Consumer medicine information

Monace

Fosinopril sodium

BRAND INFORMATION

Brand name

Monace

Active ingredient

Fosinopril sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Monace.

What is in this leaflet

Please read this leaflet carefully before you start taking Monace tablets.

This leaflet answers some common questions about Monace 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 benefits and risks. Your doctor has weighed the risks of you taking Monace tablets against the benefits expected for you.

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

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

What Monace is used for

Monace is used for treating high blood pressure (hypertension) or heart failure. Both of these are long term (chronic) diseases so it is important that you continue to take your Monace tablets every day.

High blood pressure (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. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and 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.

Heart Failure
Heart failure means that the heart muscle is weak and cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops. Heart failure may start off with no symptoms, but as the condition progresses, patients may feel short of breath or may get tired easily after light physical activity such as walking. Some patients may wake up short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet.

How Monace tablets work

Monace contains fosinopril sodium. 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.

Your doctor may have prescribed Monace for another reason.

Ask your doctor if you have any questions about why Monace has been prescribed for you.

Monace is not addictive.

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

Use in children
The safety and effectiveness of Monace in children has not been established.

Before you take Monace

When you must not take it

Do not take Monace tablets if:

  • you are allergic to any other medicines containing fosinopril sodium (the active ingredient in Monace), or to any of the inactive ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include skin rash, itchiness, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain.
  • 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 before, you may be allergic to Monace.
  • you have a history of angioedema or angioneurotic oedema, which is swelling of the face, lips, tongue, throat (which may cause difficulty in breathing or swallowing), hands or feet, for no apparent reason.
  • you are using ACE inhibitors with aliskiren-containing products

Do not take Monace tablets if you are pregnant or trying to become pregnant. Monace may cause serious injury to your developing baby if you take it during pregnancy.

Do not take Monace tablets if you are breastfeeding or intend to breastfeed.

Do not take Monace tablets after the expiry date (EXP.) printed on the pack.

Do not take Monace tablets if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking Monace, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to:

  • any other medicines
  • 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 breathing and swallowing.

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

  • diabetes
  • take any other medicines including any immunosuppressant medicines or trimethoprim containing medicines
  • kidney problems, or have had kidney problems in the past, or are having dialysis
  • liver problems, or have had liver problems in the past
  • low blood pressure, which you may notice as dizziness or lightheadedness
  • are going to have surgery (including dental surgery) involving a general anaesthetic, even if it is minor

Tell your doctor if you are pregnant or plan to become pregnant or breastfeed.

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

Taking other medicines

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

Some medicines may affect the way Monace works. It is especially important that you tell your doctor if you are taking any of the following:

  • diuretics, also known as fluid or water tablets (for example Lasix®, Urex®, Natrilix®, Moduretic®)
  • lithium or lithium containing preparations (for example Lithicarb®, Priadel®)
  • potassium tablets (for example SPAN-K®, SLOW-K® or MAG-K®)
  • potassium-containing salt substitutes (for example PRESSOR-K®)
  • antacids, medicines used to treat heartburn and indigestion
  • medicines used to treat diabetes (such as insulin, sulphonylurea and vildagliptin)
  • aspirin
  • anti-inflammatory medicines (those that are used to relieve pain, swelling and other symptoms of inflammation, including arthritis) and include non-steroidal anti-inflammatory drugs (NSAIDs (for example Voltaren®, Indocid®) and COX-2 inhibitors (for example Celebrex). Taking a combination of Monopril with a thiazide diuretic (fluid tablet) and an anti-inflammatory medicine may damage your kidneys.
  • medicines that lower your immune system, such as medicines used to prevent rejection of transplant organs.
  • trimethoprim containing medicines (for example Bactrim, Septrim, Alprim) used to treat certain types of infections.

If you are taking Monace for high blood pressure do not take any medicine (including ones bought without prescription) for appetite control, asthma, colds, coughs, hayfever or sinus problems unless you have discussed the medicine with your doctor or pharmacist.

These medicines may be affected by Monace, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

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

How to take Monace

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet. Your doctor or pharmacist will tell you how many tablets you will need to take each day.

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

How much to take

Monace is usually taken at a dose of 10mg to 40mg once a day. Your doctor may have prescribed a different dose for you.

When to take it

Take Monace at about the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

It does not matter if you take Monace before or after food.

If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of Monace.

