Consumer medicine information

Dolapril

Trandolapril

BRAND INFORMATION

Brand name

Dolapril Capsules

Active ingredient

Trandolapril

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dolapril.

What is in this leaflet

This leaflet answers some common questions about DOLAPRIL.

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

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

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

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

What DOLAPRIL is used for

DOLAPRIL is used to treat:

  • high blood pressure (hypertension)
  • some heart conditions.

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. You may feel fine and have no symptoms, but eventually hypertension can lead to serious health problems, including stroke, heart disease and kidney failure. DOLAPRIL helps to lower your blood pressure.

DOLAPIRL belongs to a group of medicines called Angiotensin Converting Enzyme (ACE) inhibitors. It works by relaxing your blood vessels, making it easier for blood to move around your body. This helps lower blood pressure and increase the supply of blood and oxygen to the heart.

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

DOLAPRIL is not addictive.

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

Before you take DOLAPRIL

When you must not take it

Do not take DOLAPRIL if you:

  • Are allergic (sensitive) to trandolapril or any of the ingredients in DOLAPRIL capsules 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, tongue, throat, hands or feet.
  • Have ever had an allergic reaction to any other ACE inhibitor. If you have had an allergic reaction to an ACE inhibitor before, you may be allergic to DOLAPRIL.
  • You have a history of swelling of the face, lips, mouth, tongue, throat, hands or feet for no apparent reason.
    Taking DOLAPRIL could cause this problem to happen again.
  • Are pregnant or planning to become pregnant DOLAPRIL may affect your developing baby if you take it during pregnancy
  • Are breastfeeding or planning to breastfeed Like most ACE inhibitors, DOLAPRIL is not recommended while you are breastfeeding.
  • Are suffering from any obstruction that slows the flow of blood to the heart, such as narrowing of one of the valves in the heart (aortic stenosis)
  • Recently had severe or prolonged sickness or diarrhoea
  • Have ever had the condition known as angioedema (a severe allergic skin condition)
  • Are undergoing haemodialysis or having your blood treated outside your body.
    Taking DOLAPRIL could cause an allergic reaction.
  • Are taking any of the following medications, or medications containing these ingredients:
    - aliskiren (under certain conditions)
    - neutral endopeptidase (NEP) inhibitors such as sacubitril and racecadotril.

DOLAPRIL must not be given to children.

Do not take DOLAPRIL if the expiry date (EXP) printed on the pack has passed.

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

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

Before you start to take it

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

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

  • kidney problems
  • regular dialysis, blood filtration or other similar procedures
  • liver problems
  • heart conditions
  • low blood pressure, which you may notice as dizziness or light-headedness
  • high levels of potassium in your blood
  • dizzy spells
  • diabetes
  • connective tissue disease
  • are about to have surgery or a general anaesthetic.

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

Tell you doctor if you are following a very low salt diet.

Tell your doctor if you are about to receive desensitisation therapy for an allergy e.g. to insect stings.

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

DOLAPRIL should not be used during pregnancy or while breastfeeding.

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

Taking other medicines

Tell your doctor 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 and DOLAPRIL may interfere with each other. These include:

  • other medicines used to treat high blood pressure
  • aliskiren
  • neutral endopeptidase (NEP) inhibitors such as sacubitril or racecadotril
  • diuretics, also known as fluid or water tablets
  • anti-inflammatory pain medicines used to treat arthritis, pain or fever
  • potassium supplements, large amounts of salt or potassium-containing salt substitutes in your food (check the label)
  • any other medication associated with increases in potassium (e.g. trimethoprim/sulfamethoxazole - an antibiotic)
  • any antidiabetic medicine (used to lower blood glucose)
  • lithium or tricyclic antidepressants (used to treat mood changes)
  • sympathomimetics - these may be found in some decongestants, cough / cold remedies and asthma
  • medicinesantacids, used to treat heartburn and reflux
  • immunosuppressants (medicines which lower the body's resistance to disease)
  • procainamide (used for abnormal heart rhythms)
  • allopurinol (medicines used to treat gout)
  • cytostatic medicines (medicines used to treat certain cancers)
  • neuroleptic medicines (medicines used to treat certain mental and emotional conditions)
  • general anaesthetics
  • injectable gold (sodium aurothiomalate) (medicine used to treat rheumatoid arthritis).

These medicines may be affected by DOLAPRIL, 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 have more information on medicines to be careful with or avoid while taking DOLAPRIL.

How to take DOLAPRIL

How much to take

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

They may differ from the information contained in this leaflet.

