Consumer medicine information

Triasyn

Felodipine; Ramipril

BRAND INFORMATION

Brand name

Triasyn

Active ingredient

Felodipine; Ramipril

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Triasyn.

What is in this leaflet

This leaflet answers some common questions about Triasyn.

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 this medicine against the benefits they expect it will have for you.

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

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

What Triasyn is used for

Triasyn contains two types of medicine. These are an angiotensin converting enzyme (ACE) inhibitor and a calcium channel blocker.

Triasyn is used to lower 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 and can be influenced by how busy or worried you are. You have hypertension 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.

Triasyn works by widening the blood vessels, which reduces the pressure in the vessels, making it easier for your heart to pump blood around your body.

Ask your doctor or pharmacist if you have any questions about why it has been prescribed for you.

Triasyn is only available with a doctor's prescription.

Triasyn is not addictive.

Before you take it

When you must not take it

Do not take Triasyn if you:

  • are allergic to Triasyn or any other medicine containing ramipril or felodipine, or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include skin rash, itching, shortness of breath, swelling of the face, lips or tongue that may cause difficulty in swallowing or breathing, abdominal pain, muscle pain or tenderness, or joint pain.
  • 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 Triasyn.
  • are taking sacubitril/valsartan therapy, medication used to treat heart failure
  • or your family have a history of swelling of the face, lips, tongue, throat, intestines, hands or feet, for no apparent reason.
  • have kidney problems or a condition called 'renal artery stenosis'.
  • have problems or conditions affecting the flow of blood in and out of your heart (e.g. aortic or valvular stenosis).
  • have low blood pressure.
  • undergo dialysis using certain high-flux membranes.
  • have unstable angina, stroke or other heart and blood flow conditions.
  • are diabetic or have kidney problems and are being treated with aliskiren-containing medications (a medication also used to treat high blood pressure).
  • are pregnant or intend to become pregnant.
    Triasyn may affect your developing baby if you take it during pregnancy.
  • are breastfeeding.
    Triasyn may pass into the breast milk and there is a possibility that your baby may be affected.

Do not give Triasyn to a child or adolescent. There is no experience with its use in children or adolescents under 18 years of age.

Do not take Triasyn after the expiry date (EXP) printed on the pack. If you take it after the expiry date has passed, it may not work as well.

Do not take Triasyn if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you have allergies to:

  • any of the ingredients listed at the end of this leaflet
  • any other medicines
  • any other substances, such as foods, preservatives or dyes

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

  • kidney problems, or you are having dialysis
  • liver problems
  • heart problems
  • low blood pressure, which you may notice as dizziness or light-headedness
  • low white blood cell counts
  • diabetes
  • high levels of potassium in your blood
  • Systemic Lupus Erythematosus (SLE), sclerodoma or other autoimmune conditions

Tell your doctor if you have a family history of swelling of the face, lips, tongue, throat, intestines, hands or feet.

You must also tell your doctor if you:

  • are following a very low or very high salt diet
  • are dehydrated, or have had a recent bout of vomiting or diarrhoea
  • are about to have surgery or a general anaesthetic
  • plan to become pregnant or breastfeed

If you have not told your doctor about any of the above, tell them before you take Triasyn.

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 store.

Some medicines and Triasyn may interfere with one another. These include:

  • other medicines used to treat high blood pressure, including those containing the active ingredient aliskiren
  • sacubitril/valsartan therapy, medication used to treat heart failure
  • neprilysin (NEP) inhibitors, medicines used to treat heart failure
  • beta blockers
  • diuretics, also known as fluid or water tablets
  • lithium, a medicine used to treat mood swings and some types of depression
  • potassium supplements or potassium-containing salt substitutes
  • non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation
  • insulin and tablets used to treat diabetes
  • heparin
  • general anaesthetics
  • medicines which may affect the blood cells, such as allopurinol, procainamide, corticosteroids, immunosuppressants (e.g. tacrolimus), or medicines used to treat cancer
  • antibiotics that contain trimethoprim
  • some epilepsy medicines, sedatives, antibiotics and antifungal medicines
  • medicines (including the ones bought without a prescription) for appetite control, asthma, colds, coughs, hayfever or sinus problems; do not take these medicines unless you have discussed it with your doctor or pharmacist

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

Alcohol and grapefruit juice may affect how well Triasyn works.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking Triasyn.

How to take it

How much to take

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

Take Triasyn only when prescribed by your doctor.

The usual dose of Triasyn is one 2.5/2.5mg tablet or one 5.0/5.0mg tablet per day. Your doctor will select a dose when they prescribe Triasyn for you. Depending on your response, your doctor may adjust the dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Triasyn may not work as well and your problem may not improve.

How to take it

Swallow the tablet whole with a full glass of water or other liquid.

Do not crush or chew the tablets. These tablets are designed so that the two active ingredients enter the bloodstream at different rates. If you crush or chew them, the active ingredients may enter your bloodstream too quickly.

When to take it

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

It does not matter if you take Triasyn before, after or during a meal.

If you are not sure when to take it, ask your doctor or pharmacist.

How long to take it

Continue taking Triasyn for as long as your doctor tells you.

Triasyn helps control your condition, but it does not cure it. Therefore, you must take it every day.

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.

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

If there is still a long time to go before your next dose, take it as soon as you remember, and then go back to taking it as you would normally.