How long to take it

Monace helps to control your condition, but does not cure it. Therefore you must take Monace every day. Continue taking your medicine for as long as your doctor tells you.

If you forget to take Monace

If you have forgotten to take your dose of Monace tablets take your next dose at the normal time and in the normal amount.

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

Do not take a double dose to make up for the dose that you missed. Do not take any more than what your doctor has prescribed for you.

If you are not sure what to do or have any questions, 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 Monace (overdose)

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

While you are taking Monace

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking Monace.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking Monace. Tell your doctor if you have excessive vomiting or diarrhoea or experience any of the following symptoms:

  • light-headed, dizzy or faint
  • dry mouth or thirst
  • weakness, tiredness or drowsiness
  • fast heart beat
  • passing less urine than normal
  • muscle pain or cramps

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 Monace or if your dose is increased.

Make sure you drink enough water during exercise and hot weather when you are taking Monace, especially if you sweat a lot. If you do not drink enough water while taking Monace, 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 Monace. Having a general anaesthetic while taking Monace may also cause your blood pressure to drop suddenly.

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

If you are about to have any blood tests, tell your doctor that you are taking Monace. Monace may interfere with the results of some tests.

Have your blood pressure checked when your doctor says, to make sure Monace is working.

Go to your doctor regularly for a check-up. Your doctor may occasionally do a blood test to see how the Monace is affecting you.

Things you must not do

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

Do not use Monace to treat any other conditions unless your doctor or pharmacist tells you to.

Do not stop taking Monace or lower the dose, without 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 Monace 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 Monace, especially if you are elderly.

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

Monace may cause drowsiness, dizziness or lightheadedness in some people and affect alertness.

Make sure you know how you react to Monace 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 that would be helpful for your blood pressure

  • 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 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 Monace.

Monace helps most people with high blood pressure, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Following is a list of possible side effects. Do not be alarmed by this list. You may not experience any of them.

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

  • feeling light-headed, dizzy or faint
  • dry cough
  • headache
  • feeling sick (nausea) or vomiting
  • stomach pain
  • upset stomach (dyspepsia) or heartburn
  • diarrhoea
  • muscle cramps
  • pain in the joints
  • unusual tiredness or weakness, fatigue

These are the more common side effects of Monace. (Mostly these are mild and short-lived.)

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

  • 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)
  • confusion; irregular heartbeat; nervousness; numbness or tingling of the hands, feet or lips; shortness of breath or difficulty breathing; weakness or heaviness of legs. (You may experience these symptoms if too much potassium builds up in your body.)

These may be serious side effects. You may need medical attention. Serious side effects are rare.

If any of the following happen, stop taking Monace and either tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth, throat, hands and feet
  • difficulty in breathing
  • feeling faint or if skin turns yellow
  • sore throat and fever
  • chest pain
  • itchy skin and/or rash
  • not urinating (passing water) as much as usual
  • stomach pain with or without nausea

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

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

After taking Monace

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the pack they will not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

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

Do not leave it on a window sill or in the car on hot days. Heat and dampness can destroy some medicines.

Keep it 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 Monace, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Monace tablets are available in two strengths: -

  • Monace 10 - white to off-white, arc-rectangular shaped, with "G|G" on one side and "FS|10" on the other side.
  • Monace 20 - white to off-white, capsule shaped, with "G|G" on one side and "FS|20" on the other side.

Monace 10 mg and 20 mg tablets are available in blister packs of 30 tablets.

Ingredients

The active ingredient in Monace is Fosinopril sodium.

Each Monace 10 tablet contains 10 mg of Fosinopril sodium.

Each Monace 20 tablet contains 20 mg of Fosinopril sodium.

The tablets contain the following inactive ingredients:

  • microcrystalline cellulose
  • sodium starch glycollate
  • pregelatinised maize starch
  • hydroxypropylcellulose
  • ethanol
  • crospovidone
  • glyceryl behenate

Monace tablets also contain traces of benzoates and sulfites.

Manufacturer/Supplier

Monace is supplied by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

Monace 10 Blister - AUST R 101878

Monace 20 Blister - AUST R 101901

This leaflet was prepared in November 2019.

Monace_cmi\Nov19/00

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Monace

Active ingredient

Fosinopril sodium

Schedule

S4

 

1 Name of Medicine

Fosinopril sodium.

