Consumer medicine information

Hyforil 10/12.5 mg Tablets

Fosinopril sodium; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Hyforil 10/12.5 mg Tablets

Active ingredient

Fosinopril sodium; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Hyforil 10/12.5 mg Tablets.

What is in this leaflet

This leaflet answers some common questions about HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg (fosinopril + hydrochlorothiazide tablets).

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg against the benefits it is expected to have for you.

If you have any concerns about using/taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with this medicine.

You may need to read it again.

What HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg are used for

HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg contain two medicines, fosinopril sodium and hydrochlorothiazide. Both medicines reduce blood pressure, but work in different ways. Fosinopril belongs to the class of medicines called Angiotensin Converting Enzyme (ACE) inhibitors that act on the heart and blood vessels. Hydrochlorothiazide is a diuretic, i.e., it works by making your kidneys pass more water and salt. Together fosinopril and hydrochlorothiazide lower high blood pressure.

Your doctor would have prescribed HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg (fosinopril + hydrochlorothiazide tablets) for the following:

  • treatment of high blood pressure if treatment of high blood pressure is not satisfactory with fosinopril alone.

Fosinopril and hydrochlorothiazide tablets are not suitable for initial therapy of high blood pressure.

Your doctor may prescribe HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg for another reason. Ask your doctor if you have any questions about why HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg has been prescribed for you.

There is no evidence that HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets are addictive.

Fosinopril + hydrochlorothiazide may affect your ability to drive a car or operate machinery.

Before you take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg

When you must not take it

Do not take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg if you are allergic to fosinopril (or other ACE inhibitors) or hydrochlorothiazide (or other thiazides) or sulphonamides (possible cross-reaction) or to any of the tablet ingredients at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching, shortness of breath, swelling of the tongue or face.

Do not take if any of the following applies to you:

  • You have a condition known as angioneurotic oedema that manifests with swelling of face, lips, hands/feet, or breathing difficulties.
  • You are not producing urine (anuric).
  • You are pregnant, or planning to become pregnant, or are breast-feeding currently.

Do not take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg after the expiry date printed on the pack.

If you take it after the expiry date has passed, it may not work as well or may cause harm. Do not take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg if the tablets do not look quite right.

Do not take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you have any allergies to:

  • any other medicines containing ACE inhibitors or any thiazide group of diuretics or sulphonamides
  • any other substances, such as foods, preservatives or dyes

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.

Tell your doctor if you are pregnant or intend to become pregnant.

Like many other medicines, HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg may affect your developing baby if you take it during pregnancy. Your baby may absorb this medicine in the womb and therefore there is a possibility of harm to the baby.

If it is necessary for you to take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg, your doctor can help you decide whether or not to take it during pregnancy.

Tell your doctor if you are breast-feeding or planning to breast-feed.

Your baby may absorb this medicine from breast milk and therefore there is a possibility of harm to the baby. Your doctor will discuss the possible risks and benefits of using HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg during breast-feeding.

Tell your doctor if you have or have had any of the following conditions:

  • You have been diagnosed to have conditions known as systemic lupus erythematosus or scleroderma.
  • You have a condition known as gout (problem with your joints).
  • You are dehydrated (e.g. have had diarrhoea and/or vomiting recently).
  • You have sugar diabetes (diabetes mellitus).
  • You have problems with your kidney(s) and/or liver.
  • You have very high blood pressure at the start of treatment.
  • You are on a low salt diet.
  • You are an elderly person (more than 65 years of age).
  • You have problems with the performance of your heart.
  • You have been diagnosed to have a condition known as renal artery stenosis.
  • You have had a kidney transplant or are on haemodialysis.
  • You have been told by your doctor that you have abnormal levels of electrolytes (increased or decreased levels of sodium, potassium or chloride) in your blood.
  • You are about to have a treatment called LDL apheresis.
  • You are going to have desensitisation treatment (e.g. treatment to reduce the effects of an allergy to bee or wasp stings).
  • You are going to have surgery (including dental surgery) involving a general anaesthetic, even if it is minor.

HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg tablets are not recommended for use in children.

Avoid alcoholic beverages until you have discussed their use with your doctor.

Your medicine also contains small amounts of an inactive ingredient called anhydrous lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Tell your doctor if you plan to have a blood/urine test.

If you need a laboratory investigation such as blood test or urine test, do inform your doctor about the medicine you are taking.

If you have not told your doctor about any of the above, tell them before you take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg.

Taking other medicines

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

Some medicines may interfere with the absorption or action of fosinopril + hydrochlorothiazide.