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

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

If you take too much (overdose)

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

If you take too much Triasyn, you may feel light-headed, dizzy or you may faint. You may also experience slow heart beat.

While you are taking it

Things you must do

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

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Triasyn.

Make sure you drink enough water during exercise and hot weather when you are taking Triasyn, especially if you sweat a lot. If you do not drink enough water while taking Triasyn, you may feel faint, light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.

If you have excess vomiting or diarrhoea while taking Triasyn, tell your doctor. You may lose too much water and salt and your blood pressure may drop too much.

If you feel light-headed or dizzy after taking your first dose of Triasyn, or when your dose is increased, tell your doctor immediately.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking Triasyn. Your blood pressure may drop suddenly.

If you become pregnant or intend to become pregnant while taking Triasyn, tell your doctor immediately.

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

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

Go to your doctor regularly for a check-up. Your doctor may occasionally do a blood test to check your potassium levels and see how well your kidneys are working.

Things you must not do

Do not take more than the recommended dose unless your doctor tells you to.

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

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not stop taking Triasyn, or lower or increase the dosage, without checking with your doctor.

Things to be careful of

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. If this problem continues or gets worse, talk to your doctor.

Be careful driving or operating machinery until you know how Triasyn affects you. As with other ACE inhibitor medicines, Triasyn may cause dizziness, light-headedness, tiredness or drowsiness in some people. Make sure you know how you react to Triasyn 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 may help your condition

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.
  • Diet - eat a healthy low-fat diet which includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar.
  • Exercise - regular exercise helps to reduce blood pressure 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.
  • Salt - your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake you should avoid using salt in cooking or at the table.
  • Smoking - your doctor may advise you to stop or at least cut down smoking.
  • 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.

Side effects

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

Triasyn helps most people, 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 if you notice any of the following and they worry you:

  • feeling light-headed, dizzy or faint
  • dry cough
  • respiratory tract infections
  • headache
  • feeling sick (nausea) or vomiting
  • stomach pain
  • diarrhoea
  • unusual tiredness or weakness, fatigue
  • decreased physical fitness
  • muscle cramps
  • ringing or buzzing in the ears
  • forgetfulness or confusion
  • feeling warm (flushed)
  • mild swelling of hands and feet
  • skin sensitivity
  • enlargement of gums
  • taste disturbances or loss of taste

These side effects are usually mild.

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

  • disturbed vision
  • symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly than normal
  • itchy or raised skin rash, hives or nettlerash
  • signs of anaemia such as tiredness, being short of breath and looking pale
  • yellowing of the skin and/or eyes
  • fast or irregular heart beat
  • shortness of breath or tightness in the chest
  • numbness, tingling and colour change (white, blue then red) in the fingers or toes when exposed to the cold
  • numbness or tingling in the hands or feet
  • severe upper stomach pain, often with nausea and vomiting
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • passing little or no urine or more urine than is normal for you
  • bleeding or bruising more easily than normal

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

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

  • fainting within a few hours of taking a dose
  • severe dizziness and confusion with visual disturbances and speech problems
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • pink or red itchy spots on the skin which may blister and progress to form raised, red, pale-centred marks
  • severe blisters and bleeding in the lips, eyes, mouth, nose or genitals
  • chest pain

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

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 it

If you have any questions about any aspect of your medicine, or any questions regarding the information in this leaflet, discuss them with your doctor or pharmacist.

Storage

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

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

Do not store Triasyn or any other medicine in the bathroom or near a sink. Do not leave it on window sills or in the car. 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 Triasyn, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Triasyn comes in two types of tablets:

  • Triasyn 2.5/2.5mg - apricot-coloured, circular, film-coated tablets, marked H/OD on one side and 2.5 on the other
  • Triasyn 5.0/5.0mg - reddish-brown, circular, film-coated tablets, marked H/OE on one side and 5 on the other

Triasyn is available in blister packs of 30 tablets.

Ingredients

Active Ingredients:

  • Triasyn 2.5/2.5mg - 2.5mg ramipril and 2.5mg felodipine per tablet
  • Triasyn 5.0/5.0mg - 5mg ramipril and 5mg felodipine per tablet

Inactive Ingredients:

  • aluminium sodium silicate
  • cellulose - microcrystalline
  • hyprolose
  • hypromellose
  • iron oxide yellow
  • iron oxide red
  • lactose
  • macrogol 6000
  • paraffin - hard
  • hydrogenated castor oil
  • propyl gallate
  • sodium stearylfumarate
  • starch - pregelatinised maize
  • titanium dioxide

Manufacturer/Sponsor

Triasyn is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113

This leaflet was prepared in November 2019.

Australian Register Numbers

2.5/2.5mg tablets: AUST R 67184

5.0/5.0mg tablets: AUST R 67183

triasyn-ccdsv11-cmiv7-nov19

® Registered Trademark

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Triasyn

Active ingredient

Felodipine; Ramipril

Schedule

S4

 

1 Name of Medicine

Triasyn 2.5/2.5 (ramipril/felodipine) 2.5 mg/2.5 mg modified release tablets.
Triasyn 5.0/5.0 (ramipril/felodipine) 5.0 mg/5.0 mg modified release tablets.