6.7 Physicochemical Properties

Chemical name: Sodium(4S)-4-cyclohexyl-1- {[(RS)-2-methyl-1-1- (propionyloxy)- proxoxyl]} (4-phenyl butyl)[phosphinoylacetyl]- 1-proline; [1[S*(R*),2α,4β]-4- cyclohexyl-1- [[[2-methyl-1-(-oxopropoxy)propoxyl] (4-phenylbutyl)phosphinyl] acetyl]-L-proline sodium salt.
Molecular formula: C30H45NNaO7P.
Molecular weight: 585.65.

Chemical structure.


CAS number.

88889-14-9.

2 Qualitative and Quantitative Composition

Each Monace tablet contains 10 mg or 20 mg of fosinopril sodium as the active ingredient.

List of excipients with known effect.

Monace tablets also contain traces of benzoates and sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Monace 10.

Fosinopril sodium 10 mg tablets; white to off-white, arc-rectangular shaped, with "G/G" on one side and "FS/10" on the other side.

Monace 20.

Fosinopril sodium 20 mg tablets; white to off-white, capsule shaped, with "G/G" on one side and "FS/20" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Monace (fosinopril sodium) is the sodium salt of fosinopril, the ester prodrug of a long-acting angiotensin converting enzyme (ACE) inhibitor, fosinopril diacid. Fosinopril is a sub-class of ACE inhibitors. It contains a phosphinate group that 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 a small increase of serum potassium.
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.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of fosinopril remains to be elucidated.
Administration of fosinopril to patients with mild to moderate hypertension has reduced both supine and standing blood pressures, usually without orthostatic effects. Symptomatic postural hypotension was infrequent, although it should be considered in salt and/or volume depleted patients (see Section 4.4 Special Warnings and Precautions for Use).
Following oral administration of a single dose of fosinopril, the onset of an antihypertensive effect was seen within 1 hour and peak blood pressure reduction within 2 to 6 hours.
At the usual daily dose (10 to 40 mg/day), antihypertensive effects of fosinopril have been maintained for 24 hours. In some patients at lower doses, these effects may diminish toward the end of the dosing interval (see Section 4.2 Dose and Method of Administration).
For optimal blood pressure reduction, dosage may need to be adjusted during the early stages of treatment (see Section 4.2 Dose and Method of Administration).
The antihypertensive effect of fosinopril has been shown to continue during long term therapy for at least 2 years.
As with other ACE inhibitors, abrupt withdrawal of fosinopril has not been associated with rapid increases in blood pressure.
The antihypertensive effects of fosinopril and diuretics used concurrently are approximately additive.
In patients with heart failure, the beneficial effects of fosinopril are thought to result primarily from suppression of the renin angiotensin aldosterone system; inhibition of the angiotensin converting enzyme produces decreases in both preload and afterload.
In heart failure patients fosinopril improves symptoms and exercise tolerance, reduces severity of heart failure and decreases the frequency of hospitalisation for heart failure. The beneficial effect of fosinopril does not require the concomitant use of digoxin.

Clinical trials.

Serum ACE activity was inhibited by ≥ 90% at 2 to 12 hours after single doses of 10 to 40 mg of fosinopril. At 24 hours, serum ACE activity remained suppressed by 85%, 93% and 93% in the 10, 20 and 40 mg dose groups, respectively.
In haemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in BP, heart rate, cardiac index and PVR) to various stimuli (e.g. isometric exercise, 45° head up tilt and mental challenge) were unchanged compared to baseline, suggesting that fosinopril does not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral, and skeletal muscle blood flow were unchanged compared to baseline, as was glomerular filtration rate.
In a double blind, controlled trial among patients with heart failure treated with diuretics and with or without digoxin, the initial dose of fosinopril resulted in an acute decrease in pulmonary capillary wedge pressure (preload) and mean arterial blood pressure and systemic vascular resistance (afterload). Single daily doses of fosinopril, maintained the positive haemodynamic effects throughout the 24 hour dosing interval among patients completing 10 weeks of treatment. In addition, heart rate decreased from baseline and stroke volume index increased despite the reduced left ventricular filling pressure. No tachyphylaxis was seen.
Fosinopril improved exercise tolerance at 24 hours in two placebo-controlled studies (271 patients with heart failure treated with fosinopril once daily) of up to six months duration, including one trial in which patients were not treated concomitantly with digoxin. Clinical manifestations of heart failure also improved, as measured by study withdrawals (risk reduction 66%, p < 0.001) or hospitalisations for worsening heart failure (risk reduction 66%, p = 0.001). Fosinopril reduced the need for additional diuretic to control symptoms of heart failure. Severity of heart failure, as measured by favourable changes in New York Heart Association classification and on symptoms of heart failure, including dyspnoea and fatigue, improved.
The effects of fosinopril on long-term mortality in heart failure have not been evaluated.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, fosinopril (the prodrug) is absorbed slowly. The absolute absorption of fosinopril averaged 36% of an oral dose. The primary site of absorption is the proximal small intestine (duodenum/ jejunum). The extent of absorption of fosinopril is essentially unaffected (but the rate may be slowed) by the presence of food in the gastrointestinal tract.
After single and repeated doses, areas under serum concentration time curves (AUC) and peak concentrations (Cmax) were directly proportional to the dose of fosinopril. The time to reach Cmax (Tmax) was independent of dose, achieved in approximately three hours, and consistent with peak inhibition of the angiotensin I pressor response 3 to 6 hours following the dose.

