Consumer medicine information

APO-Fosinopril HCTZ 20/12.5 Tablets

Fosinopril sodium; Hydrochlorothiazide

BRAND INFORMATION

Brand name

APO-Fosinopril HCTZ 20/12.5 mg Tablets

Active ingredient

Fosinopril sodium; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Fosinopril HCTZ 20/12.5 Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about APO-Fosinopril HCTZ 20/12.5. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up-to-date leaflet from www.apotex.com.au.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Fosinopril HCTZ 20/12.5 Tablets. It contains the active ingredient fosinopril sodium and hydrochlorothiazide.

It is used to lower high blood pressure (hypertension).

Hypertension

Everyone has blood pressure. This pressure helps get your blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. If you have hypertension (high blood pressure), this means that your blood pressure stays higher than is needed, even when you are relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems, including stroke, heart disease and kidney failure.

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

This medicine is available only with a doctor's prescription.

Things that would be helpful for your blood pressure

Some self help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information.

  • Alcohol - your doctor may advise you to limit your alcohol intake.
  • Weight - your doctor may suggest losing some weight to help lower your blood pressure and help lessen the amount of work your heart has to do. Some people may need a dietician's help to lose weight.
  • Diet - eat a healthy low-fat diet which includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar.
  • 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.
  • Exercise - regular exercise helps to reduce blood pressure and helps to get the heart fitter, but it is important not to overdo it. Walking is good exercise, but try to find a route that is reasonably flat. Before starting any exercise, ask your doctor about the best kind of program for you.
  • Smoking - your doctor may advise you to stop smoking or at least cut down.

How it works

Fosinopril sodium belongs to a group of medicines called angiotensin converting enzyme (ACE) inhibitors. It works by widening your blood vessels, reducing the pressure in the vessels (reducing 'blood pressure') and by making it easier for your heart to pump blood around your body. This helps your heart to work better by increasing the supply of oxygen to your heart.

Hydrochlorothiazide is a diuretic (fluid tablet). It helps reduce the amount of excess fluid in the body by increasing the amount of urine produced. It also lowers high blood pressure, particularly when combined with other blood pressure reducing medicines such as ACE inhibitors.

There is no evidence that this medicine is addictive.

Use in children

The safety and effectiveness of fosinopril HCTZ in children have not been established.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are pregnant
    Fosinopril HCTZ may affect your developing baby if you take it during pregnancy
  • Do not take fosinopril HCTZ if you are not producing any urine (anuric)
  • You have taken any other ACE Inhibitor medicine before, which caused your face, lips, tongue, throat, hands or feet to swell up or made it hard for you to breathe
    If you have had an allergic reaction to an ACE inhibitor medicine before, you may be allergic to APO-Fosinopril HCTZ 20/12.5.
  • You have had an allergic reaction to another medicine which contains an ingredient with a name like "sulphonamide" or a "-thiazide" (like hydrochlorothiazide)
    Ask your doctor or pharmacist if you are not sure.
  • You have a history of angioedema or angioneurotic oedema, which is swelling of the face, lips, tongue, throat (which may cause difficulty in swallowing or breathing), hands or feet, for no apparent reason
  • You are hypersensitive to, or have had an allergic reaction to, fosinopril sodium or hydrochlorothiazide or any of the ingredients listed at the end of this leaflet
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital
  • The expiry date (EXP) printed on the pack has passed
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  2. Tell your doctor if you have a family history of swelling of the face, lips, tongue, throat that may cause difficulty in swallowing or breathing.
  3. You have or have had any medical conditions, especially the following:
    - kidney problems, or have had kidney problems in the past, or are having dialysis
    - liver problems, or have ever had liver problems in the past
    - low blood pressure, which you may notice as dizziness or light-headedness
    - systemic lupus erythematosus (SLE), scleroderma or other autoimmune diseases
    - impaired immune system either due to certain medical conditions or medications
    - diabetes or pre-diabetes
    - high levels of potassium in your blood (hyperkalaemia)
    - gout
    - have a problem passing urine
    - are going to have surgery (including dental surgery) involving a general anaesthetic, even if it is minor.
  4. You plan to become pregnant. Do not take this medicine whilst pregnant.
  5. You are currently breastfeeding or you plan to breastfeed. Do not take this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved.
    Both fosinopril and hydrochlorothiazide are detectable in breast milk.
  6. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with fosinopril HCTZ. These include:

  • diuretics, also known as fluid tablets (for example Lasix®, Urex®, Natrilix®, Moduretic®)
  • other medicines used to treat high blood pressure
  • lithium or lithium-containing medicine (for example Lithicarb®)
  • potassium tablets (for example Span-K® or Slow-K®)
  • potassium-containing salt substitutes (for example Pressor-K®)
  • antacids
  • alcoholic drinks
  • sleeping tablets
  • strong pain relieving medicines
  • antidiabetic medicines (for example insulin)
  • medicines or other tablets containing calcium
  • antigout medicines
  • cholestyramine resin and colestipol hydrochloride medicines to treat high cholesterol (for example Questran® Lite, Colestid® Granules)
  • some medicines used during surgery or emergency situations, such as anaesthetics
  • medicines that lower your immune system
  • anti-inflammatory medicines (these are used to relieve pain, swelling and other symptoms of inflammation, including arthritis) and include nonsteroidal anti-inflammatory agents - NSAIDs (for example Voltaren®, Indocid®) and COX-2 inhibitors (for example Celebrex®)
    Taking a combination of APO-Fosinopril HCTZ 20/12.5 and an anti-inflamatory medicine may damage your kidneys.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with fosinopril HCTZ.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

If you do not understand the instructions on the label on the pack, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Fosinopril HCTZ is usually taken at a dose of one 20/12.5 mg tablet per day. Your doctor may have prescribed a different dose for you.