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

The usual dose is one or two capsules taken once daily, up to a maximum of 4 mg once daily. The usual starting dose for older people (over 65 years) is less than that for younger adults. Your doctor will adjust the dose of DOLAPRIL, depending on how quickly your kidneys and liver can remove it from your body.

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

How to take it

Swallow DOLAPRIL whole with a glass of water.

When to take it

Take DOLAPRIL at about the same time each day.

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

It does not matter if you take DOLAPRIL before, during or after food.

How long to take it

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

If you forget to take DOLAPRIL

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

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

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

This may increase the chance of you getting an unwanted side effect.

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

If you take too much (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 DOLAPRIL. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much DOLAPRIL, you may feel light-headed, dizzy, weak, have heart palpitations or faint.

While you are taking DOLAPRIL

Things you must do

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

If you become pregnant while taking DOLAPRIL tell your doctor immediately.

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

Tell your doctor if you have excessive vomiting and/or diarrhoea while taking DOLAPRIL.

You may lose too much water and salt and your blood pressure may drop too much.

Drink plenty of water when you are using DOLAPRIL, especially if you sweat a lot (e.g. during hot weather or exercise).

If you do not drink enough water while taking DOLAPRIL, you may faint or feel light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.

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

If you are about to be started on any new medicines, tell your doctor, dentist or pharmacist that you are taking DOLAPRIL.

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

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

DOLAPRIL may interfere with the results of some tests.

Go to your doctor regularly for a check-up.

Your doctor may occasionally do a blood test to check your potassium level in the blood and to see how your kidneys are working.

Things you must not do

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

Do not take DOLAPRIL to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking DOLAPRIL, or lower 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 out of 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 DOLAPRIL affects you.

As with other ACE inhibitors, DOLAPRIL may cause dizziness, light-headedness or tiredness in some people. Make sure you know how you react to DOLAPRIL before you drive, 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.

Side effects

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

DOLAPRIL helps most people with hypertension and some heart conditions, 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.

If you are over 65 years of age you may have an increased chance of getting 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:

  • light-headedness or dizziness
  • nausea, vomiting, diarrhoea or stomach pains
  • indigestion
  • persistent dry cough
  • headache
  • unusual tiredness or weakness
  • aching, tender or weak muscles not caused by exercise
  • taste disturbance

These are the more common side effects of DOLAPRIL.

Tell your doctor immediately if you notice any of the following:

  • fast or irregular heartbeat, also called palpitations
  • signs of worrying or frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • itchy skin rash or other skin problems
  • symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly 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 DOLAPRIL and either tell your doctor immediately or go to Accident and Emergency at the nearest hospital:

  • fainting within a couple of hours of taking DOLAPRIL
  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • severe dizziness and confusion with visual disturbances and speech problems
  • chest pain
  • rapid, shallow breathing, cold clammy skin, a rapid, weak pulse, dizziness, weakness and fainting.

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 also occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After using DOLAPRIL

Storage

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

If you take the capsules out of the pack they may not keep well.

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

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

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 or pharmacist tells you to stop taking DOLAPRIL or the capsules have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

DOLAPRIL comes in 4 strengths of capsules:

  • DOLAPRIL 0.5 - white opaque capsule marked ‘TN’ over ‘5’ in black ink
  • DOLAPRIL 1 – scarlet and peach opaque capsule marked ‘TN’ over ‘1’ in black ink
  • DOLAPRIL 2 - scarlet opaque capsule marked ‘TN’ over ‘2’ in black ink
  • DOLAPRIL 4 - white opaque capsule marked ‘TN’ over ‘4’ in black ink.

Each blister pack contains 28 capsules.

Ingredients

The active ingredient in DOLAPRIL is trandolapril.

  • each DOLAPRIL 0.5 capsule contains 0.5 mg of trandolapril
  • each DOLAPRIL 1 capsule contains 1 mg of trandolapril
  • each DOLAPRIL 2 capsule contains 2 mg of trandolapril
  • each DOLAPRIL 4 capsule contains 4 mg of trandolapril

The capsules also contain:

  • lactose monohydrate
  • povidone
  • maize starch
  • croscarmellose sodium
  • sodium stearyl-fumarate.

The capsule shells contain:

  • titanium dioxide (171)
  • gelatin
  • black printing ink
  • brilliant blue FCF CI42090 (133; 1 mg and 2 mg only)
  • erythrosine CI45430 (127; 1 mg and 2 mg only)
  • allura red AC CI16035 (129; 1 mg and 2 mg only)
  • sunset yellow FCF CI15985 (110; 1 mg only).

