medicine

Hydrochlorothiazide 50 mg, amiloride hydrochloride 5 mg.

Excipients.

Lactose, wheat starch, povidone, sodium starch glycollate, magnesium stearate.

Description

Hydrochlorothiazide.

Chemical name: 6-chloro-3,4-dihydro-2H- 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Molecular formula: C7H8ClN3O4S2. MW: 297.7. CAS: 58-93-5. Hydrochlorothiazide is a white or almost white, odourless, crystalline powder with a slightly bitter taste. It is very slightly soluble in water, sparingly soluble in ethanol (96%) and soluble in acetone. It dissolves in dilute solutions of alkali hydroxides.

Amiloride hydrochloride.

Chemical name: 3,5-diamino-N-carbamimidoyl-6- chloropyrazine-2-carboxamide hydrochloride dihydrate. Molecular formula: C6H8ClN7O.HCl. MW: 302.1. CAS: 17440-83-4. Amiloride hydrochloride is a pyrazinecarbonylguanidine that is unrelated chemically to other known diuretic or antikaliuretic agents. It is not acidic like the thiazides, but is the salt of a moderately strong base, amiloride, pKa 8.7. Amiloride hydrochloride is a pale yellow to greenish yellow, almost odourless powder. It is slightly soluble in water and ethanol (96%) and practically insoluble in chloroform and in ether.

Pharmacology

Amizide combines the potassium conserving action of amiloride hydrochloride with the natriuretic action of hydrochlorothiazide.
Amizide provides diuretic and antihypertensive activity (principally due to the hydrochlorothiazide component), while acting through the amiloride component to prevent the excessive potassium loss that may occur in patients receiving a thiazide diuretic. Due to its amiloride component, the urinary excretion of magnesium is less with Amizide than with a thiazide or loop diuretic used alone (see Precautions). The onset of the diuretic action of Amizide is within one to two hours and this action appears to be sustained for approximately 24 hours.
Amiloride hydrochloride is a potassium conserving (antikaliuretic) drug that possesses weak (compared to the thiazide diuretics) natriuretic, diuretic and antihypertensive activity. These effects have been partially additive to the effects of thiazide diuretics in some clinical studies. Amiloride hydrochloride has potassium conserving activity in patients receiving kaliuretic diuretic agents.
Amiloride hydrochloride is not an aldosterone antagonist and the effects are seen even in the absence of aldosterone.
Amiloride hydrochloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct. This decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. This mechanism accounts in large part for the potassium sparing action of amiloride.
Amiloride hydrochloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24 hours. Effects on electrolytes increase with single doses of amiloride hydrochloride up to approximately 15 mg.

Hydrochlorothiazide.

The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases the excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Pharmacokinetics.

Amiloride hydrochloride.

Peak plasma levels are obtained in 3 to 4 hours and the plasma half-life varies from 6 to 9 hours. Amiloride hydrochloride is not metabolised by the liver but is excreted unchanged by the kidneys. About 50% of a 20 mg dose of amiloride hydrochloride is excreted in the urine and 40% in the stool within 72 hours. Amiloride hydrochloride has little effect on glomerular filtration rate or renal blood flow. Because amiloride hydrochloride is not metabolised by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if the hepatorenal syndrome develops.

Hydrochlorothiazide.

Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placenta but not the blood brain barrier and is excreted in breast milk.

Indications

Amizide is indicated in the treatment of patients with oedema of cardiac origin; hepatic cirrhosis with ascites; and hypertension, in whom potassium depletion might be anticipated.
Amizide, with its combination of amiloride hydrochloride and hydrochlorothiazide, minimises the possibility of the development of excessive potassium loss in patients during vigorous diuresis for prolonged periods. Amizide, with its built in potassium sparing agent, is especially indicated in those conditions where the positive effect on potassium balance is particularly important.

Hypertension.

Amizide may be used alone or as an adjunct to other antihypertensive drugs. Since it enhances the action of these agents, the dosage of these antihypertensive drugs may need to be reduced to avoid the risk of an excessive drop in blood pressure.

Contraindications

Impaired renal function.