APO-Fosinopril HCTZ 20/12.5 tablet is not scored and must not be broken.

Since there is no lower dose (10/12.5 mg) of APO-Fosinopril HCTZ available, if a dose of 10/12.5 mg is required, an alternative product must be used.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow the tablet whole with a glass of water.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

Fosinopril HCTZ helps to control your condition but does not cure it. Therefore you must take APO-Fosinopril HCTZ 20/12.5 every day. Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

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

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.
  • Tell your doctor if you have excessive vomiting or diarrhoea or experience any of the following symptoms:
    - light-headed or dizzy
    - dry mouth or thirst
    - weakness, tiredness or drowsiness
    - muscle pain or cramps
    - fast heart beat
    - passing less urine than normal.
    If you experience these symptoms, you may be dehydrated because you are losing too much water.
    This is more likely to occur when you begin to take fosinopril HCTZ or if your dose is increased.
  • Make sure you drink enough water during exercise and hot weather while you are taking this medicine, especially if you sweat a lot, or your blood pressure may drop suddenly and you may dehydrate. If you experience any of the previous symptoms, tell your doctor.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

As with other ACE inhibitor medicines, you may feel light-headed or dizzy when you begin to take APO-Fosinopril HCTZ 20/12.5 or after your dose is increased. This is because your blood pressure is dropping suddenly.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. Be careful the first time you take fosinopril HCTZ, especially if you are elderly.

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

Fosinopril HCTZ may cause dizziness, or light-headedness in some people. Make sure you know how you react to this medicine before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs, do not drive.

If you drink alcohol, dizziness or light-headedness may be worse.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking fosinopril HCTZ.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • feeling light-headed, dizzy or faint
  • headache
  • tiredness, fatigue or weakness
  • dry cough
  • sore throat or runny nose
  • feeling sick (nausea) or vomiting
  • upset stomach (dyspepsia) or heartburn
  • diarrhoea
  • stomach pains
  • muscle cramps or pains
  • flushing
  • any problem urinating (passing water)

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

These may be serious side effects and you may need medical attention:

  • changes to your heart rhythm
  • infections of your urinary tract or upper respiratory tract (URTI, or cold or flu symptoms)
  • severe dizziness (vertigo)
  • impotence (inability to get or maintain an erection)
  • mild rash or itching
  • gout (painful, swollen joints)
  • diabetes (symptoms include - excessive thirst, greatly increased amount of urine, increase of appetite with a loss of weight,
  • feeling tired, drowsy, weak, depressed, irritable and generally unwell)
  • sore throat and fever
  • hepatitis (symptoms include - nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes and dark coloured urine)

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • fainting within a few hours of taking a dose of APO-FOSINOPRIL HCTZ 20/12.5
  • swelling to the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing; swelling of the hands or feet; severe itching and/or rash
  • difficulty breathing
  • not urinating (passing water)
  • chest pain
  • stomach pain with or without nausea.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to fosinopril HCTZ, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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.

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Fosinopril HCTZ 20/12.5 tablets looks like

20/12.5 mg tablet: light orange coloured, round tablets with "FH" on one side.

APO-Fosinopril HCTZ 20/12.5 is available in blister packs of 30 tablets.

Ingredients

Each tablet contains 20 mg of fosinopril sodium and 12.5 mg of hydrochlorothiazide as the active ingredient.

It also contains the following inactive ingredients:

  • lactose
  • croscarmellose sodium
  • starch - pregelatinised maize
  • glycerol dibehenate
  • pigment blend PB-23061orange.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Fosinopril HCTZ 20/12.5 mg tablet (blister): AUST R 223503.

Sponsor

Medis Pharma Pty Ltd
5 Essex St
The Rocks
Sydney NSW 2000

APO and APOTEX are registered trade marks of Apotex Inc.

Distributor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was last updated in August 2014.

BRAND INFORMATION

Brand name

APO-Fosinopril HCTZ 20/12.5 mg Tablets

Active ingredient

Fosinopril sodium; Hydrochlorothiazide

Schedule

S4

 

Name of the medicine

Fosinopril sodium, hydrochlorothiazide.

Excipients.

Lactose, pregelatinised starch, croscarmellose sodium, glycerol dibehenate, magnesium stearate and pigment blend PB-23061.

Description

Fosinopril sodium.

Chemical name: L-proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy) propoxy] (4-phenylbutyl) phosphinyl]acetyl]-, sodium salt, trans-. Molecular formula: C30H45NNaO7P. MW: 585.65. CAS: 88889-14-9. Fosinopril sodium is a white to off white crystalline powder. It is soluble in water (100 mg/mL), methanol and ethanol and slightly soluble in hexane.