The capsules do not contain gluten, sucrose, tartrazine or any other azo dyes.

Sponsor

Arrow Pharma Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
Australia

Australian registration numbers

DOLAPRIL 0.5 AUST R 125432

DOLAPRIL 1 AUST R 125433

DOLAPRIL 2 AUST R 125434

DOLAPRIL 4 AUST R 125435

Date of last revision:
March 2018

BRAND INFORMATION

Brand name

Dolapril Capsules

Active ingredient

Trandolapril

Schedule

S4

 

1 Name of Medicine

Trandolapril.

6.7 Physicochemical Properties

Chemical name: (2S,3aR,7aS)-1- [(2S)-2-[[(1S)-1- (ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl] octahydro-1H-indole-2-carboxylic acid. Molecular formula: C24H34N2O5. MW: 430.5.

Chemical structure.


CAS number.

CAS: 87679-37-6.

2 Qualitative and Quantitative Composition

Dolapril 0.5 capsules contain 0.5 mg of trandolapril.
Dolapril 1 capsules contain 1 mg of trandolapril.
Dolapril 2 capsules contain 2 mg of trandolapril.
Dolapril 4 capsules contain 4 mg of trandolapril.

Physical and Chemical characteristics.

Trandolapril is a colourless, crystalline powder that is soluble in chloroform, dichloromethane and methanol, slightly soluble in water and sparingly soluble in hydrochloric acid.
Dolapril capsules come in four strengths and contain 0.5 mg, 1 mg, 2 mg or 4 mg of trandolapril.

Excipients.

The capsules contain sugars as lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dolapril 0.5 capsules: White opaque capsule with 'TN' over '5' on the cap.
Dolapril 1 capsules: Peach and scarlet opaque capsule with 'TN' over '1' on the cap.
Dolapril 2 capsules: Scarlet opaque capsule with 'TN' over '2' on the cap.
Dolapril 4 capsules: White opaque capsule with 'TN' over '4' on the cap.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Dolapril is administered as a prodrug (trandolapril) which is rapidly converted to its biologically active metabolite trandolaprilat, a compound which binds tightly to, and dissociates slowly from, angiotensin converting enzyme (ACE). There is evidence that trandolapril itself has a marked affinity for ACE and may therefore have an antihypertensive effect.
Angiotensin converting enzyme is a peptidyl dipeptidase which catalyses the transformation of angiotensin I to vasoconstrictive angiotensin II and the degradation of bradykinin to inactive fragments. By potently inhibiting converting enzyme at very low concentrations, Dolapril decreases angiotensin II production and causes a reduction in aldosterone secretion and an increase in plasma renin activity by suppressing negative feedback.
Dolapril thus modulates the renin angiotensin aldosterone system which plays a major part in regulating blood volume and blood pressure.
Other mechanisms of action which may be related to the vasodilator activity of ACE inhibitors include inhibition of the degradation of bradykinin, prostaglandin release and a decrease in sympathetic nervous system activity.
The decrease in peripheral resistance induced by Dolapril reduces systolic and diastolic blood pressure. There is a marked reduction of both supine and erect blood pressure. The decrease is not accompanied by either water and sodium retention or tachycardia. The antihypertensive activity of Dolapril is independent of plasma renin levels.

Pharmacodynamics.