  • Antacids (medicines used to relieve heartburn, indigestion). These products can reduce the absorption of fosinopril. If it is essential that you take these products, it is recommended that ingestion of fosinopril and hydrochlorothiazide tablets and antacids be separated by at least 2 hours.
  • Barbiturates (sedative drugs which may be used in the treatment of sleeplessness or epilepsy)
  • Benzodiazepines (such as midazolam used as tranquillizers).
  • Medicines containing calcium salts
  • Cholesterol lowering medicines (eg colestyramine or colestipol)
  • Cimetidine (a medicine for a type of digestive disorder)
  • Cyclosporin or tacrolimus (used following organ transplants for immunosuppression)
  • Excess of common table salt
  • Corticosteroids (used to treat various conditions including rheumatism, arthritis, allergic conditions, certain skin diseases, asthma or certain blood disorders)
  • Hypnotics (eg diazepam)
  • Anaesthesia-inducing medicines
  • Isoniazid (antibacterial agent used to treat an infection called tuberculosis)
  • Lithium (used in treatment of certain mental illnesses)
  • Medicines called catecholamines [ephedrine, noradrenaline or adrenaline; drugs used for treatment of low blood pressure, heart failure, asthma or allergies (noradrenaline and adrenaline are always given under medical supervision)]
  • Medicines that relax muscles (eg tizanidine)
  • Medicines used to prevent blood from clotting normally (warfarin or coumarin drugs)
  • Medicines used to treat certain heart conditions (eg digoxin)
  • Medicines used to treat gout (allopurinol used for treatment of gout)
  • Methyldopa (used for treatment of high blood pressure)
  • Narcotics (morphine like medicines to reduce pain)
  • Other blood pressure lowering medicines e.g. diuretics (furosemide), beta-blockers (atenolol); nitrates (e.g. isosorbide mononitrate, nitroglycerine), vasodilators (e.g. hydralazine, nifedipine, amlodipine), barbiturates (eg phenobarbitone), phenothiazines (eg chorpromazine), tricyclic antidepressants (eg amitryptaline) or alcohol
  • Pain relievers known as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (e.g. ibuprofen, aspirin)
  • Phenytoin, valproic acid (used to treat convulsions)
  • Potassium supplements or potassium containing salt substitutes
  • Sugar diabetes medicines (such as oral hypoglycaemic agents or insulin)
  • Water tablets especially the ones that prevent loss of potassium in urine (e.g. spironolactone, amiloride, triamterene)

These medicines may be affected by fosinopril + hydrochlorothiazide, or may affect how well it works. You may need to use different amounts of your medicine or you may need to take different medicines. Your doctor or pharmacist will be able to tell you what to do when taking/being given HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets with other medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets.

How HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg is given

How much to take

Your doctor will tell you how many tablets you will need to take each day. This may depend on your age, your condition and whether or not you are taking any other medicines.

Take your medicine as instructed by your doctor. Do not take more than the doctor told you to. Check the label carefully for how much to take and how often to take. Your pharmacist or doctor can help if you are not sure.

How to take it

Swallow the tablet whole with a glass of water. HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets may be taken with or without food.

Adults

The usual starting dose is one HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg (fosinopril + hydrochlorothiazide 10 + 12.5 mg or fosinopril + hydrochlorothiazide 20 + 12.5 mg) tablet taken once daily. Your daily dose will depend on your condition and your response to treatment.

HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg tablets are not recommended if you have severe kidney problems.

When to take it

Take your HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets at about the same time everyday. Taking your tablets at the same time will have the best effect. It will also help you to remember when to take the tablets.

If you need to take an antacid, take it at least 2 hours before or two hours after your dose of HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg.

How long to take it

Continue taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets until your doctor tells you to stop. HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg help to control your condition but does not cure it. Therefore you must take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg every day. Continue taking it for as long as your doctor tells you.

Do not stop taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets because you begin to feel better

Do not stop taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg, or lower the dosage, without checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Stopping HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg without doctor’s advice may worsen your condition. Your doctor will decide when you should stop taking it.

If you forget to take it

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 it as soon as you remember, then go back to taking it as you would normally.

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

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

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

If you take too much (Overdose)

Immediately telephone your doctor, or the Poisons Information Centre on 13 11 26 for advice on the management of overdosage or go to Emergency department at your nearest hospital, if you think that you or anyone else has taken too much of HYFORIL 10/12.5 mg or 20/12.5 mg tablets. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Keep these telephone numbers handy.