Distribution.

Fosinopril diacid is highly protein bound (≥ 95%), has a relatively small volume of distribution and negligible binding to cellular components in blood.

Metabolism.

In healthy subjects and renally impaired patients, hydrolysis of fosinopril to the active fosinopril diacid is rapid and complete. This biotransformation probably occurs in the gastrointestinal mucosa and liver. Although the rate of hydrolysis may be slowed, the extent of hydrolysis is not appreciably reduced in patients with hepatic impairment.
After an oral dose of radiolabelled fosinopril to healthy subjects, 75% of radioactivity in plasma was present as active fosinopril diacid, 20-30% as a glucuronide conjugate of fosinopril diacid and 1-5% as a p-hydroxy metabolite of fosinopril diacid. In urine, 75% of the drug excreted was fosinopril diacid, the remainder consisted primarily of the glucuronide conjugate of fosinopril diacid. Since fosinopril diacid is not biotransformed after intravenous administration, fosinopril (the prodrug) may actually be the substrate for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinopril diacid is as potent an inhibitor of ACE as fosinopril diacid. As expected, the glucuronide conjugate of fosinopril diacid is devoid of ACE inhibitory activity.

Excretion.

In healthy subjects, the terminal elimination half-life (t½) of an intravenous dose of fosinopril diacid was approximately 12 hours. In patients with heart failure, the effective t½ was 14 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t½ for accumulation of fosinopril diacid averaged 11.5 hours.

Special populations.

In patients with renal insufficiency (creatinine clearance < 80 mL/min/1.73 m2), the following pharmacokinetic alterations were noted in comparison with normals. (See Table 2).
Absorption, bioavailability and protein binding were not appreciably altered; in the quoted trial, nonrenal excretion of IV fosinopril diacid did not increase in absolute terms, however the increased faecal excretion of the active compound partially compensated for the reduced renal clearance even in patients with end stage renal failure (creatinine clearance < 10 mL/min/1.73 m2). Therefore, dosage adjustment during the initial stages of treatment will depend on blood pressure response. The initial dose should be 5-10 mg (see Section 4.2 Dose and Method of Administration).
Clearance of fosinopril diacid by haemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.
In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), 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 is approximately one-half of that in patients with normal hepatic function.
In clinical studies of fosinopril, no overall differences in effectiveness or safety were observed between elderly (> 65 years old) and younger patients. Additional clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out.
In a pharmacokinetic study comparing elderly (65-74 years old) and nonelderly (20-35 years old) healthy volunteers, there were no significant differences in pharmacokinetic parameters of fosinopril diacid.
Studies in animals indicate that fosinopril and fosinopril diacid do not cross the blood brain barrier.
In lactating women, bioavailability parameters (AUC, Cmax, Tmax) for fosinopril diacid were similar to healthy males. Fosinopril diacid was detectable but not quantifiable in breast milk.

5.3 Preclinical Safety Data

Genotoxicity.

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.

Carcinogenicity.

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 man 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Monace is indicated in the treatment of mild to moderate hypertension.
Monace is effective alone as initial therapy or in combination with other antihypertensive agents. The antihypertensive effects of Monace and diuretics used concomitantly are approximately additive.
Data have not been provided to support the use of Monace in severe or renovascular hypertension.

Heart failure.

Monace is indicated for the management of heart failure when added to conventional therapy, including diuretics.