Dolapril is highly lipophilic compared with other ACE inhibitors (trandolaprilat > ramiprilat > perindoprilat > enalaprilat > captopril), allowing high tissue penetration.
Recent data show that renin and angiotensin are locally generated in many organ tissues involved in cardiovascular regulation. This implies that angiotensin II not only acts as a circulating hormone but also as a locally generated modulator of organ function at the tissue level and may play an important role in the tonic control of vascular resistance, and cardiac and renal function.
Studies with rats show that trandolapril inhibits plasma and tissue (particularly vascular, renal, cardiac and adrenal) angiotensin converting enzyme.
Inhibition of angiotensin converting enzyme activity in tissues, with subsequent local reduction of angiotensin II generation, may significantly contribute to the antihypertensive effect of ACE inhibitors and is important for effective treatment of hypertension and its consequences. Dolapril's affinity for the tissue isoenzyme may be the basis of the regression of cardiac and vascular hypertrophy and improvement in vascular compliance observed in rats.
Hypertension is associated with significant changes in arterial wall functions due to the increase in thickness of the tunica media caused by hypertrophy and hyperplasia of the smooth muscle cell and in collagen network density. A number of animal studies have shown that trandolapril treatment significantly regressed vascular hypertrophy of the aorta, the femoral artery and the mesenteric artery. Marked regression in left ventricular hypertrophy has also been noted.
Other animal studies have demonstrated a total inhibition of induction by angiotensin I of several cardiac and vascular growth signals (the c-fos and c-myc oncogenes and the stress protein HSP 68) and rectification of the V3/V1 myosin ratio.
Animal studies on renal function have shown an increase in urine flow and sodium and chloride excretion. Trandolapril was shown to cause a regression of renal hypertrophy.
In humans, Dolapril's antihypertensive activity appears one hour after administration and persists for greater than 24 hours without modifying the circadian rhythm of blood pressure. The antihypertensive activity continues without the appearance of acquired tolerance in long-term treatment. There is no rebound effect on discontinuation of treatment.
Dolapril has a sustained effect on blood pressure. Comparing the fall in blood pressure at the steady-state trough level of trandolaprilat (i.e. at 24 hours, immediately before the next dose) with that at the steady-state peak level, the trough/ peak ratio is almost 100% for a 24 hour period and approximately 70 to 80% for a 48 hour period after a dose. Thus, at steady state, the antihypertensive effect of Dolapril is maintained for up to 48 hours after a dose. Dolapril is, however, administered as a single daily dose to achieve and maintain effective steady-state levels.
Combinations with hydrochlorothiazide or nifedipine produced further falls in blood pressure without increasing adverse events.

Clinical trials.

In a long-term clinical study involving hypertensive patients with abnormal fasting glucose levels and/or diabetes mellitus, and hypertensive patients without signs of glucose intolerance, trandolapril produced a similar efficacy level and incidence of side effects in both groups. No cases of hypoglycaemia were reported.
The study also included hypertensive patients who were overweight (> 130% of ideal weight at baseline). In comparison with patients of normal weight, no significant differences in efficacy or incidence of side effects were observed during trandolapril therapy.
The same study also included hypertensive patients with elevated serum creatinine and patients with normal creatinine levels. Efficacy and incidence of side effects produced by trandolapril were similar in both groups.
In studies in spontaneously hypertensive (SH) rats or in other rat studies of cardiac failure secondary to myocardial infarction (e.g. ligation of left coronary artery, doxorubicin hydrochloride induced impairment of cardiac function, pacing induced cardiac failure), trandolapril showed a beneficial effect on cardiac failure. The beneficial effects included reduction of cardiac hypertrophy and myocardial fibrosis, normalisation of cardiac reserve, improved left ventricular end diastolic pressure (LVEDP). The ultimate demonstration of efficacy in cardiac failure, however, would depend upon clinical data.

Trandolapril cardiac evaluation study (TRACE).

In a multicentre, double blind, placebo controlled, parallel group study conducted in 27 centres in Denmark, 1,749 patients (876 patients on trandolapril; 873 patients on placebo) with left ventricular dysfunction (LVD) following myocardial infarction (MI) were studied. Subjects with residual ischaemia or overt heart failure were included. The LVD was measured by standard echocardiographic examination and patients with a wall motion index (WMI) of less than or equal to 1.2 (corresponding to a LV ejection fraction of approximately 35%) were eligible for entry into the study.
Trandolapril or placebo was started between days 3 and 7 after MI. After administration of a test dose of 0.5 mg, the medication (trandolapril 1 mg or placebo) was started. Patients were given the highest tolerated dose of trandolapril (up to a maximum of 4.0 mg daily). The duration of follow-up was 24 to 50 months. Results of the TRACE study are presented in Table 3.
The long-term use of trandolapril was associated with a reduction in all cause mortality (22%), largely cardiovascular mortality. Trandolapril was also associated with a 29% reduction in risk to progression of heart failure.
The beneficial effect of trandolapril on morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction was not affected by concomitant administration of thrombolytics, aspirin, heparin, beta-blockers, calcium channel blockers, nitrates, diuretics or digoxin.

5.2 Pharmacokinetic Properties

Absorption.

Trandolapril is very rapidly absorbed after oral administration and achieves its peak plasma level at 30 minutes after administration. Trandolapril disappears rapidly from plasma with a half-life of less than one hour, being nonspecifically hydrolysed to its potent, long acting, active metabolite, trandolaprilat. The peak plasma concentration of trandolaprilat is achieved after four hours.
The absolute bioavailability of trandolaprilat is 40 to 60% after administration of Dolapril capsules.
While food intake delays Tmax from 0.5 to 2 hours for trandolapril and from six to eight hours for trandolaprilat, there is no significant clinical alteration in the other aspects of their pharmacokinetics and pharmacodynamics. Since there is no clinically significant effect of food on the absorption of trandolapril, the capsules may be taken before, during or after a meal.