6.7 Physicochemical Properties

Felodipine is a racemic mixture of ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro 2,6-dimethyl-3,5 pyridine dicarboxylate. It is a slightly yellowish crystalline powder with a melting point between 142 and 145°C. Felodipine is freely soluble in ethanol, acetone and dichloromethane, but practically insoluble in water at 37°C. It is moderately light sensitive and has a molecular weight of 384.26. The empirical formula is C18H19Cl2NO4.
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white to almost white crystalline powder with a melting point between 105°C and 112°C. Ramipril is freely soluble in polar organic solvents and buffered aqueous solutions. It is slightly soluble in water. Ramipril has a molecular weight of 416.52 and an empirical formula of C23H32N2O5. Its chemical name is (2S,3aS,6aS)-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid,1-ethyl ester.

Chemical structure.


CAS number.

Felodipine: CAS No. 72509 76 3.
Ramipril: CAS No. 87333 19 5.

2 Qualitative and Quantitative Composition

Triasyn 2.5/2.5 contains 2.5 mg of ramipril and 2.5 mg of felodipine.
Triasyn 5.0/5.0 contains 5.0 mg of ramipril and 5.0 mg of felodipine.

Excipient of known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release tablet.
Triasyn tablets are circular, biconvex, film-coated, two-layered tablets, with felodipine in an extended-release gel matrix formulation in one layer and rapidly dissolving ramipril in the other layer.

Triasyn 2.5/2.5.

Apricot, circular, biconvex, film-coated tablets 9 mm diameter, engraved H/OD on one side and 2.5 on the other.

Triasyn 5.0/5.0.

Reddish-brown, circular, biconvex, film-coated tablets 9 mm diameter, engraved H/OE on one side and 5 on the other.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antihypertensive drugs. ATC code: C09B B05.

Mechanism of action.

The calcium antagonist felodipine and the angiotensin converting enzyme (ACE) inhibitor ramipril both reduce blood pressure by vasodilatation. However, they have complementary mechanisms of action. Calcium antagonists dilate the arterial beds while ACE inhibitors dilate both arterial and venous beds. This vasodilatation and reduction of blood pressure may lead to activation of the sympathetic nervous system. ACE inhibitors reduce this sympathetic nervous system activation and block the renin angiotensin system. These complementary mechanisms of action underlie the additive antihypertensive response and the improved side effect profile observed with combinations of calcium antagonists and ACE inhibitors.
The onset of the antihypertensive effect of a single dose of Triasyn is 1-2 hours. The maximum antihypertensive effect occurs within 2-4 weeks and is maintained on long-term therapy. The blood pressure reduction is even and effective throughout the 24 hour dosage interval.

Felodipine.

Felodipine is a calcium antagonist which lowers arterial blood pressure by decreasing vascular resistance. It exhibits a high degree of selectivity for smooth muscle in the arterioles and in therapeutic doses has no direct effect on cardiac contractility or conduction. Felodipine inhibits the electrical and contractile activity of vascular smooth muscles via an action at the cell membrane. Because of its lack of effect on venous smooth muscle and its adrenergic vasomotor control, felodipine does not cause orthostatic hypotension.
The renal vascular resistance is decreased by felodipine. Normal glomerular filtration rate is unchanged. In patients with impaired renal function glomerular filtration rate may be increased. Felodipine possesses a mild natriuretic/ diuretic effect and therefore does not produce any general fluid retention.

Ramipril.

Ramiprilat, the active metabolite of the prodrug ramipril, is a potent and long acting ACE inhibitor. In plasma and tissue, ACE catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II and also the breakdown of the vasodilator bradykinin. The vasodilatation induced by ramiprilat causes a reduction in blood pressure preload and afterload.
Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in the secretion of aldosterone. The latter decrease may result in a small increase in serum potassium. In hypertensive patients, ramipril leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.
Whilst the mechanism by which ramiprilat lowers blood pressure is believed to be primarily suppression of the renin angiotensin aldosterone system, ramiprilat has an antihypertensive effect even in patients with low renin hypertension.

Clinical trials.

2194 patients have participated in short-term studies and 278 patients have participated in long-term studies investigating the efficacy and safety of the combination of ramipril and felodipine. These studies have shown that the combination significantly reduced blood pressure both at the beginning and at the end of the dosage period.
The efficacy of felodipine in combination with ramipril was studied in four pivotal clinical studies. The findings of these studies are summarised in Tables 6 and 7.
In patients not responding to ramipril monotherapy, the addition of felodipine resulted in a further decrease in blood pressure. No data have been evaluated on the efficacy of the addition of ramipril to patients not responding to felodipine monotherapy.
Long-term studies using the approved dosages demonstrated that the combination maintains antihypertensive efficacy over a 12 month period.

5.2 Pharmacokinetic Properties

In Triasyn, the pharmacokinetics of felodipine, ramipril and ramiprilat are essentially unaltered from those of the monocomponents. Felodipine does not influence the ACE inhibition caused by ramipril. The fixed combination tablets are thus regarded as bioequivalent to the free combination.

Felodipine.

Absorption.

Felodipine is completely absorbed from the gastrointestinal tract after administration, regardless of food intake. Peak plasma concentrations following administration are usually reached within 3-5 hours.
The systemic availability of felodipine is independent of dose in the therapeutic dose range. Due to presystemic metabolism of felodipine, the bioavailability of extended release felodipine is approximately 20%. Extended release felodipine produces a relatively flat plasma concentration versus time curve, minimising the postabsorption peak seen with conventional tablets and maintaining therapeutic levels over the 24 hours following dosing. This permits single daily dosing of felodipine.
In some patients administered a single dose of 5 mg felodipine, there was no detectable blood level of felodipine, indicating a significant interindividual variation in pharmacokinetic response.