4.3 Contraindications

Monace is contraindicated in patients who are hypersensitive to fosinopril sodium, or to any other angiotensin converting enzyme inhibitor (e.g. a patient who has experienced angioedema during therapy with any other ACE inhibitor) or to any of the Monace tablet excipients.
Patients with history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an angiotensin converting enzyme inhibitor.
Monace is contraindicated in pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
The concomitant use of ACE inhibitor with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

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, including fosinopril. In such cases, the product should be discontinued promptly and appropriate monitoring instituted to ensure complete resolution of symptoms. In instances where 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. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur and can be fatal. Emergency therapy, including but not necessarily limited to adrenaline (epinephrine) 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 Section 4.3 Contraindications).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblack patients.
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g. temsirolimus, sirolimus, everolimus) or vildagliptin therapy may be at increased risk for angioedema.

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 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 adsorption. These combinations should therefore be avoided, either by use of a different class of medication or alternative membranes (e.g. cuprophane or polysulphone (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.

Hypotension.

Monace can cause symptomatic hypotension. Like other ACE inhibitors, fosinopril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been 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 Monace. A transient hypotensive response is not a contraindication to further doses which may be given without difficulty after replacement of salt and/or volume.
The risk of an exaggerated hypotensive response (and also hyponatraemia) can be minimised by discontinuing the diuretic and ensuring adequate hydration and salt intake prior to initiation of treatment with fosinopril. If diuretics are continued, the patient should be closely observed for several hours following an initial dose and until blood pressure has stabilised.
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 or azotaemia and, rarely, with acute renal failure and death. In such patients, Monace therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased.
Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatraemic. Hypotension is not per se a reason to discontinue fosinopril. Some decrease of systemic blood pressure is not an uncommon observation upon initiation of Monace treatment in heart failure. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilises within a week or two, and generally returns to pretreatment levels without a decrease in therapeutic efficacy.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Monace 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 receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical attention.

Hyperkalaemia.

Because the ACE inhibitors decrease the formation of angiotensin II, which results in decreased production of aldosterone, increase in serum potassium levels (> 5.5 mEq/L) are not unexpected with this class of drugs. Hyperkalaemia is more likely in patients with some degree of renal impairment, those treated with potassium sparing diuretics or potassium supplements and/or consuming potassium containing salt substitutes or those patients taking other medicines associated with an increase in serum potassium (e.g. trimethoprim containing medicines). Diabetics, and particularly elderly diabetics, may be at increased risk of hyperkalaemia. In some patients, hyponatraemia may coexist with hyperkalaemia. It is recommended that patients undergoing ACE inhibitor treatment should have measurement of serum electrolytes (including potassium, sodium and urea) from time to time. This is more important in patients taking diuretics.

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 2/3 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.

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 suggests minimal accumulation during 10 days therapy with fosinopril 10 mg daily, dosage reduction in this patient group may be necessary and renal function should be closely monitored.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases are usually reversible upon discontinuation of ACE treatment and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine which is usually minor and transient, especially when given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic may be required.
ACE inhibitors have a real potential to delay progression of nephropathy in diabetic as well as in hypertensive patients. The antiproteinuric effect of ACE inhibitors could depend upon the dose, selective availability at the renal tissue site and on the patient's sodium status. Nevertheless, some ACE inhibitors have been associated with the occurrence of proteinuria (up to 0.7%) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium sparing diuretics or high doses of other diuretics, limited cardiac reserve or treatment with a nonsteroidal anti-inflammatory drug.
Evaluation of the hypertensive patient should always include assessment of renal function (see Section 4.2 Dose and Method of 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.

Dual blockade of the renin angiotensin aldosterone system (RAAS).

There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Surgery/ anaesthesia.

In patients undergoing major surgery or anaesthesia who are being treated 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 disturbance (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 is 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 1-3 months of treatment.

Use in hepatic impairment.

Patients with impaired liver function could develop elevated plasma levels of fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the apparent total body clearance of fosinopril was decreased and the plasma AUC approximately doubled.

Use in the elderly.

No dosage reduction is necessary in patients with clinically normal renal and hepatic function as no significant differences in the pharmacokinetic parameters or antihypertensive effect of fosinopril diacid have been found compared with younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

Safety and effectiveness in individuals less than 18 years old have not been established.