Hydrochlorothiazide.

Chemical name: 6-chloro-3,4-dihydro- 2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Molecular formula: C7H8CIN3O4S2. MW: 297.72. CAS: 58-93-5. Hydrochlorothiazide is the 3,4-dihydro derivative of chlorothiazide. It is a white or practically white, crystalline powder which is very slightly soluble in water, soluble in acetone; sparingly soluble in ethanol (96%) but it dissolves in dilute solutions of alkali hydroxides.

Pharmacology

Pharmacodynamics.

Fosinopril sodium.

Fosinopril sodium is the ester prodrug of a long acting angiotensin converting enzyme (ACE) inhibitor, fosinopril diacid. It is a subclass of ACE inhibitors containing a phosphinate group which makes it different from other marketed ACE inhibitors.
In humans and animals, fosinopril sodium following absorption is hydrolysed to the pharmacologically active fosinopril diacid, a specific competitive inhibitor of angiotensin converting enzyme (ACE). ACE, a peptidyldipeptidase, catalyses the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II. Angiotensin II is a potent vasoconstrictor and it also stimulates aldosterone secretion by the adrenal cortex, thereby contributing to sodium and fluid retention.
The effects of fosinopril in hypertension appear to result primarily from inhibition of angiotensin II formation and decreased aldosterone secretion. Inhibition of ACE activity leads to decreased levels of angiotensin II, thereby resulting in diminished vasoconstriction, aldosterone secretion, peripheral vascular resistance, and sodium and fluid retention. Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal secretion results in increases in plasma renin activity. Decreased level of aldosterone results in small increases of serum potassium.
Inhibition of ACE also interferes with the degradation of bradykinin a potent vasodepressor peptide, which may contribute to the therapeutic effect. While the mechanism through which fosinopril lowers blood pressure is believed to be primarily suppression of the renin angiotensin aldosterone system, fosinopril has an antihypertensive effect even in patients with low renin hypertension. Although fosinopril was antihypertensive in all races studied, black hypertensive patients (usually a low renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than nonblack patients.

Hydrochlorothiazide.

The mechanism of antihypertensive effect of hydrochlorothiazide is unknown. Thiazide diuretics affect the renal tubular mechanisms of electrolyte reabsorption, increasing excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate.
Hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion and decreases potassium. Concurrent administration of fosinopril attenuates the potassium loss associated with hydrochlorothiazide. With hydrochlorothiazide, the onset of diuresis occurs in two hours, and peak effect at about four hours, and the action persists for approximately six to twelve hours.

Pharmacokinetics.

In single dose studies in healthy volunteers concomitant administration of fosinopril and hydrochlorothiazide had little or no effect on the pharmacokinetics of either drug. Kinetic parameters for each constituent derived following either monotherapy or combination therapy are as follows.

Fosinopril sodium.

Absorption.

The extent of absorption for fosinopril is 30 to 40% and is essentially unaffected by food although the rate of absorption may be slowed. The time to peak plasma concentrations of fosinopril diacid is approximately three hours and is independent of the dose of fosinopril administered. After single and multiple oral doses Cmax and area under the curve (AUC) are directly proportional to the administered dose of fosinopril.

Distribution.

Fosinopril diacid is highly protein bound (greater than or equal to 95%) but has negligible binding to cellular components of blood. It has a relatively small volume of distribution.
Studies in animals indicate that fosinopril and fosinopril diacid do not cross the blood brain barrier but fosinopril diacid does cross the placenta of pregnant animals.

Metabolism.

In healthy subjects and renally impaired patients, hydrolysis of fosinopril to the active fosinopril diacid is rapid and complete. This transformation probably occurs in the gastrointestinal mucosa and liver. After an oral dose of radiolabelled fosinopril, 75% of radioactivity in plasma was present as active fosinopril diacid, 20 to 30% as glucuronide conjugate and 1 to 5% as a para-hydroxy metabolite.
The para-hydroxy metabolite is as potent an inhibitor of ACE as fosinopril diacid; the glucuronide conjugate is devoid of ACE inhibitory activity. The conversion of fosinopril to fosinopril diacid may be slowed in patients with hepatic dysfunction although the extent of this conversion is unchanged.

Excretion.

After intravenous administration, fosinopril diacid is eliminated approximately equally by the liver and kidneys. In healthy subjects, mean body clearance of intravenous fosinopril diacid was 26 to 39 mL/minute. In hypertensive patients with normal renal and hepatic function who received repeated doses of fosinopril, the effective t1/2 for the accumulation of fosinopril diacid averaged 5 hours.
Fosinopril is not well dialysed with the clearance of fosinopril diacid by haemodialysis and peritoneal dialysis averaging 2 and 7% of urea clearance respectively.

Hydrochlorothiazide.

Absorption.

The extent of absorption for hydrochlorothiazide is 50 to 80%. Peak plasma concentrations of hydrochlorothiazide are reached approximately two hours after oral administration.

Distribution.

Its apparent volume of distribution is 0.83 to 1.141 L/kg and its plasma protein binding is 68%. Hydrochlorothiazide does not cross the blood brain barrier but does cross the placenta freely producing fetal plasma levels similar to those found in the maternal circulation.

Metabolism and excretion.