Distribution.

The plasma protein binding of felodipine in man is approximately 99%. It is bound predominantly to the albumin fraction. In man, felodipine has a volume of distribution at steady state of approximately 10 L/kg.

Metabolism.

Felodipine is extensively metabolised by the liver. All identified metabolites are inactive.

Excretion.

Approximately 70% of a given dose is excreted as metabolites in the urine; the remaining fraction is excreted in the faeces. Less than 0.5% of a dose is recovered unchanged in urine.
The elimination of felodipine from plasma follows a biphasic pattern, with the mean half-life of the α-phase approximately 4 hours and that of the β-phase approximately 24 hours. There is no significant accumulation during long-term treatment.

Use in the elderly.

Average peak plasma concentrations of felodipine tend to be higher in elderly patients than in young healthy individuals. This can be attributed to reduced systemic clearance of felodipine and a corresponding increase in plasma half-life.
The systemic availability, time to peak plasma concentration and volume of distribution do not appear to be significantly affected by age.

Ramipril.

Absorption.

Following oral administration, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50-60% and not significantly influenced by the presence of food in the GI tract, although the rate of absorption is reduced. Peak plasma concentrations of ramiprilat are reached within 2 to 4 hours and the absolute bioavailability of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg oral ramipril was compared with the same dose of IV ramipril.
Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose proportional. The 24 hour AUC for ramiprilat, however, is proportional to dose over the 2.5-20 mg dose range.

Distribution.

Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a larger peripheral compartment and subsequent binding to both plasma and tissue ACE and kininase II, has a half-life of 2-4 hours. The effective half-life, which is relevant for dosage, is 13 to 17 hours under multiple dose conditions and the terminal phase with very low ramiprilat plasma concentrations has a prolonged half-life of > 50 hours. This terminal phase is probably due to the slow dissociation of ramiprilat from ACE. After once daily doses, steady-state plasma concentrations are obtained by the fourth dose. There is no relevant accumulation of ramipril and ramiprilat after oral administration.
The protein binding of ramipril and ramiprilat is approximately 73% and 56%, respectively.

Metabolism.

The prodrug ramipril undergoes extensive hepatic first-pass metabolism (hydrolysis) which is essential for the formation of ramiprilat, the sole active metabolite. In addition to this activation into ramiprilat, ramipril is glucuronized to form ramipril diketopiperazine (ester).

Excretion.

After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine and about 40% in the faeces. Less than 2% of the administered dose is recovered in the urine as unchanged ramipril.

Use in hepatic impairment.

In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.

Use in renal impairment.

Renal excretion of ramiprilat is reduced in patients with impaired renal function and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in patients with normal renal function.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No evidence of a carcinogenic effect was found when ramipril was given to rats (up to 500 mg/kg/day for 24 months) or to mice (up to 1000 mg/kg/day for 18 months).
An increased incidence of oxyphilic cells in the renal tubules and oxyphilic microadenomas was observed in rats treated for 24 months with ramipril (3.2 to 500 mg/kg/day). Data from historical control animals showed that the spontaneous occurrence of oxyphilic cells in rat kidney is age related, is higher in males and reaches a level similar to that seen in the ramipril treated group. There is no evidence in humans that the occurrence of oxyphilic cells is age related. Moreover, progression of oxyphilic cells to neoplasia (oncocytoma) is rare and, when it occurs, is considered to be benign. Whether this finding in rats represents any potential risk to man is therefore unclear.
An increased incidence of benign interstitial cell testicular tumours (Leydig cell tumours) has been observed in rats but not in mice following dosing with felodipine. The relevance of this finding in man is not known, although clinical studies have demonstrated that felodipine has no influence on testosterone formation or on luteinising hormone secretion.

Fibromuscular pad formation.

In several repeated dose studies in rats, especially male animals, treated with ramipril (3.2 - 500 mg/kg b.w./day) showed an increased incidence of so called fibromuscular pad formation in the basal region of the gastric mucosa. The findings suggest an increased connective tissue formation and partly also increased formation of smooth muscle (lamina muscularis mucosae) due to a predominantly round cell inflammatory reaction. In all studies (1 - 24 months, carcinogenicity) the changes are always of the same type and no tendency of proliferation is obvious. Thus, it seems to be rather a reactive process with circumscribed scar tissue formation. The changes in the rat stomach mucosa could not be reproduced in other species (i.e. mouse, dog, rabbit, monkey).
This lesion was also observed when rats were treated with a relatively high dose (90 mg/kg/day for 3 to 6 months) of another ACE inhibitor. In the light of the available data, fibromuscular pad formation in the rat would not appear to present a serious risk in humans.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of mild to moderate hypertension. This combination should not be used to commence therapy.