While you are using HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg

Things you must remember

Take HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets exactly as your doctor tells you to.

Try not to miss any doses and take the medicine even if you feel well.

Visit your doctor regularly for check ups.

Tell all doctors, dentists and pharmacists who are treating you that you are taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets.

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets.

Tell your doctor if you are to undergo any blood or urine test.

If you become pregnant while taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets, tell your doctor immediately.

Things you must do

Tell your doctor if you have excessive vomiting or diarrhoea or experience any of the following symptoms:

  • light-headedness or dizziness
  • 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 HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg or if your dose is increased.

Make sure you drink enough water during exercise and hot weather when you are taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg, especially if you sweat a lot.

If you do not drink enough water while taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg, your blood pressure may drop suddenly and you may dehydrate. If you experience any of the above symptoms, tell your doctor.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg.

Having a general anaesthetic while taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg may also cause your blood pressure to drop 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 HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg, especially if you are elderly.

Be careful driving or operating machinery until you know how HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg affects you.

As with other ACE inhibitor medicines, HYFORIL 10/12.5 mg and HYFORIL 20/12.5 mg may cause dizziness, or light-headedness in some people. Make sure you know how you react to your 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.

Things you must not do

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

Do not use HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets to treat any other complaints unless your doctor tells you to.

Do not stop taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets, or lower the dose, 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 HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg or after your dose is increased. This is because your blood pressure is dropping suddenly.

If you have a pre-existing kidney problem you should follow up regularly with your doctor.

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 loose 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 programme for you.
  • Smoking - your doctor may advise you to stop smoking or at least cut down.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg.

Ask your doctor or pharmacist any questions you may have.

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

  • Feeling sick (nausea), being sick (vomiting), constipation, diarrhoea (loose stools), pain in the belly, indigestion, wind (flatulence), increased or decreased appetite, dryness of mouth, altered taste, increased thirst, ulceration in the mouth, burping, heart burn, difficulty in swallowing
  • Headache, tiredness, generalized weakness, aches and pain, chills, shivers, dizziness, sleep disturbances, hot flushes, flushing, flu-like symptoms, weight loss
  • Depressed mood, loss of memory, sleep disturbances, labile mood, drowsiness, confusion, behavioral change, mood swings, restlessness
  • Pins and needles sensation, numbness, weakness of the extremities
  • Blurred vision, visual disturbances, yellowish hue in vision (manifestation of a condition called xanthopsia, also called distortion of color vision)
  • Increased urination, pain in the loin
  • Vaginal bleeding
  • Sexual dysfunction
  • Foul-smelling breath
  • Increased blood pressure
  • Diminished hearing, ear infection, ringing in the ears
  • Muscle cramps, spasm and pain, restricted mobility, joint pains
  • Pain in the tendons
  • Runny or stuffy nose, sore throat, cough, difficulty in breathing
  • Urinary disturbances (associated with burning sensation or pain on passing urine)
  • Excessive sweating
  • Increased sensitivity to light
  • Sexual inability in males
  • Enlarged glands
  • Hoarseness of voice

These are the more common side effects of fosinopril + hydrochlorothiazide. These side effects are usually mild and occur at the start of treatment.

Tell your doctor immediately if you notice any of the following

  • Unusual bleeding or increased tendency to bleed, persistent sore throat and frequent infections, and/or anaemia
  • Yellowing of skin and whites of eyes with decreased appetite
  • Irregular heart beat
  • Pain and distension of the belly with no passage of wind or motions and being sick (vomiting) (manifestations of a condition called intestinal obstruction)
  • Feeling faint and lightheaded on change of posture
  • Chest pain and or chest infection
  • Bleeding from the nose
  • Swelling of face, ankles or other parts of the body, with sudden increase or decrease in the amount of urine passed or have passed dark coloured urine
  • Sudden onset of severe abdominal pain with vomiting (manifestations of a condition called pancreatitis)
  • Awareness of heart beat
  • Angina (feeling of tightness, heaviness, dull discomfort, or crushing pain that is felt behind the breastbone and may spread to the arms, neck and jaw. It is often brought on by exercise, eating, or stress; or may occur at rest. Angina occurs due to narrowing of blood vessels which supply the muscles of the heart, and the resulting failure to deliver enough oxygen for normal functioning of the heart)
  • Myocardial Infarction (chest pain is more severe and prolonged than angina pain described above and may be associated with nausea (feeling sick), vomiting (being sick) and excessive sweating (occurs due to a complete blockade in one or more of the blood vessels, which supply the muscles of the heart, and the resulting failure to deliver oxygen for normal functioning of the heart)
  • Sudden onset of a severe headache, dizziness, numbness/weakness in the face, arm, or leg, especially on one side of the body (or) altered speech and mental ability to understand, disturbed vision in one or both eyes, and loss of balance or coordination These symptoms may be short-lasting and reversible (“transient ischaemic attack”) or may continue (“stroke”)