Hydrochlorothiazide is not metabolised and is eliminated rapidly by the kidney. The mean plasma half-life ranged from four hours in young subjects to eleven hours in the elderly.

Renal impairment.

The pharmacokinetics of fosinopril diacid and hydrochlorothiazide were examined following administration of one fosinopril/ hydrochlorothiazide 20/12.5 tablet once daily for five days, in subjects with renal impairment (mean creatinine clearance 56 mL/minute; range 27 to 76 mL/minute) and a group with normal renal function. Renal impairment led to increased serum concentrations of fosinopril diacid and hydrochlorothiazide with repeated administration. On day 5, the ratio of AUC geometric mean in the renal impaired group/ geometric mean in the normal group was 1.43 for fosinopril diacid and 2.24 for hydrochlorothiazide. Increased fosinopril diacid concentrations were reflected by greater ACE inhibition.
It is not clear that steady state would have been reached for fosinopril diacid in the renally impaired patients by day 5, so fosinopril diacid levels in such patients during chronic administration may be higher than in this study.
These findings are of no significance for patients who have been stabilised on coadminstered fosinopril and hydrochlorothiazide before switching to fosinopril/ hydrochlorothiazide, as dose titration will have already taken place.

Hepatic insufficiency (alcoholic or biliary cirrhosis).

No information is available from studies involving concurrent administration of fosinopril and hydrochlorothiazide. In studies using fosinopril alone, the extent of hydrolysis of fosinopril is not appreciably reduced, although the rate of hydrolysis may be slowed. The apparent total body clearance of fosinopril diacid is approximately one-half that in patients with normal hepatic function.

Elderly.

In elderly male subjects (66 to 75 years old) with clinically normal renal and hepatic function, the mean peak concentration and systemic exposure of fosinopril diacid were respectively 21% (single dose) and 44% (multiple dose) and 19% (single dose) and 23% (multiple dose) greater than those observed in the young subjects (21 to 30 years old).
For hydrochlorothiazide, the mean peak serum/ plasma concentration was increased by 27% (single dose) and 39% (multiple dose) for the elderly group compared to the young subjects.
The area under the plasma concentration time curve (AUC) for hydrochlorothiazide was increased by 91% in the elderly group following multiple dosing.

Clinical Trials

Both agents reduce blood pressure by different but complementary mechanisms and are used in combination for the treatment of hypertension. Clinical studies have shown that blood pressure reduction achieved with the combination of fosinopril and hydrochlorothiazide was approximately additive.
Peak blood pressure reductions were achieved six to eight hours after dosing and the hypertensive effect persisted for 24 hours. Symptomatic postural hypotension was infrequent but can occur in patients who are salt and/or volume depleted. Once daily doses of fosinopril and hydrochlorothiazide lowered 24 hour trough, seated systolic/ diastolic blood pressure by 10 to 17 mmHg/ 6 to 7 mmHg (10 mg/12.5 mg dose) and 11 to 13 mmHg/ 7 to 8 mmHg (20 mg/12.5 mg dose) when compared to placebo in the intention to treat population. These trough effects were 60 to 90% of the corresponding peak response.
The effectiveness of the fosinopril/ hydrochlorothiazide combination was not influenced by age, sex or race. Abrupt withdrawal of the combination did not result in rebound hypertension.

Indications

Mild to moderate hypertension. Treatment should not be initiated with this combination.

Contraindications

Patients who are hypersensitive to fosinopril sodium or hydrochlorothiazide, other ACE inhibitors or other sulfonamide derived drugs (e.g. thiazides) or any of the inactive components of the tablets.
Patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an angiotensin converting enzyme inhibitor.
Pregnancy (see Precautions, Use in pregnancy).
Patients who are anuric.

Precautions

Anaphylactoid and possibly related reactions.

Head and neck angioedema.

Severe life threatening angioedema has been reported rarely with angiotensin converting enzyme (ACE) inhibitors. The overall incidence is approximately 0.1 to 0.2%. There seems to be no sex difference in the incidence of angioedema or in the predisposition to angioedema in patients with heart failure or hypertension. In the majority of reported cases, the symptoms occurred during the first week of therapy. However, the onset of angioedema may be delayed for weeks or months.
Patients may have multiple episodes of angioedema with long symptom free intervals. The aetiology is thought to be nonimmunogenic and may be related to accentuated bradykinin activity. Angioedema may occur with or without urticaria but usually the angioedema involves nonpitting oedema of the skin and oedema of the subcutaneous tissues and mucous membranes. Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors.
In such cases, the product should be discontinued promptly and appropriate monitoring instituted to ensure complete resolution of symptoms. In instances when swelling has been confined to the face and lips, the angioedema has generally resolved either without treatment or with antihistamines.
Angioedema associated with laryngeal oedema is potentially life threatening. Where involvement of the tongue, glottis or larynx is likely to cause airway obstruction appropriate therapy, including adrenaline and oxygen administration, should be carried out promptly or the patient hospitalised. Patients who respond to medical treatment should be observed carefully for a possible re-emergence of symptoms of angioedema.
There are reports where changing the patient over to another ACE inhibitor was followed by recurrence of oedema and others where it was not. Because of the potential severity of this rare event another ACE inhibitor should not be used in patients with a history of angioedema to a drug of this class (see Contraindications).