4.3 Contraindications

Triasyn contraindications are in line with those expected of any ACE inhibitor-calcium channel blocker combination. These include pregnancy or lactation and hypersensitivity to felodipine, ramipril or any of the tablet excipients or any ACE inhibitor.
As with all ACE inhibitors, Triasyn is contraindicated in renal failure or haemodynamically relevant bilateral or, in the single kidney, unilateral renal artery stenosis; in patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor; haemodynamically relevant left ventricular inflow or outflow impediment, e.g. stenosis of the aortic or mitral valve; hypotensive or haemodynamically unstable patients.
Triasyn is contraindicated in patients undergoing extracorporeal treatment leading to contact of blood with negatively charged surfaces as this may lead to severe anaphylactoid reactions. For example, dialysis with certain high flux membranes (e.g. polyacrylonitrile) or low density lipoprotein apheresis with dextrose sulfate.
Triasyn is also contraindicated in unstable haemodynamic conditions: cardiovascular shock, untreated heart failure, acute myocardial infarction, unstable angina pectoris, stroke.
Triasyn must not be used with aliskiren containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance < 60 mL/min).
Triasyn is contraindicated in patients with haemodynamically significant cardiac valvular obstruction or with dynamic cardiac outflow obstruction.
Triasyn must not be used with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
Triasyn must not be used concomitantly with sacubitril/valsartan therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Do not initiate Triasyn until sacubitril/valsartan is eliminated from the body. In case of switch from Triasyn to sacubitril/valsartan, do not start sacubitril/valsartan until Triasyn is eliminated from the body.

4.4 Special Warnings and Precautions for Use

Patients with a significantly activated renin angiotensin system.

These patients are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor, a fixed dose combination product containing an ACE inhibitor or a concomitant diuretic is given for the first time or for the first time at an increased dose. They therefore need close blood pressure monitoring until no further acute reduction in blood pressure is expected. Significant activation of the renin angiotensin system is to be expected in patients with severe hypertension, patients with concomitant moderate heart failure, patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve) in which the initial phase of treatment requires special medical supervision, patients with haemodynamically relevant renal artery stenosis, patients on concomitant diuretic therapy or patients in whom fluid and salt depletion is present, including those who have suffered severe diarrhoea and patients undergoing dialysis.
It is recommended that dehydration, hypovolaemia or salt depletion be corrected before initiating treatment with an ACE inhibitor.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, be given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of an ACE inhibitor, which usually can be given without difficulty once the blood pressure has increased after volume expansion.

Patients at particular risk from pronounced reduction in blood pressure.

Patients with haemodynamically relevant stenosis of the coronary arteries or of the cerebral blood vessels will require careful monitoring in, preferably, a hospital or a similar setting during commencement of antihypertensive therapy, as an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.
Rarely, too great a reduction in blood pressure with an initial reflexogenic increase in heart rate may lead to increased frequency, duration and/or severity of angina, particularly in patients with severe coronary artery disease. Therefore, the possibility of precipitation of myocardial ischaemia exists. This may occur in the initial stages of felodipine treatment or following a dosage increase.

Angioneurotic oedema.

Due to its ACE inhibitor component, Triasyn is contraindicated in patients with a history of angioedema. Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors. If angioedema occurs, the product should be promptly discontinued and the patient carefully observed until the swelling disappears. In instances where swelling has been confined to the face and lips, the condition should resolve without treatment, although antihistamines may be useful in relieving symptoms. Laryngeal oedema, however, can be fatal, thus, where there is angioedema involving swelling of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g. subcutaneous adrenaline (epinephrine) solution 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see Section 4.8 Adverse Effects (Undesirable Effects)) and accompanied with monitoring of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Angioedema may occur with or without urticaria. The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom free periods.
Medical therapy of progressive angioedema should be aggressive. Failing a rapid response, mechanical methods to secure an airway should be undertaken before massive oedema complicates oral or nasal intubation or surgical procedures (e.g. cricothyrotomy or tracheostomy). Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases facial angioedema also occurred. The intestinal angioedema symptoms resolved after stopping the ACE inhibitor.
An increased risk of angioedema is possible with concomitant use of other drugs which may cause angioedema (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
ACE inhibitors cause an increased likelihood and greater severity of anaphylactic and anaphylactoid reactions to other substances or to, for example, insect bites.

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

Dual blockade of the renin angiotensin aldosterone system by combining Triasyn with an angiotensin II receptor antagonist (AIIRA) or with aliskiren is not recommended since there are increased risks of hypotension, hyperkalaemia and changes in renal function. The use of Triasyn in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (creatinine clearance < 60 mL/min) (see Section 4.3 Contraindications).
The use of Triasyn in combination with an AIIRA is contraindicated in patients with diabetic nephropathy.

Combination with beta-blockers in patients with congestive heart failure.

Beta-blockers are contraindicated in patients with uncompensated heart failure. While felodipine may appear safe in these patients, the combination of Triasyn and beta-blockers is not recommended.

Potassium monitoring.

Because the ACE inhibitors decrease the formation of angiotensin II, which results in decreased production of aldosterone, increases 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 in patients taking other medicines associated with increases 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) regularly. This is more important in patients taking diuretics. It is recommended that serum potassium be monitored regularly and more frequent monitoring of serum potassium is necessary in patients with impaired renal function.

Sodium monitoring.

Treatment with Triasyn requires regular monitoring of serum sodium.

Cough.

Clinical trials have shown that patients treated with Triasyn experience significantly less cough than patients treated with ramipril monotherapy.
A persistent dry (nonproductive) irritating cough has been reported with most 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 15% depending upon the drug, dosage and duration of use.
The cough is often worse when lying down or at night. The cough is more common in women (who account for 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 it is most likely secondary to the effects of converting enzyme inhibition 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. Nonsteroidal anti-inflammatory drugs (e.g. sulindac) have been reported to be effective in relieving coughing induced by ACE inhibitors. In mild hypertensive patients, or patients likely to be treated with other antihypertensive agents, it is unlikely that risks of prescribing a nonsteroidal anti-inflammatory drug will outweigh the benefit of relieving cough.