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

  • Some of the symptoms of an allergic reaction may include rashes, hives, itching, chest constriction, shortness of breath or swelling of face, lips, tongue, hands/feet, fainting, dizziness.
  • Severe skin reactions with blisters, sores or ulceration

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

Changes in the laboratory tests

  • Abnormal liver function tests
  • Increase in number of a type of cells in blood called eosinophils
  • Abnormal deposits in urine
  • Altered levels of electrolytes sodium and potassium
  • Increased blood levels of uric acid/ glucose/ cholesterol/ triglycerides
  • Abnormal kidney function tests

Some side effects have been reported with the use of other ACE inhibitors and may also occur with the use of HYFORIL. One of these is psychiatric reactions (mental illness with strange or disturbing thoughts) like hallucinations (seeing, feeling, or hearing things that are not there.)

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

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

You may not experience any of them.

After using it

Storage

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

If you take the tablets out of the box or the original pack they may not keep well.

Keep your HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg in a cool, dry place where it stays below 25°C.

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

Do not leave it in the car on hot days.

Heat and dampness can destroy some medicines.

Keep this medicine where young children cannot reach it.

Disposal

If your doctor tells you to stop taking HYFORIL 10/12.5 mg or HYFORIL 20/12.5 mg tablets or you find that they have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

HYFORIL 10/12.5 mg tablets are white to off-white, circular tablets, debossed with ‘RC3’ on one side and plain on the other side. Available in packs of 30 tablets.

HYFORIL 20/12.5 mg tablets are white to off-white, flat beveled edged, circular tablets, debossed with ‘FH1’ on one side and plain on the other side. Available in packs of 30 tablets.

Ingredients

Active ingredient:
HYFORIL 10/12.5 mg tablets contains 10.0 mg of fosinopril sodium & 12.5 mg of hydrochlorothiazide.
HYFORIL 20/12.5 mg tablets contains 20.0 mg of fosinopril sodium & 12.5 mg of hydrochlorothiazide.

Inactive ingredients:
Anhydrous lactose, crospovidone, povidone, microcrystalline cellulose, colloidal anhydrous silica, purified talc.

Sponsor

HYFORIL is supplied in Australia by:
Ranbaxy Australia Pty Limited
Suite 4.02, Level 4, Building D
12 - 24 Talavera Rd
North Ryde, NSW 2113
Australia

Australian Registration Numbers

HYFORIL 10/12.5 mg tablets blister pack:
AUST R 124585

HYFORIL 20/12.5 mg tablets blister pack:
AUST R 124589

HYFORIL® is a registered trade mark owned by Ranbaxy Laboratories Limited.

This leaflet was prepared in Oct 2008.

BRAND INFORMATION

Brand name

Hyforil 10/12.5 mg Tablets

Active ingredient

Fosinopril sodium; Hydrochlorothiazide

Schedule

S4

 

Name of the medicine

Hyforil 10/12.5 mg.

Fosinopril sodium 10 mg, Hydrochlorothiazide Ph. Eur. 12.5 mg.

Hyforil 20/12.5 mg.

Fosinopril sodium 20 mg, Hydrochlorothiazide Ph. Eur. 12.5 mg.

Excipients

Anhydrous lactose, crospovidone, povidone, microcrystalline cellulose, anhydrous colloidal silica, purified talc.

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 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.

Hydrochlorothiazide.

Chemical name: 6-chloro-3,4-dihydro- 2H-1,2,4-benzothiadiazine- 7-sulfonamide 1,1-dioxide. Molecular formula: C7H8ClN3O4S2. MW: 297.72. CAS: 58-93-5. Hydrochlorothiazide is the 3,4-dihydro derivative of chlorothiazide.

Actions

ACE inhibitor and thiazide diuretic.

Pharmacology

Pharmacodynamics.

Fosinopril sodium.

In humans and animals, fosinopril sodium following absorption is hydrolysed to the pharmacologically active fosinopril diacid, a specific competitive inhibitor of 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 increase 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 6 to 12 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 shown below.