Amizide is contraindicated in cases of acute renal failure, diabetic nephropathy, anuria and severe progressive renal disease. Patients with increases in blood urea nitrogen (BUN) over 10.7 mmol/L, in serum creatinine levels over 0.13 mmol/L or in whole blood urea values over 10.0 mmol/L should not be given the drug without careful, frequent monitoring of serum electrolytes and BUN levels. In the presence of renal impairment, potassium retention is accentuated by the addition of an antikaliuretic agent and may result in the rapid development of hyperkalaemia.

Hyperkalaemia.

Amizide should not be used in the presence of elevated plasma potassium levels (interpreted as over 5.5 mmol/L).

Antikaliuretic therapy or potassium supplements.

Other antikaliuretic agents and potassium supplements or a potassium rich diet are contraindicated in patients receiving Amizide; such combination therapy is commonly associated with rapid increases in plasma potassium levels.

Known sensitivity to the drug.

Amizide is contraindicated in patients who are hypersensitive to this product or to other sulfonamide derived drugs.

Use in children.

The safety for use of amiloride hydrochloride in children has not been established, therefore Amizide is not recommended in the paediatric age group (see also Precautions, Use in pregnancy; Use in lactation).

Precautions

Diabetes mellitus.

In diabetic patients, hyperkalaemia has commonly occurred during therapy with amiloride hydrochloride, particularly if chronic renal disease or prerenal azotaemia is present. Therefore, the status of renal function should be known before starting therapy in diabetic or suspected diabetic patients. Amizide should be discontinued for at least three days before glucose tolerance testing.
Insulin requirements in diabetic patients may be increased, decreased or unchanged due to the hydrochlorothiazide component. Latent diabetes mellitus may become manifest during thiazide administration.

Metabolic or respiratory acidosis.

In severely ill patients in whom respiratory or metabolic acidosis may occur, antikaliuretic therapy should be instituted only with caution. Such patients include those with cardiopulmonary disease and those with decompensated diabetes. Shifts in acid base balance alter the balance of extracellular/ intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels.

Hyperkalaemia.

Defined as serum potassium levels over 5.5 mmol/L, hyperkalaemia has been observed in patients who received amiloride hydrochloride either alone or in combination with other diuretic drugs. This has been noted particularly in aged patients, diabetic patients and in hospitalised patients with hepatic cirrhosis or cardiac oedema who have known renal involvement, are seriously ill or are undergoing vigorous diuretic therapy. These patients should be monitored carefully for clinical, laboratory and electrocardiographic (ECG) evidence of hyperkalaemia. Some deaths have been reported in this group of patients.
Warning signs of hyperkalaemia include paraesthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock and serum potassium and ECG abnormalities. As hyperkalaemia is not always associated with an abnormal electrocardiogram, careful monitoring of the plasma potassium level is important. When abnormal, the ECG in hyperkalaemia is characterised primarily by tall, peaked T waves or elevations from previous tracings. There may also be lowering of the R wave and increased depth of the S wave, widening and even disappearance of the P wave, progressive widening of the QRS complex and prolongation of the PR interval and ST depression.
In the event of hyperkalaemia occurring in patients taking Amizide, the drug should be discontinued immediately and, if necessary, active measures taken to reduce the plasma potassium level. Discontinuation of antikaliuretic therapy should be followed by intravenous administration of sodium bicarbonate solution, or oral or parenteral glucose with a rapid acting insulin. If needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema. Patients with persistent hyperkalaemia may require dialysis.

Electrolyte imbalance and reversible BUN increases.

Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Patients should be observed for clinical signs of fluid or electrolyte imbalance: hyponatraemia, hypochloraemic 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. Warning signs or symptoms of fluid and electrolyte imbalance include: dryness of mouth, thirst, weakness, lethargy, drowsiness, confusion, restlessness, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.
Hyponatraemia and hypochloraemia may occur during the use of thiazide and other oral diuretics even when amiloride hydrochloride is used. Any chloride deficit during thiazide therapy is generally mild and may be lessened by the amiloride hydrochloride component of Amizide. Hypochloraemia usually does not require specific treatment except under extraordinary circumstances (as in hepatic disease or renal disease). Dilutional hyponatraemia may occur in oedematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatraemia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hypokalaemia may develop during thiazide therapy, especially with brisk diuresis, when severe cirrhosis is present, during concomitant use of corticosteroids or ACTH or after prolonged therapy. However, this is usually prevented by the amiloride hydrochloride component of Amizide.
Interference with adequate oral electrolyte intake will also contribute to hypokalaemia. Hypokalaemia may cause cardiac arrhythmia and may sensitise or exaggerate the response of the heart to toxic effects of digitalis (e.g. increased ventricular irritability).
Reversible increases in BUN levels have been reported. These have accompanied vigorous fluid elimination, especially when diuretic combinations were used in seriously ill patients, such as those who have hepatic cirrhosis with ascites and metabolic alkalosis or those with resistant oedema. Therefore, careful monitoring of serum electrolytes and BUN levels is important when Amizide is given to such patients.