Dermatological reactions.

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

Taste disturbances (dysgeusia).

Taste disturbances were reported to be high (up to 12.5%) with high doses of another ACE inhibitor. The actual incidence of taste disturbance is probably low (< 0.5%) but data in this respect are scarce and difficult to interpret.
Taste disturbances with ACE inhibitors are described as suppression of taste or a metallic sensation in the mouth or sometimes there may be taste reduction or even complete loss of taste. The dysgeusia occurs usually in the first weeks of treatment and usually disappears within 1-3 months of treatment.

Gingival enlargement.

Mild gingival enlargement has been reported in patients taking felodipine with pronounced gingivitis/ periodontitis. The enlargement can be avoided or reversed by careful dental hygiene.

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. If hypotension occurs, and is considered to be due to this mechanism, it can be corrected by volume expansion.

Peripheral oedema.

Mild to moderate peripheral oedema resulting from precapillary vasodilation may occur in about 20% of patients treated with felodipine. This oedema appears to be dose related. The effect of a diuretic on this oedema has not been investigated.

Haematological monitoring.

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, immunosuppressant 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 count should be considered to permit detection of a possible leucopenia, particularly in the initial phase of treatment. More frequent monitoring is advised in the initial phase of treatment and 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.

Use in hepatic impairment.

There is no experience with the use of Triasyn in patients with severe impairment of liver function. In patients in whom severe liver cirrhosis with oedema and/or ascites is present, the renin angiotensin system may be significantly activated; therefore, particular caution must be exercised in treating these patients with ramipril. In patients with impaired liver function, the metabolism of ramipril - and therefore the formation of the bioactive metabolite ramiprilat - is delayed due to diminished activity of hepatic esterases, resulting in elevated plasma ramipril levels. Treatment with ramipril should therefore be initiated under close medical supervision and should not exceed 2.5 mg daily. Therefore, Triasyn 5.0/5.0 should not be used in this patient group (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. It is recommended that renal function is monitored, particularly in the initial weeks of treatment with an ACE inhibitor. Careful monitoring is required in patients with concomitant heart failure, renovascular disease, impairment of renal function or patients who have undergone a kidney transplant.
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, including ramipril, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.
In patients after renal transplantation, there is a risk of renal impairment.
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% 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. In patients with haemodynamically relevant unilateral renal artery stenosis even a small increase in serum creatinine may be indicative of unilateral loss of renal function.
Patients with unilateral renal artery disease present a special problem, as deterioration of function may not be apparent from measurement of blood urea nitrogen and serum creatinine.
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 ramipril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ramipril and/or discontinuation of the diuretic may be required. Additionally, in patients with renal insufficiency, serum potassium should be monitored more frequently, as there is a risk of hyperkalaemia.
There is insufficient experience in the use of ramipril in patients with severe renal impairment (i.e. creatinine clearance less than 20 mL/min/1.73 m2 body surface area). Ramipril is not suitable for the treatment of patients requiring haemodialysis for endstage renal failure, since only negligible amounts are dialysable. Therefore Triasyn should not be prescribed for such patients.
Evaluation of the hypertensive patient or patient with heart failure 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, other classes of antihypertensive agent should be preferred.

Use in the elderly.

In clinical trials, no overall difference in effectiveness or safety has been observed between patients over 65 and younger patients. However, since both liver and kidney function may decline with age, the starting dose of ramipril should be reduced to 1.25 mg daily. Therefore, Triasyn should not be used to initiate ACE inhibitor therapy in the elderly (see Section 4.2 Dose and Method of Administration).
Felodipine plasma levels are higher on average in elderly patients than in young and middle aged patients due to reduced first pass effect, reduced clearance capacity or both. An initial dose of 2.5 mg should be considered.

Paediatric use.

Clinical data on the use of Triasyn in children are not currently available, therefore use in this age group is not recommended.

Effects on laboratory tests.

Ramipril.

The serum sodium level may decrease. Elevation of serum potassium may occur, since ramipril leads to a decrease in aldosterone secretion; potassium-sparing diuretics or potassium supplements should therefore be avoided. Increases in serum bilirubin and/or liver enzymes have been observed. Mild to severe decreases in haemoglobin (also due to haemolytic anaemia), red blood cells, platelets and white blood cells have been observed with ACE inhibitors. Eosinophilia has also been seen. Raised titres of antinuclear antibodies have been observed with other ACE inhibitors.

Felodipine.

Slight increases in thrombocyte count and rare, usually transient, elevations of enzymes such as alkaline phosphatase, ASAT and ALAT have occasionally been noted during felodipine treatment. These laboratory abnormalities have not been associated with clinical symptoms and their relationship to felodipine is uncertain.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Sacubitril/valsartan.

The concomitant use of ACE inhibitors with sacubitril/valsartan therapy is contraindicated as this increases the risk of angioedema (see Section 4.3 Contraindications).

Cytochrome P450 inducers and inhibitors.