Effects 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 Monace should be interrupted for a few days before carrying out tests of parathyroid function.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Diuretics.

Since the antihypertensive effects of ACE inhibitors are enhanced by diuretics, patients on diuretics, especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restrictions, dialysis or with intravascular volume depletion, may occasionally experience excessive blood pressure reduction or hypotensive symptoms (e.g. dizziness, etc.) with the initiation of ACE inhibitor therapy (see Section 4.4 Special Warnings and Precautions for Use, Hypotension; Section 4.2 Dose and Method of Administration).
Since increases in serum potassium have been observed with ACE inhibitors, including fosinopril, the potassium wasting effect of most diuretics may be blunted by concomitant ACE inhibitor therapy. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride) should be used with caution when administered concomitantly with ACE inhibitors. Monitor serum potassium in such patients frequently.
Decreases in serum sodium and increases in serum creatinine occurred more frequently in patients receiving concomitant diuretics than in those treated with fosinopril alone.

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.

Lithium.

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Hyperkalaemia.

Potassium sparing diuretics, potassium supplements, potassium salts or other medicinal products that may increase serum potassium levels (e.g. trimethoprim containing medicines) can increase the risk of hyperkalaemia. These products should therefore be used with caution and serum potassium should be monitored frequently.

Anti-diabetics.

ACE inhibitors, including captopril, can potentiate the blood glucose reducing effects of insulin and oral anti-diabetics such as sulphonylurea in diabetics. Glycaemia levels should be monitored at the beginning of initiation therapy to adjust the dose of the anti-diabetic medications.
Patients taking concomitant vildagliptin may be at increased risk for angioedema.

Dual blockade of the renin angiotensin aldosterone system.

Clinical trial data has shown that dual blockade of the renin angiotensin aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia, and decreased renal function (including acute renal failure) compared to the use of a single RAAS acting agent (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Inhibitors of endogenous prostaglandin synthesis.

It has been reported that indometacin may reduce the antihypertensive effect of other ACE inhibitors, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (e.g. aspirin) and selective COX-2 inhibitors may have a similar effect. In patients who are elderly, volume depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including fosinopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving fosinopril and NSAID therapy.

Antacids.

In a clinical pharmacology study, coadministration of an antacid (aluminium hydroxide, magnesium hydroxide, and simethicone) with fosinopril reduced serum levels and urinary excretion of fosinopril diacid as compared with fosinopril administered alone, suggesting that antacids may impair absorption of fosinopril. Therefore, if concomitant administration of these agents is indicated, dosing should be separated by 2 hours.

Mammalian target of rapamycin (mTOR) inhibitors.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk of angioedema.

Other agents.

In pharmacokinetic interaction studies with nifedipine, propranolol, cimetidine and metoclopramide and propantheline the bioavailability of fosinopril diacid was not altered by coadministration of fosinopril with any one of these drugs. In studies with concomitant administration of aspirin and Monace, 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%.
In pharmacokinetic studies in healthy volunteers, no clinically significant interactions occurred when fosinopril was coadministered with either digoxin or warfarin.

4.6 Fertility, Pregnancy and Lactation

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.
(Category D)
As with all ACE inhibitors, Monace should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Monace and avoided during the 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 foetus.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with foetal 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 foetal function; oligohydramnios has been associated with foetal 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 1st 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.
Ingestion of 20 mg daily for three days resulted in detectable levels of fosinopril diacid in human breast milk. Monace (fosinopril sodium) should not be administered to breastfeeding mothers.

4.8 Adverse Effects (Undesirable Effects)

Hypertension.

Fosinopril has been evaluated for safety in more than 1500 individuals, including 300 patients treated for a year or more. In placebo-controlled clinical trials, the usual duration of therapy was two to three months.
In placebo-controlled clinical trials (633 fosinopril-treated patients) 3.3 percent of patients were discontinued from fosinopril and 1.2 percent from placebo due to any adverse experience.

Heart failure.

In placebo-controlled clinical trials of 3-6 month duration, the discontinuation rates due to any clinical or laboratory adverse event, except for heart failure, were 8.0% and 7.5% in fosinopril-treated and placebo-treated patients, respectively.
During clinical trials with any fosinopril regimen, the incidence of adverse experiences in the elderly (≥ 65 years old) was similar to that seen in younger patients.
Clinical adverse events (and consequent study discontinuations) occurring in patients treated with fosinopril alone in placebo-controlled trials are summarised in Table 1. The incidences in columns A and B represent all clinical adverse events, observed in hypertension trials regardless of their attribution to study therapy, that occurred in at least 1% of patients. Columns C and D give the incidences for clinical adverse events to therapy occurring in at least 1% of patients treated with fosinopril in placebo-controlled trials in heart failure.
Other clinical adverse experiences reported with fosinopril and other ACE inhibitors are listed below by body system.