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 plasma concentration time curve (AUC) are directly proportional to the administered dose of fosinopril.

Distribution.

Fosinopril diacid is highly protein bound (≥ 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 p-hydroxy metabolite. The p-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 (IV) administration, fosinopril diacid is eliminated approximately equally by the liver and kidneys. In healthy subjects, mean body clearance of IV 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 t½ for the accumulation of fosinopril diacid averaged 11.5 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.

Pharmacokinetics in special populations.

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) and a group with normal renal function. Renal impairment lead 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 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

Treatment of mild to moderate hypertension. Treatment should not be initiated with these combinations.

Contraindications

Hypersensitivity 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.
History of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor.
Pregnancy (see Precautions, Use in pregnancy).
Anuria.

Precautions

General.

Anaphylactoid and possibly related reactions.

Head and neck angioedema.

Severe life threatening angioedema has been reported rarely with 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 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 computerised tomography (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 desensitisation.

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 ≥ 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.

Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide (HCTZ), 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 commoner 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 regime 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) 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 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

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

Carcinogenicity/ mutagenicity.

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.

Effects on fertility.

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, Hyforil 10/12.5 mg or Hyforil 20/12.5 mg should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Hyforil 10/12.5 mg or Hyforil 20/12.5 mg 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 11.37 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 and hydrochlorothiazide, a decision should be made whether to discontinue breastfeeding or to discontinue Hyforil 10/12.5 mg and Hyforil 20/12.5 mg tablets, taking into account the importance of fosinopril and 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 and 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 sulfinpyrazone 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 and 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 and 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.

The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (nonsteroidal anti-inflammatory drug (NSAID), including cyclooxygenase (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 institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients and in those with pre-existing renal impairment.

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 and hydrochlorothiazide and such agents is indicated, they should be given with caution and the patient's 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 and 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, propanolol, propantheline or warfarin.

Effect on 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 and hydrochlorothiazide should be interrupted for a few days before carrying out tests of parathyroid function.

Adverse Effects

Clinical trials.

Adverse events in patients receiving fosinopril and 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 (≥ 65 years) were similar to those seen in younger patients.
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 and hydrochlorothiazide 10/12.5 mg or fosinopril and hydrochlorothiazide 20/12.5 mg.
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/ HCTZ 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/ HCTZ treated patients, 2.7% of fosinopril treated patients, 2.7% of HCTZ 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 (1) 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 flashes, libido change, menstrual disorder and polydipsia.

Gastrointestinal.

Uncommon: abnormal stool, constipation, decreased appetite, diarrhoea, abdominal distension, dry mouth, eructation, gastrointestinal (GI) 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, tendonitis 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 senses.

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 BUN.

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

Include the following.

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 and photosensitivity.

Endocrine/ metabolic.

Diabetes mellitus and gout.

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.)

Gastrointestinal.

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

General.

Pain and 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.
Among other potential adverse effects reported with ACE inhibitors, psychiatric reactions such as hallucinations (especially visual) have been reported with the use of ACE inhibitors.

Dosage and Administration

Adults.

Adults including the elderly.

The usual dose is one Hyforil 10/12.5 mg or Hyforil 20/12.5 mg (fosinopril + hydrochlorothiazide tablets 10 + 12.5 mg or fosinopril + hydrochlorothiazide tablets 20 + 12.5 mg tablets) once daily.

Children (< 18 years).

The safety and efficacy of Hyforil 10/12.5 mg and Hyforil 20/12.5 mg have not been established.

Hepatic impairment.

The usual dose of Hyforil 10/12.5 mg or Hyforil 20/12.5 mg is recommended in patients with mild to moderate hepatic impairment (see Precautions).

Renal impairment.

The usual dose of Hyforil 10/12.5 mg or Hyforil 20/12.5 mg is recommended for patients with mild to moderate renal impairment (creatinine clearance > 30 mL/minute, serum creatinine approximately ≤ 265 micromol/L). Fosinopril and 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

Treatment.

No specific information is available on the treatment of overdose with fosinopril and hydrochlorothiazide; treatment should be symptomatic and supportive. Therapy with fosinopril and 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.
Contact the Poisons Information Centre on 131 126 for advice on the management of overdosage.

Presentation

Hyforil 10/12.5 mg.

Tablets, white to off white, circular, marked RC3, plain on reverse: 30's.

Hyforil 20/12.5 mg.

Tablets, white to off white, flat beveled edged, circular, marked FH1, plain on reverse: 30's.

Poison Schedule

S4.