Concomitant administration of substances which interfere with the cytochrome P450 system may affect plasma concentrations of felodipine. Enzyme inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates and Hypericum perforatum (Saint John's wort)) cause a decrease in plasma levels of felodipine. Enzyme inhibitors (e.g. cimetidine, erythromycin, itraconazole, ketoconazole and certain flavonoids found e.g. in grapefruit juice) have been shown to cause an increase in felodipine plasma levels.

Diuretics.

Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimised by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, the starting dose should be reduced (see Section 4.2 Dose and Method of Administration). Regular monitoring of serum sodium is necessary in patients undergoing concurrent diuretic therapy.

Anaesthetics.

General anaesthetics or anaesthetics with an antihypertensive action may cause the blood pressure to drop further in patients taking ramipril. Appropriate counter-measures, such as increasing the blood volume or, if necessary, administering angiotensin II, should be taken before or during surgery.

Grapefruit juice.

An increase in the bioavailability of dihydropyridines has been shown when they have been taken with grapefruit juice. The interaction is thought to be due to a bioflavonoid present in grapefruit juice which is not found in other citrus fruits. The interaction is more pronounced with immediate release formulations.

Potassium supplements and potassium-sparing diuretics.

Since ACE inhibitors may cause a rise in serum potassium, concurrent use of Triasyn and potassium-sparing diuretics (e.g. spironolactone, amiloride, triamterene), potassium supplements, potassium salts or other medicinal products (e.g. trimethoprim containing medicines) that may increase serum potassium levels can increase the risk of hyperkalaemia. This increase can sometimes be severe, and should be anticipated. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be closely monitored.

High-flux dialyser membranes.

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux (e.g. polyacrylonitrile) membranes and low density lipoprotein apheresis with dextrose sulfate have been reported to increase the risk of severe anaphylactoid reactions. This combination should therefore be avoided.

Aliskiren-containing medicines.

The combination of Triasyn with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or with moderate to severe renal impairment (creatinine clearance < 60 mL/min) and is not recommended in other patients (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Angiotensin-II receptor antagonists (AIIRAs).

The use of Triasyn in combination with an AIIRA is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Antihypertensive drugs.

Possible potentiation of the antihypertensive effect must be anticipated when Triasyn is administered concurrently with other antihypertensives and other substances with antihypertensive potential (e.g. nitrates, tricyclic antidepressants, narcotics, anaesthetics).

Vasopressor sympathomimetics.

The antihypertensive effect of ramipril may be reduced by concurrent administration of vasopressor sympathomimetics. Particularly close blood pressure monitoring is recommended.

Lithium.

Excretion of lithium may be reduced by ACE inhibitors. Increased serum lithium levels and symptoms of lithium toxicity (e.g. cardiotoxic and neurotoxic effects) 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.

NSAIDs.

As with other ACE inhibitors, the antihypertensive effects of ramipril may be decreased in patients taking NSAIDs. Furthermore, concomitant administration of ACE inhibitors and NSAIDs may exacerbate declining renal function and lead to an increase in serum potassium.

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.

Antidiabetic agents.

The possibility of a greater reduction in blood sugar must be considered in patients treated concurrently with ramipril and antidiabetic agents such as insulin, metformin and sulphonylurea derivatives. This effect is most pronounced at the beginning of treatment.

Vildagliptin.

An increased incidence of angioedema was found in patients taking ACE inhibitors and vildagliptin.

Food and alcohol.

The absorption of Triasyn is not influenced by food intake, however, concomitant administration with alcohol may lead to increased vasodilatation. A high intake of dietary salt may decrease the antihypertensive effects of Triasyn.

Desensitisation therapy.

ACE inhibitors may lead to an increased likelihood and greater severity of anaphylactoid and anaphylactic reactions. This must be considered when desensitisation is performed.

Tacrolimus.

Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.

Heparin.

A rise in serum potassium concentration is possible when ramipril and heparin are administered concurrently.

Other.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents and other substances may change the blood picture. The likelihood of blood picture changes is increased when ramipril is administered with these substances.
mTOR inhibitors (e.g. temsirolimus): An increased incidence of angioedema was observed in patients taking ACE inhibitors and mTOR inhibitors (mammalian target of rapamycin inhibitors).
Neprilysin (NEP) inhibitors: An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and NEP inhibitors.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
As with all products containing ACE inhibitors, Triasyn should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Triasyn 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. Otherwise there is a risk of harm to the foetus.
If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
There are no adequate and well controlled studies of ramipril in pregnant women. Data, however, show that ramipril crosses the human placenta. Postmarketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero.
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 the first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02), respectively, compared to no exposure.
When ACE inhibitors have been used during the second and third trimesters of pregnancy, there have been reports of neonatal hypotension, renal failure, skull hypoplasia and death.
Oligohydramnios has also been reported, presumably resulting from decreased foetal renal function; oligohydramnios has been associated with foetal limb contractures, craniofacial malformations, hypoplastic lung development and intrauterine growth retardation. Prematurity and patent ductus arteriosus have been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure or to the mother's underlying disease. Infants exposed to ACE inhibitors in utero must be closely monitored for hypotension, oliguria and hyperkalaemia. If oliguria is present or developing, support of blood pressure and renal perfusion may be necessary.
Following administration of felodipine to pregnant dams during the period of organogenesis, morphological abnormalities of the phalanges were observed in the rabbit foetus.
In rats, oral doses of felodipine 3.8 mg/kg or higher caused prolongation of labour.
Both felodipine and ramipril are excreted in breast milk. It is therefore recommended that Triasyn is not given to nursing mothers. An alternative treatment with better established safety profile during breastfeeding is preferable, especially while nursing a newborn or preterm infant (see Section 4.3 Contraindications).