Intestinal angioedema.

Intestinal angioedema has been reported rarely in patients treated with angiotensin converting enzyme (ACE) inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including CT scans or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid reactions during desensitization.

Two patients undergoing desensitising treatment with hymenoptera venom while receiving another ACE inhibitor, enalapril, sustained life threatening anaphylactoid reactions. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.

Anaphylactoid reactions during high flux dialysis/ lipoprotein apheresis membrane exposure.

Patients haemodialysed using high flux polyacrylonitrile (‘AN69’) membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. Anaphylactoid reactions have also been reported in patients undergoing low density lipoprotein apheresis with dextran sulfate absorption. These combinations should therefore be avoided, either by use of a different class of medication or alternative membranes (e.g. cuprophane or polysulfone PSF for haemodialysis).

Neutropenia/ agranulocytosis.

Agranulocytosis and bone marrow depression (including leucopenia/ neutropenia) have been reported with ACE inhibitors. These have mostly occurred in patients with pre-existing impaired renal function, collagen vascular disease, immunodepressant therapy or a combination of these complicating factors. Most episodes of leucopenia and neutropenia have been single, transient occurrences without any associated clinical symptoms. In addition, data to establish a causal relationship are currently lacking. It is recommended that periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease, renal disease (serum creatinine greater than or equal to 180 micromol/L) and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive. Thiazide diuretics have been also reported rarely to cause agranulocytosis and bone marrow depression.

Hypotension.

Fosinopril/ hydrochlorothiazide can cause symptomatic hypotension and should be used cautiously in patients receiving concomitant therapy with other antihypertensive agents. Symptomatic hypotension is most likely to occur in patients who are volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril/ hydrochlorothiazide. A transient hypotensive response is not a contraindication to further doses which may be given without difficulty after replacement of salt and/or volume.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotaemia and rarely with acute renal failure and death. In such patients fosinopril/ hydrochlorothiazide therapy should be initiated under close medical supervision. Patients should be followed closely for the first two weeks of the treatment and whenever the dose is increased.
The antihypertensive effect of thiazide diuretics may be increased in the postsympathectomy patient. If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of physiological saline. Fosinopril/ hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume.

Hepatic failure.

Rarely, ACE inhibitors have been associated with the syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients who develop jaundice or marked elevations of hepatic enzymes should discontinue receiving fosinopril/ hydrochlorothiazide and receive appropriate medical attention.

Electrolyte imbalance/ hypokalaemia.

Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Patients should be periodically observed for clinical signs or symptoms of fluid and electrolyte imbalance, such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea or vomiting.
Although hypokalaemia may develop when thiazide diuretics are used, especially with brisk diuresis or in the presence of severe cirrhosis, concurrent therapy with fosinopril reduces diuretic induced hypokalaemia. The net effect of fosinopril/ hydrochlorothiazide may be to elevate, reduce or leave serum potassium unchanged.
Chloride deficit is generally mild and usually does not require treatment. Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcaemia and hypophosphataemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen. Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Metabolic disorders.

Hyperuricaemia and gout may be precipitated by thiazides. Insulin requirements in diabetic patients may be altered and latent diabetes mellitus may become apparent during thiazide administration. Increases in cholesterol and triglyceride levels may be associated with thiazide therapy.

Cough.

A persistent dry (nonproductive) irritating cough has been reported with all ACE inhibitors in use. The frequency of reports has been increasing since cough was first recognised as a side effect of ACE inhibition. In various studies, the incidence of cough varies between 2 to > 9% depending upon the drug, dosage and duration of use. The cough is often worse when lying down or at night. The cough is more common in women (who account for two-thirds of the reported cases).
Patients who cough may have increased bronchial reactivity compared to those who do not cough. The observed higher frequency of this complication in nonsmokers may be due to higher level of tolerance to cough by smokers. The mechanism of this adverse reaction is not clear but most likely to be secondary to the effects of converting enzyme inhibitor on kinins (bradykinin and/or prostaglandin) resulting in stimulation of pulmonary cough reflex. Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor. The reaction may recur on rechallenge with another ACE inhibitor but this is not invariably the case. A change in antihypertensive regimen may be required in severe cases.

Systemic lupus erythematosus.

Thiazide diuretics have been reported to cause exacerbation of systemic lupus erythematosus.

Surgery/ anaesthesia.

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, ACE inhibitors may block angiotensin II formation secondary to compensatory renin release and may thus augment the hypotensive response. If hypotension occurs, and is considered to be due to this mechanism, it can be corrected by volume expansion.

Dermatological reactions.

Dermatological reactions characterised by maculopapular pruritic rashes and sometimes photosensitivity has been reported with another ACE inhibitor. Rare and sometimes severe skin reactions (lichenoid eruptions, psoriasis, pemphigus like rash, rosacea, Stevens-Johnson syndrome etc.) have been reported. A causal relationship is difficult to assess. Patients who developed a cutaneous adverse event with one ACE inhibitor may be free of reaction when switched to another drug of the same class, but there are also reports of cross reactivity.

Taste disturbances (dysgeusia).