Azotaemia.

As azotaemia may be precipitated or increased by hydrochlorothiazide, special caution is necessary in patients with impaired renal function to avoid cumulative or toxic effects of the components. If increasing azotaemia and oliguria occur during treatment, Amizide should be discontinued.

Metabolic.

Hyperuricaemia may occur or gout may be precipitated in certain patients receiving thiazide therapy.
Because calcium excretion is decreased by thiazides, Amizide should be discontinued before carrying out tests for parathyroid function. Pathological changes in the parathyroid glands, with hypercalcaemia and hypophosphataemia have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Sensitivity reactions.

Such reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Impaired hepatic function.

In patients with pre-existing severe liver disease, hepatic encephalopathy manifested by tremors, confusion and coma and increased jaundice have been reported in association with diuretic therapy, including with amiloride hydrochloride and hydrochlorothiazide.

Use in pregnancy.

(Category C)
Thiazides, amiloride, related diuretics and loop diuretics enter the foetal circulation and may cause electrolyte disturbances. Neonatal thrombocytopenia has been reported with thiazides and related diuretics. Loop diuretics like frusemide and bumetanide are probably also associated with this risk. During the latter part of pregnancy, products of this type should only be given on sound indications, and then in the lowest effective dose.
Because clinical experience is limited, Amizide is not recommended for use during pregnancy. Thiazides cross the placental barrier and appear in the cord blood. Therefore, the use of Amizide when pregnancy is present or suspected requires that the potential benefits of the drug must be weighed against possible hazards to the foetus. These hazards include foetal or neonatal jaundice, thrombocytopenia and possibly other side effects that have occurred in the adult.
The routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated.

Use in lactation.

Amizide is not recommended for use in breastfeeding mothers due to the fact that thiazides appear in breast milk. If use of the drug is considered to be essential, the patient should stop breastfeeding.

Interactions

Medicines and foods that can interact with both hydrochlorothiazide and amiloride hydrochloride.

Alcohol.

Potentiation of orthostatic hypotension.

Antihypertensive drugs.

Additive effect and increased risk of first dose hypotension. To reduce the risk of first dose hypotension, diuretic therapy should be discontinued for two to three days and salt/ volume depletion should be corrected prior to initiation of therapy with an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist or α-adrenoceptor antagonist (α-blocker).

Amantadine.

Thiazide diuretics and amiloride may compete with amantadine for renal tubular secretion, leading to increased plasma concentrations of amantadine.

Barbiturates or narcotics.

Potentiation of orthostatic hypotension.

Dofetilide.

Thiazide diuretics and amiloride compete with dofetilide for renal tubular secretion, leading to increased plasma concentrations of dofetilide. Hypokalaemia and hypomagnesaemia caused by diuretics may also increase the risk of dofetilide toxicity.

Drugs that prolong the QT interval (e.g. astemizole, dofetilide, droperidol, pimozide, sotalol, terfenadine).

Diuretic induced hypokalaemia and hypomagnesaemia increases the risk of arrhythmia with drugs that prolong the QT interval.

Ephedrine, pseudoephedrine.

Ephedrine and pseudoephedrine are present in various prescription medicines, over the counter cold and flu remedies and the complementary medicine Ma Huang (ephedra). These drugs may reduce the effectiveness of antihypertensive medications, including diuretics. Diuretic induced hypokalaemia may increase the risk of premature ventricular contractions associated with ephedrine and pseudoephedrine.

Liquorice.

Liquorice may reduce the antihypertensive effect of hydrochlorothiazide and amiloride. Liquorice may also increase the risk of diuretic induced hypokalaemia.

Lithium.

Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the product information for lithium preparations before use.

Nonsteroidal anti-inflammatory drugs.