4.8 Adverse Effects (Undesirable Effects)

Generally, Triasyn is well tolerated. Most adverse reactions reported in clinical trials were mild and were typical of reactions that can be expected from experience with the individual components, felodipine and ramipril. Experience in clinical trials indicates that Triasyn may result in a lower incidence of flushing than felodipine alone as well as a lower incidence of cough than ramipril alone.
The following list of adverse reactions and their frequencies are based upon experience with the monotherapies in their usual dosage range. See Tables 1-5.

Other adverse effects have been reported.

Bone marrow failure, pancytopaenia, haemolytic anaemia, psychomotor skills impaired (impaired reactions), burning sensation, parosmia (smell disturbances), aphthous stomatitis (inflammatory reactions of the oral cavity), pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, Syndrome of inappropriate antidiuretic hormone secretion (SIADH), blood sodium decreased, anaphylactic or anaphylactoid reactions (severe anaphylactic and anaphylactoid reactions to insect venom is increased under ACE inhibition), antinuclear antibody increased, acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional), gynaecomastia and disturbance in attention.

Reporting suspected adverse reactions.

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

Adults, including the elderly.

One tablet per day of Triasyn 2.5/2.5 mg or Triasyn 5.0/5.0 mg. Patients treated with Triasyn 2.5/2.5 mg may be titrated to Triasyn 5.0/5.0 mg after 2 to 4 weeks if necessary. There is limited experience with higher doses.
Tablets must be swallowed whole. They must not be divided, crushed or chewed. They should be swallowed with a generous amount of liquid and may be administered before, after or during meals.

Elderly (over 65 years of age).

Because liver and renal function decline with age, patients over 65 whose previous therapy did not include an ACE inhibitor should be initiated on ramipril 1.25 mg. These patients may then be switched to Triasyn 2.5/2.5 mg. For elderly patients not previously taking felodipine, an initial dose of 2.5 mg may be considered appropriate and thus Triasyn 2.5/2.5 mg is the starting dose (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dosage recommendations for special patient groups if the existing treatment does not include an ACE inhibitor.

Patients on diuretics.

Consideration should be given to temporarily discontinuing the diuretic or at least reducing the dose 2 to 3 days before initiation of treatment with Triasyn 2.5/2.5 mg. If this is not possible, start with ramipril 1.25 mg daily and increase to ramipril 2.5 mg daily before transferring to Triasyn 2.5/2.5 mg.

Patients with incompletely corrected fluid or salt depletion.

Start with ramipril 1.25 mg daily and increase to ramipril 2.5 mg daily before transferring to Triasyn 2.5/2.5 mg.

Patients with severe hypertension or those in whom a hypotensive reaction would constitute a particular risk.

Start with ramipril 1.25 mg daily and increase to ramipril 2.5 mg daily before transferring to Triasyn 2.5/2.5 mg.

Patients with impaired renal function (20 to 50 mL/min).

Start with ramipril 1.25 mg daily and increase to ramipril 2.5 mg daily before transferring to Triasyn 2.5/2.5 mg daily. A maximum dose of 5 mg ramipril daily must not be exceeded.

Patients with impaired hepatic function.

Treatment with ramipril should not exceed 2.5 mg daily and therefore Triasyn 2.5/2.5 is the maximum dose in this patient group. Triasyn 5.0/5.0 should not be used (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.7 Effects on Ability to Drive and Use Machines

The antihypertensive effect in individual cases may be symptomatic. Some undesirable effects (e.g. some symptoms of reduction in blood pressure such as dizziness) may be accompanied by an impairment of the ability to concentrate and react. Treatment with any blood pressure lowering agent may, therefore, affect the ability to drive, cross the road safely or operate machinery, especially at the start of treatment or when changing over from other preparations, or during concomitant use with alcohol.

4.9 Overdose

Symptoms.

Overdosage may cause excessive peripheral vasodilatation with marked hypotension and sometimes bradycardia, shock, electrolyte disturbances and renal failure.

Management.

Primary detoxification by, for example, gastric lavage, administration of adsorbents and/or sodium sulfate if possible should be initiated during the first 30 minutes.
If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. In cases of accompanying bradycardia, atropine 0.5 - 1.0 mg should be administered intravenously. If this is not sufficient, plasma volume should be increased by electrolyte infusion (e.g. glucose, saline or dextran). Sympathomimetic drugs with predominant effect on the alpha adrenoreceptors or angiotensin II should be considered if the above-mentioned measures are insufficient.
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

The excipients contained in Triasyn tablets are aluminium sodium silicate, microcrystalline cellulose, hyprolose, hypromellose, iron oxide red CI 77491, iron oxide yellow CI 77492, lactose, macrogol 6000, hard paraffin, PEG-40 hydrogenated castor oil, propyl gallate, sodium stearylfumarate, pregelatinised maize starch and titanium dioxide.

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

Store below 25°C.

6.5 Nature and Contents of Container

Triasyn is packaged in PVC/PVDC/Aluminium foil blister packs.
Pack sizes: 5*, 7#, 10*, 28* and 30 tablets.
# Starter pack.
* Non-marketed pack.

6.6 Special Precautions for Disposal

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

Summary Table of Changes