Taste disturbances were reported to be high (up to 12.5%) with high doses of another ACE inhibitor. The actual incidence of taste disturbance is probably low (< 0.5%) but data in this respect are scarce and difficult to interpret. Taste disturbances with ACE inhibitors are described as suppression of taste or a metallic sensation in the mouth. The dysgeusia occurs usually in the first weeks of treatment and usually disappears within one to three months of treatment.

Impaired renal function.

Fosinopril/ hydrochlorothiazide is contraindicated in patients who are anuric.
Fosinopril/ hydrochlorothiazide is not recommended in patients with severe renal disease (creatinine clearance less than 30 mL/minute). The cumulative effects of hydrochlorothiazide and hydrochlorothiazide associated precipitation of azotaemia may occur in some patients with impaired renal function.
As a consequence of inhibiting the renin angiotensin aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin angiotensin aldosterone system, treatment with ACE inhibitors may be associated with oliguria and/or progressive azotaemia but rarely with acute renal failure and/or death.
In patients with congestive heart failure and pre-existing renal failure, fosinopril like other ACE inhibitors should be used with caution. Although available data suggest minimal accumulation during ten days therapy with fosinopril 10 mg daily, dosage reduction of fosinopril in this patient group may be necessary and hence treatment with fosinopril/ hydrochlorothiazide may be inappropriate. Renal function should be closely monitored. In hypertensive patients with renal artery stenosis in one or both kidneys, increases in blood urea nitrogen and serum creatinine may occur during treatment with an ACE inhibitor. These increases are usually reversible upon discontinuation of therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients may develop increases in blood urea nitrogen and serum creatinine, usually minor and transient, when fosinopril was given concurrently with a diuretic. This effect is most likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of fosinopril/ hydrochlorothiazide may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see Dosage and Administration). If a deterioration in renal function has occurred after treatment with one ACE inhibitor then it is likely to be precipitated by another and in these patients another class of antihypertensive agent should be preferred.

Impaired hepatic function.

Fosinopril/ hydrochlorothiazide 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.

Use in the elderly (> 65 years).

Among patients who received fosinopril/ hydrochlorothiazide in clinical studies, 20% were 65 to 75 years old. Overall differences in effectiveness or safety were not observed between these patients and younger patients, however greater sensitivity of some older individuals cannot be ruled out.

Carcinogenesis, mutagenesis, impairment of fertility.

At least one other ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential to cause this effect with other ACE inhibitors in humans is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when it does occur, it is considered to be benign. In two year studies involving both mice and rats at doses up to 400 mg/kg daily, there was no evidence of a carcinogenic effect. Neither fosinopril sodium nor the active fosinopril diacid was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay.
Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo. In the Chinese hamster ovary cell cytogenic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation. There were no adverse reproductive effects in male and female rats treated with 15 to 60 mg/kg daily. There was no effect on pairing time prior to mating in rats until a daily dose of 240 mg/kg, a toxic dose, was given; at this dose, a slight increase in pairing time was observed.

Use in pregnancy.

(Category D)
As with all ACE inhibitors, APO-Fosinopril HCTZ 20/12.5 should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with APO-Fosinopril HCTZ 20/12.5 and avoided during treatment.
If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment.
If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
When used in pregnancy, ACE inhibitors can cause injury and even death to the developing fetus.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure and death.
Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios has been associated with fetal limb contractures, craniofacial malformations, hypoplastic lung development and intrauterine growth retardation. Prematurity and patent ductus arteriosus have also been reported.
A historical cohort study in over 29,000 infants born to nondiabetic mothers has shown 2.7 times higher risk for congenital malformations in infants exposed to any ACE inhibitor during first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02), respectively, compared to no exposure.

Use in lactation.

Both fosinopril and hydrochlorothiazide are detectable in breast milk. Because of the potential for serious adverse reactions in breastfed infants from fosinopril/ hydrochlorothiazide, a decision should be made whether to discontinue breastfeeding or to discontinue fosinopril/ hydrochlorothiazide, taking into account the importance of fosinopril/ hydrochlorothiazide to the treatment of the mother.

Use in children.

Safety and effectiveness in children have not been established.

Interactions

Alcohol, barbiturates or narcotics.

Potentiation of thiazide diuretic induced orthostatic hypotension may occur.

Antacids.

Antacids (aluminium hydroxide, magnesium hydroxide, simethicone) may impair absorption of fosinopril/ hydrochlorothiazide. If concomitant administration of these agents is indicated dosing should be separated by two hours.

Antidiabetic drugs (oral agents and insulin).

Thiazides may elevate blood glucose levels; thus dosage adjustments of antidiabetic agents may be necessary.

Antigout medication.

Dosage adjustments of antigout medication may be necessary since hydrochlorothiazide may raise the level of blood uric acid. Increase in the dosage of probenecid or sulphinpyrazone may be necessary.

Calcium salts.

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Cholestyramine resin and colestipol hydrochloride.

May delay or decrease absorption of hydrochlorothiazide. Fosinopril/ hydrochlorothiazide should be taken at least one hour before or four to six hours after these medications.

Lithium.

Increased serum lithium levels and risk of lithium toxicity have been reported in patients receiving ACE inhibitors and/or diuretic agents concomitantly with lithium.
Fosinopril/ hydrochlorothiazide and lithium should be coadministered with caution and frequent monitoring of serum lithium levels is recommended.