In some patients, the administration of a NSAID can reduce the diuretic, natriuretic and antihypertensive effects of diuretics. Concomitant administration of NSAIDs and potassium sparing agents, including amiloride hydrochloride, may cause hyperkalaemia and renal failure, particularly in elderly patients. Therefore, when amiloride hydrochloride is used concomitantly with NSAIDs, renal function and serum potassium level should be carefully monitored.
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 nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the coadministration 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.
These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Opioids.

Potentiation of orthostatic hypotension.

Sulfonylureas (e.g. chlorpropamide, glibenclamide, gliclazide, glimepride, tolbutamide).

Diuretics and sulfonylureas may have an additive hyponatraemic effect.

Other medicines that can interact with amiloride hydrochloride.

ACE inhibitors, angiotensin receptor antagonists.

Increased risk of hyperkalaemia.

Cyclosporin.

Increased risk of hyperkalaemia.

Indomethacin.

Increased risk of hyperkalaemia.

Tacrolimus.

Increased risk of hyperkalaemia.
If concomitant use of the above agents and amiloride is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Quinidine.

The combination of amiloride and quinidine has been reported to have a proarrhythmic effect in patients with a history of ventricular tachycardia.

Other medicines that can interact with hydrochlorothiazide.

Allopurinol.

The risk of hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently.

Amphotericin B.

Increased risk of hypokalaemia.

Antidiabetic drugs (oral agents and insulin).

Dosage adjustment of the antidiabetic drug may be required.

Antineoplastic drugs.

Thiazide diuretics may enhance the myelosuppressive effects of antineoplastic drugs.

Beta2–agonists.

Increased risk of hypokalaemia.

Calcium salts, calcitriol.

Increased risk of hypercalcaemia.

Carbamazepine.

Increased risk of hyponatraemia.

Cholestyramine and colestipol resins.

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 gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, adrenocorticotrophic hormone.

Intensified electrolyte depletion, particularly hypokalaemia.

Diazoxide.

Potentiation of hyperuricaemic and hypotensive effects. The combination of diazoxide and thiazide diuretics has also been reported to blunt insulin secretion and may cause hyperglycaemia.

Pressor amines (e.g. noradrenaline).

Possible decreased response to pressor amines but not sufficient to preclude their use.

Propranolol.

Increased risk of elevated blood glucose, triglycerides and uric acid.

Nondepolarising skeletal muscle relaxants (e.g. tubocurarine).

Possible increased responsiveness to the muscle relaxant.

Reboxetine.

Increased risk of hypokalaemia.

Sulfamethoxazole, trimethoprim.

An increased incidence of thrombocytopenia with purpura has been observed in elderly patients concurrently receiving sulfamethoxazole-trimethoprim and certain diuretics, primarily thiazides. Severe hyponatraemia has been reported in patients taking trimethoprim with hydrochlorothiazide or hydrochlorothiazide-amiloride.

Tetracyclines.

The antianabolic action of tetracyclines may cause an increase in plasma urea levels. This effect may be enhanced by diuretics.

Effects on laboratory tests.

Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see Precautions).

Adverse Effects

Amizide is usually well tolerated. Although minor adverse reactions have been reported relatively frequently, significant adverse effects have been reported infrequently.
Adverse effects that have been reported with Amizide are generally those known to be associated with diuresis, thiazide therapy or with the underlying disease being treated. Clinical trials have not demonstrated that combining amiloride and hydrochlorothiazide increases the risk of adverse reactions over those seen with the individual components.

Amiloride/ hydrochlorothiazide.

Cardiovascular.

Arrhythmia, tachycardia, digitalis toxicity, orthostatic hypotension, angina pectoris.

Gastrointestinal.

Nausea, anorexia, vomiting, diarrhoea, constipation, abdominal pain, gastrointestinal bleeding, appetite changes, abdominal fullness, flatulence, thirst, hiccups.

Metabolic.

Elevated serum potassium levels (> 5.5 mmol/L), electrolyte imbalance, hyponatraemia, gout, dehydration, symptomatic hyponatraemia.

Dermatological.

Rash, pruritus, flushing, diaphoresis.

Musculoskeletal.

Leg ache, muscle cramps, joint pain.

Nervous system.

Dizziness, vertigo, paraesthesia, stupor.

Psychiatric.

Insomnia, nervousness, mental confusion, depression, sleepiness.

Respiratory.

Dyspnoea.

Special senses.