General.

Weakness, fever1a, hyperhidrosis, ecchymosis.

Cardiovascular.

Sudden death1, cardiac/ cardiorespiratory1 arrest, shock (0.2%)1, angina/ myocardial infarction, cerebrovascular accident, hypertensive crisis, tachycardia, cardiac rhythm disturbances1, flushing, peripheral vascular disease, peripheral oedema1, hypertension1, syncope1, conduction disorder1.
Hypotension, orthostatic hypotension, and syncope occurred in 0.1, 1.5 and 0.2%, respectively, of patients treated with fosinopril for hypertension. Hypotension or syncope was a cause for discontinuation of therapy in 0.3 percent of patients.

Dermatologic.

Pruritus1a, dermatitis, urticaria, photosensitivity.

Endocrine/ metabolic.

Gout1a, sexual dysfunction1.

Foetal/ neonatal morbidity and mortality.

The use of ACE inhibitors during pregnancy has been associated with foetal 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 foetal renal function; oligohydramnios in this setting has been associated with foetal 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 neurologic malformations, have been reported following exposure limited to the first trimester of pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Gastrointestinal.

Bleeding, pancreatitis, hepatitis, tongue swelling, dysphagia, oral lesions, abdominal distension, appetite1a/ weight change1a, constipation1a, flatulence1a, dry mouth1a.

Haematologic.

Lymphadenopathy.

Immunologic.

Angioedema1a (0.2%).

Musculoskeletal.

Arthritis, myalgia1a, weakness of an extremity1a.

Nervous/ psychiatric.

Equilibrium disturbance, memory disturbance, drowsiness, confusion, depression1, paraesthesia1, vertigo1, behaviour change1, tremor1, cerebral infarction1, transient ischaemic attack1.

Respiratory.

Dyspnoea, bronchospasm, pneumonia, pulmonary congestion, laryngitis/ hoarseness, epistaxis, rhinitis1, sinusitis1, tracheobronchitis1, pleuritis1, chest pain1.
A symptom complex of cough, bronchospasm, eosinophilia has been observed in two patients treated with fosinopril.

Special senses.

Tinnitus, ear pain, vision disturbance1, taste disturbance1.

Urogenital.

Renal insufficiency, prostate disorder, abnormal urination1.

Laboratory test abnormalities.

Leukopenia, neutropenia, eosinophilia, increased serum levels of liver function tests (transaminases, LDH, alkaline phosphatase and bilirubin), serum electrolytes: hyperkalaemia, hyponatraemia (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Diuretics).

Renal function tests.

Elevations, usually transient and minor, of BUN and creatinine have been observed. In placebo-controlled clinical trials, there were no significant differences in the number of patients experiencing increases in serum creatinine (outside the normal range or 1.33 times the pretreatment value) between the fosinopril and placebo treatment groups.
In placebo-controlled trials in hypertension, a urinary albumin ≥ 2+ or ≥ 2 times the pretreatment value was seen in 2.8 percent of fosinopril-treated and none of the placebo-treated group. Increases in urinary albumin usually developed in patients with pre-existing proteinuria or diabetes and caused no clinical adverse effect.

Haematology.

In controlled trials, a mean haemoglobin decrease of 0.13 g/dL was observed in fosinopril-treated patients. In individual patients decreases in haemoglobin or haematocrit were usually transient, small, and not associated with symptoms. No patient was discontinued from therapy due to the development of anaemia.

Other.

Leucopenia and eosinophilia have been reported. Neutropenia (see Section 4.4 Special Warnings and Precautions for Use).

Liver function tests.

Elevations of transaminases, alkaline phosphatase and serum bilirubin have been reported. Fosinopril therapy was discontinued because of serum transaminase elevations in 0.7% of patients in hypertension studies. In the majority of cases, the abnormalities were either present at baseline or were associated with other aetiologic factors. In those cases which were possibly related to fosinopril therapy, the elevations were generally mild and transient and resolved after discontinuation of therapy.
1 Clinical events probably or possibly related, or of uncertain relationship to therapy, occurring in 0.4 to 1% of patients (except as noted) treated with fosinopril in controlled clinical trials in heart failure (n = 516) and less frequent, clinically significant events.
1a Seen both in hypertension and heart failure patients. In heart failure patients in the incidence described under 1.