Inhibitors of endogenous prostaglandin synthesis.

In some patients, these agents can reduce the effects of diuretics. Indomethacin has been reported to reduce the antihypertensive effect of other ACE inhibitors, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (e.g. aspirin) may have a similar effect. In studies with concomitant administration of aspirin and fosinopril, the AUC for unbound fosinopril diacid was not altered, however the AUC for total (bound and unbound) fosinopril diacid and 48 hour cumulatory urinary excretion were reduced by 42%.

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

Concomitant use of a renin angiotensin system inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID, including COX-2 inhibitor) and a thiazide diuretic may increase the risk of renal impairment. This includes use in fixed combination products containing more than one class of drug. The combination of these agents should be administered with caution, especially in the elderly and in patients with pre-existing renal impairment. Renal function (serum creatinine) should be monitored after initiation of concomitant therapy, and periodically thereafter.

Other diuretics and antihypertensive medications.

Potassium sparing diuretics (e.g. amiloride, spironolactone, triamterene) or potassium supplements can increase the risk of hyperkalaemia. If concomitant use of fosinopril/ hydrochlorothiazide and such agents is indicated, they should be given with caution, and the patients serum potassium monitored frequently.

Potassium supplements and salt substitutes.

These supplements and salt substitutes should be used with caution and serum potassium should be monitored frequently.

Drugs used during surgery.

The effects of nondepolarising muscle relaxants, preanaesthetics and anaesthetics used during surgery (e.g. tubocurarine chloride and gallamine triethiodide) may be potentiated by hydrochlorothiazide and dosage adjustments may be required. Fluid and electrolyte imbalances should be monitored and corrected prior to surgery. Caution should be used in patients taking fosinopril/ hydrochlorothiazide and pressor agents (e.g. noradrenaline) who undergo surgery. Preanaesthetic and anaesthetic agents should be given in reduced dosage and if possible hydrochlorothiazide therapy discontinued one week prior to surgery.

Other agents.

The bioavailability of fosinopril diacid is not altered by coadministration with cimetidine, digoxin, metoclopramide, nifedipine, propranolol, propantheline or warfarin.

Laboratory tests.

Fosinopril may cause a false low measurement of serum digoxin levels with assays utilising the charcoal absorption method. Other kits which utilise the antibody coated tube method may be used instead. Therapy with fosinopril/ hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function.

Adverse Effects

Clinical trial data.

Adverse events in patients receiving fosinopril/ hydrochlorothiazide were generally mild and transient and similar to those seen with the individual components taken separately. The incidence and type of adverse events in the elderly (greater than or equal to 65 years) were similar to those seen in younger. Table 1 displays the adverse events reported among subjects in active and placebo controlled clinical trials of combination fosinopril/ hydrochlorothiazide. It includes only those adverse events reported with an incidence of 1.0% or greater in subjects receiving fosinopril/ hydrochlorothiazide 10/12.5 or fosinopril/ hydrochlorothiazide 20/12.5.
In placebo controlled clinical trials, the usual duration of therapy was two months.
Discontinuations due to any clinical or laboratory adverse event were 3.5 and 4.3% in fosinopril/ hydrochlorothiazide treated and placebo treated patients, respectively. If the total clinical trial population is considered, withdrawals due to adverse events or laboratory abnormalities occurred in 2.6% of fosinopril/ hydrochlorothiazide treated patients, 2.7% of fosinopril treated patients, 2.7% of hydrochlorothiazide treated patients and 3.5% of placebo treated patients.
The following adverse drug reactions, possibly or more strongly associated causally with the use of fosinopril/ hydrochlorothiazide, were also reported during clinical trials.
*The asterisk indicates adverse reactions that occurred in one patient only. The listing does not include events already presented in Table 1.

Cardiovascular.

Uncommon: oedema lower extremity*, cardiac rhythm disturbance*, subjective rhythm disturbance, ventricular rhythm disturbance*, flushing, orthostatic hypotension, hypertension, nonangina cardiac chest pain*, oedema and syncope.

Dermatological.

Uncommon: acne*, dermatitis*, ecchymosis*, extremity erythema*, bacterial skin infection* pruritus, rash and skin discomfort.

Endocrine/ metabolic.

Uncommon: breast disorder*, hot flushes, libido change, menstrual disorder* and polydipsia*.

Gastrointestinal.

Uncommon: abnormal stool*, constipation*, decreased appetite*, diarrhoea, abdominal distension*, dry mouth*, eructation*, gastrointestinal polyp excision*, gastritis*, increased appetite*, oral lesion*, intestinal obstruction* and abdominal pain.

General.

Uncommon: chest pain, chills*, cold sensation*, fever*, halitosis*, hyperhydrosis, malaise and weight loss*.

Hepatic/ biliary.

Uncommon: hepatitis*.

Immunological.

Uncommon: allergy* and angioedema*.

Musculoskeletal.

Uncommon: limitation of movement*, muscle cramp, musculoskeletal trauma*, musculoskeletal chest pain*, extremity swelling*, tendinitis* and extremity weakness.

Nervous system.

Uncommon: depression, neuropathy entrapment, memory impairment*, numbness*, somnolence, emotional lability/ disturbance, insomnia and paraesthesia.