Bad taste, visual disturbance, nasal congestion.

Genitourinary.

Impotence, dysuria, nocturia, incontinence, renal dysfunction including renal failure.

Body as a whole.

Headache, weakness, fatigue, malaise, chest pain, back pain, syncope.
Other adverse effects that have been reported with the individual components are listed as follows.

Amiloride.

Gastrointestinal.

Abnormal hepatic function, activation of probable pre-existing peptic ulcer, dyspepsia, jaundice.

Dermatological.

Dry mouth, alopecia, diaphoresis.

Nervous system.

Tremors, encephalopathy, numbness.

Haematological.

Aplastic anaemia, neutropenia.

Cardiovascular.

Peripheral ischaemia/ gangrene (in combination with frusemide). One patient with partial heart block developed complete heart block; palpitations.

Endocrine/ metabolic.

Metabolic acidosis.

Psychiatric.

Decreased libido, somnolence.

Respiratory.

Cough.

Special senses.

Tinnitus, increased intraocular pressure.

Genitourinary.

Polyuria, urinary frequency, bladder spasm.

Body as a whole.

Neck/ shoulder ache, pain in extremities.

Hydrochlorothiazide.

Cardiovascular.

Necrotising angiitis (vasculitis, cutaneous vasculitis), withdrawal oedema.

Gastrointestinal.

Jaundice (intrahepatic cholestatic jaundice), pancreatitis, cramping, gastric irritation, sialadenitis.

Endocrine/ metabolic.

Glycosuria, hyperglycaemia, hyperuricaemia, hypokalaemia, zinc deficiency.

Haematological.

Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia.

Dermatological.

Photosensitivity, urticaria, toxic epidermal necrolysis.

Musculoskeletal.

Myalgia.

Psychiatric.

Restlessness.

Renal.

Interstitial nephritis, urate calculi.

Respiratory.

Respiratory distress including pneumonitis and pulmonary oedema.

Special senses.

Transient blurred vision, xanthopsia.

Body as a whole.

Anaphylactic reaction, fever.

Dosage and Administration

Oedema of cardiac origin.

Initiate at a dosage of 1 or 2 tablets daily. Dosage may be increased if necessary, but must not exceed 4 tablets daily. The optimal dosage is determined by the diuretic response and the serum potassium level. Once an initial diuresis has been achieved, reduction in dosage should be attempted for maintenance therapy. Maintenance therapy may be on an intermittent basis.

Hypertension.

The usual dosage is 1 or 2 tablets, given once a day or in divided doses. The dosage may be increased if necessary; but must not exceed 4 tablets/day.

Hepatic cirrhosis with ascites.

(See Precautions.) Treatment should be initiated with a small dose (e.g. 1 tablet daily). If necessary, dosage may be increased gradually until there is effective diuresis. The dosage should not exceed 4 tablets daily. Maintenance doses may be lower than those required to initiate diuresis; therefore, reduction in the daily dose should be attempted when the patient's weight is stabilised. Gradual weight reduction in cirrhotic patients is especially desirable to reduce the likelihood of untoward reactions associated with diuretic therapy.

Overdosage

No data are available with regard to overdosage in humans. The oral LD50 of the combination drug is 189 and 422 mg/kg for female mice and female rats, respectively.
It is not known whether the drug is dialysable.
No specific information is available on the treatment of overdosage with Amizide and no specific antidote is available. Treatment is symptomatic and supportive. Therapy with Amizide should be discontinued and the patient observed closely. Activated charcoal may reduce absorption of hydrochlorothiazide and amiloride if given within one or two hours after ingestion. In patients who are not fully conscious or who have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.

Amiloride hydrochloride.

No data are available in regard to overdosage in humans.
The oral LD50 of amiloride hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain.
The most common signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. If hyperkalaemia occurs, active measures should be taken to reduce the serum potassium levels.

Hydrochlorothiazide.

The oral LD50 of hydrochlorothiazide is greater than 10.0 g/kg in both rats and mice.
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has been administered, hypokalaemia may accentuate cardiac arrhythmias.

Presentation

Tablets, hydrochlorothiazide 50 mg, amiloride hydrochloride 5 mg (off white, scored, marked H/A, α on reverse): 30's*, 50's.
*Not currently marketed in Australia.

Storage

Store below 30°C.

Poison Schedule

S4.