Post-marketing experience.

During post marketing surveillance, the following adverse reactions were detected.

Skin and subcutaneous tissue disorders.

Pemphigus, bullous pemphigoid.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Hypertension.

For hypertensive patients not being treated with diuretics.

The recommended initial dose of Monace is 10 mg once a day. The usual dose range required to maintain blood pressure control is 10 to 40 mg per day administered as a single dose. Monace should be taken at the same time each day. Dosage should then be adjusted according to blood pressure response. If blood pressure is not adequately controlled with Monace alone, a diuretic may be added.

For hypertensive patients currently being treated with diuretics (or who may be volume depleted).

The diuretic should preferably be discontinued for several days prior to beginning therapy with Monace in order to reduce the risk of an excessive hypotensive response (see Section 4.4 Special Warnings and Precautions for Use). If blood pressure is inadequately controlled after an observation period of approximately 4 weeks, diuretic therapy may be resumed. Alternatively, if diuretic therapy cannot be discontinued, an initial dose of 10 mg of Monace should be used with careful medical supervision for several hours and until blood pressure has stabilised (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Since concomitant administration of Monace with potassium supplements, potassium containing salt substitutes or potassium sparing diuretics may lead to increases in serum potassium, they should be used with caution.

Heart failure.

The recommended initial dose of Monace is 10 mg once daily. Therapy should be initiated under close medical supervision. If the initial dose of Monace is well tolerated, the dose may be titrated at weekly intervals according to clinical response up to 40 mg once daily. The appearance of hypotension after the initial dose should not preclude careful dose titration with Monace following effective management of hypotension. Monace should be used in conjunction with a diuretic (see Section 4.4 Special Warnings and Precautions for Use, Hypotension).

For patients with renal impairment.

In patients with impaired renal function, the total body clearance of fosinopril diacid is approximately 50% slower than in patients with normal renal function. However, within the population of renally impaired patients, the body clearance of fosinopril diacid does not differ appreciably with the degree of renal insufficiency, including endstage renal failure (creatinine clearance < 10 mL/min/1.73 m2), since diminished renal elimination is partially compensated by increased hepatobiliary elimination. The relatively greater clearance by the hepatobiliary route of active fosinopril diacid when compared with total clearance in patients with renal failure permits use of an initial dose of 5 to 10 mg. An initial dose of 5 mg is preferred in heart failure patients with moderate to severe renal failure or those who have been vigorously diuresed. In patients with congestive heart failure and chronic renal failure, subsequent dosage adjustments should be made to control the patient's heart failure under careful clinical monitoring including frequent determination of renal function.

For patients with hepatic insufficiency.

It is advisable to initiate treatment at a dose of 10 mg in patients with mild to moderate impairment. Although the rate of hydrolysis of fosinopril diacid may be slowed, the extent of hydrolysis is not appreciably reduced in patients with hepatic impairment. In this group of patients, there is evidence of reduced hepatic clearance of fosinopril diacid with compensatory increase in renal excretion.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, adverse effects such as hypotension, dizziness and fatigue may interfere with the ability to drive or operate machines.

4.9 Overdose

No specific information is available on the treatment of overdosage with Monace; treatment should be symptomatic and supportive. Therapy with Monace should be discontinued and the patient closely monitored. Suggested measures include correction of hypotension by established procedures. Fosinopril is poorly removed from the body by haemodialysis or peritoneal dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Pregelatinised maize starch, microcrystalline cellulose, hyprolose, ethanol, crospovidone, sodium starch glycollate and glyceryl behenate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Monace 10: Store in the original container below 25°C.
Monace 20: Store in the original container below 25°C.

6.5 Nature and Contents of Container

Monace 10: Available in PVC/PCTFE (Aclar)/Al blister packs and PP bottles in pack sizes of 14, 28, 30, 56 and 100.
Monace 20: Available in PVC/PCTFE (Aclar)/Al blister packs and PP bottles in pack sizes of 14, 28, 30, 56 and 100.
*Some pack sizes may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

Summary Table of Changes