Renal/ genitourinary.

Uncommon: abnormality urination, prostate disorder* and vaginal bleeding*.

Respiratory.

Uncommon: congestion*, subjective disorder of upper airway*, dyspnoea*, epistaxis*, sneezing*.

Special sense.

Uncommon: bad taste of medication*, ear abnormality*, ear infection* and hearing abnormality.

Laboratory test abnormalities.

Serum electrolytes, uric acid, glucose, magnesium, cholesterol, triglycerides and calcium (see Precautions). Neutropenia, decreased haematocrit and haemoglobin, eosinophilia, elevated creatinine or blood urea nitrogen (BUN).

Fetal/ neonatal morbidity and mortality.

The use of ACE inhibitors during pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development.
Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported. More recently, prematurity, patent ductus arteriosus and other structural cardiac malformations, as well as neurological malformations, have been reported following exposure limited to the first trimester of pregnancy. (See Precautions, Use in pregnancy.)

Other adverse events reported when fosinopril or hydrochlorothiazide are taken separately.

Cardiovascular.

Sudden death, cardiac/ respiratory arrest, shock, hypertensive crisis, peripheral vascular disease/ claudication, angina/ myocardial infarct, cerebrovascular accident, hypotension, conduction disorder and palpitations.

Dermatological.

Urticaria, photosensitivity.

Endocrine/ metabolic.

Diabetes mellitus, gout.

Gastrointestinal.

Bleeding, pancreatitis, tongue swelling, dysphagia, anorexia, weight change, pyrosis, sialoadenitis and flatulence.

General.

Pain, xanthopsia.

Hepatic/ biliary.

Jaundice (cholestatic) and/or liver enzyme abnormalities.

Haematological.

Aplastic anaemia, megaloblastic anaemia, agranulocytosis, leucopenia, thrombocytopenia, purpura, haemolytic anaemia, lymphadenopathy.

Immunological.

Necrotising angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary oedema), fever, anaphylaxis and toxic epidermal necrolysis (see also Dermatological).

Musculoskeletal.

Arthralgia, arthritis and myalgia.

Nervous/ psychiatric.

Lightheadedness, memory disturbance, drowsiness, confusion, behaviour change, mood change, tremor, sleep disturbance, cerebral infarction, transient ischaemic attack and restlessness.

Respiratory.

Bronchospasm, pneumonia, pulmonary congestion, laryngitis/ hoarseness, sinusitis and pleuritis. A symptom complex of cough, bronchospasm, eosinophilia has been observed in two patients treated with fosinopril.

Renal/ genitourinary.

Impotence, acute renal failure, renal insufficiency, interstitial nephritis, renal stones, abnormal urinary sediment.

Special senses.

Taste disturbances, eye disturbances - other, transient blurred vision, vision disturbances, ear pain and tinnitus.

Dosage and Administration

APO-Fosinopril HCTZ 20/12.5 tablet is not scored and must not be broken in order to attempt dose titration from a lower dose.
Since there is no lower dose (10/12.5 mg) of APO-Fosinopril HCTZ available, if a dose of fosinopril/ hydrochlorothiazide 10/12.5 mg is required, an alternative product must be used.

Adults including the elderly.

The usual dose is one fosinopril/ hydrochlorothiazide 10/12.5 tablet or 20/12.5 tablet once daily. Only the higher strength 20/12.5 tablet is available as APO-Fosinopril HCTZ 20/12.5.

Children (< 18 years).

The safety and efficacy of fosinopril/ hydrochlorothiazide has not been established.

Hepatic impairment.

The usual dose of fosinopril/ hydrochlorothiazide is recommended in patients with mild to moderate hepatic impairment (see Precautions).

Renal impairment.

The usual dose of fosinopril/ hydrochlorothiazide is recommended for patients with mild to moderate renal impairment (creatinine clearance > 30 mL/minute, serum creatinine approximately less than or equal to 265 micromol/L).
Fosinopril/ hydrochlorothiazide is not recommended for patients with severe renal dysfunction (creatinine clearance < 30 mL/minute) since loop diuretics are preferred to thiazides in these patients (see Precautions).

Overdosage

No specific information is available on the treatment of overdose with fosinopril/ hydrochlorothiazide; treatment should be symptomatic and supportive. Therapy with fosinopril/ hydrochlorothiazide should be discontinued and the patient closely monitored. Suggested measures include administration of activated charcoal and correction of dehydration, electrolyte imbalance and hypotension by established procedures.
Fosinopril is poorly removed from the body by haemodialysis or peritoneal dialysis. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.
The Poisons Information Centre, telephone number 131 126 should be contacted for advice on management.

Presentation

Tablets (round, light orange, marked FH on one side), fosinopril sodium 20 mg/ hydrochlorothiazide 12.5 mg: 30's (Al/Al blister pack).
APO-Fosinopril HCTZ 20/12.5 tablet is not scored and must not be broken in order to attempt dose titration from a lower dose.
Since there is no lower dose (10/12.5 mg) of APO-Fosinopril HCTZ available, if a dose of fosinopril/ hydrochlorothiazide 10/12.5 mg is required, an alternative product must be used.

Storage

Store below 25°C. Protect from moisture.

Poison Schedule

S4.