Distribution.

Protein binding of trandolapril and trandolaprilat are 80 and 94%, respectively. Trandolaprilat binds with a high affinity to converting enzyme. The major proportion of circulating trandolaprilat is also non-saturably bound to albumin.
After repeated administration of trandolapril in single daily doses, steady state is reached on average in four days, both in healthy volunteers and in young or elderly hypertensive patients. At a dose regimen of 2 mg once daily, minimum plasma concentrations, as measured just prior to the next dose, were 1.9 nanogram/mL.

Metabolism.

Trandolapril disappears rapidly from plasma with a half-life of less than one hour, being non-specifically hydrolysed to its potent, long acting, active metabolite, trandolaprilat.

Excretion.

The effective elimination half-life of trandolaprilat is 22 hours.
Trandolaprilat eliminated in the urine in unchanged form accounts for 15% of the dose of trandolapril administered. After oral administration of radiolabelled product to humans, 33% of the radioactivity was found in urine and 66% in faeces.

Hepatic insufficiency.

Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, nine and twofold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency (see Section 4.2 Dose and method of administration).

Renal insufficiency.

Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately two-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/minute and in patients with haemodialysis. Dosage adjustment is recommended in renally impaired patients (see Section 4.2 Dose and method of administration).

Heart failure.

There are no noteworthy differences in the pharmacokinetics of trandolapril and trandolaprilat as compared to other patient groups. The rate of absorption and clearance remains unchanged with Tmax = 30 minutes and half-life less than one hour. Steady state is reached on the fourth day without further accumulation, and inhibition of the angiotensin converting enzyme is maintained at the same level under continuous treatment.

Effect of race.

Pharmacokinetic differences have not been evaluated in different races.

Effect of gender and advanced age.

Trandolapril pharmacokinetics have been investigated in the elderly (> 65 years) and in both genders. The plasma concentration of trandolapril is increased in elderly hypertensive patients. The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activity are similar in male and female elderly hypertensive patients.

5.3 Preclinical Safety Data

Genotoxicity.

Trandolapril had no mutagenic or clastogenic activity in a standard battery of tests.

Carcinogenicity.

At least one ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential of ACE inhibitors to cause this effect in humans is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and, when it does occur, it is considered to be benign. No carcinogenic effect has been noted with long-term rat (24 months up to 8 mg/kg/day) or mice (18 months up to 25 mg/kg/day) studies with trandolapril.
Trandolapril was not mutagenic or carcinogenic.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypertension. Data to support the usage of Dolapril in renovascular hypertension are, at present, not available.
Dolapril is also indicated for patients with left ventricular dysfunction postmyocardial infarction (ejection fraction less than or equal to 35% or WMI (wall motion index) less than or equal to 1.2).

4.3 Contraindications

Hypersensitivity to trandolapril or any other ACE inhibitor.
History of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor.
Pregnancy and lactation (see Section 4.6 Fertility, pregnancy and lactation - Use in pregnancy, Use in lactation).
Children.
Concomitant use with neprilysin (neutral endopeptidase, NEP) inhibitors such as sacubitril and racecadotril (see Section 4.4 Special warnings and precautions for use and Section 4.5 Interaction with other medicines and other forms of interactions).

Haemodialysis and other extracorporeal treatments.

Patients haemodialysed using high flux polyacrylonitrile (AN69) membranes or patients undergoing low density lipoprotein aphaeresis with dextran sulfate are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes (e.g. cuprophane or polysulfone PSF) for haemodialysis.
Combination with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m2).

4.4 Special Warnings and Precautions for Use

Angioedema.

Since 1984, severe life threatening angioedema has been reported with most of the ACE inhibitors. The overall incidence is approximately 0.1 to 0.2%. ACE inhibitors have been shown to cause a higher rate of angioedema in black patients than in non-black patients. 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. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually the angioedema involves non-pitting oedema of the skin and oedema of the subcutaneous tissues and mucous membranes.
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors. In such cases, the product should be discontinued promptly and the patient observed carefully until the swelling disappears. In instances when swelling has been confined to the face and lips, the angioedema has generally resolved either without treatment or with antihistamines. Angioedema associated with laryngeal oedema is potentially life threatening.
Angioedema may occur with or without urticaria. The onset of angioedema associated with the use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom free intervals.
There are case reports where changing the patient over to another ACE inhibitor was followed by recurrence of angioedema 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).
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor therapy (e.g. temsirolimus, sirolimus, everolimus) may be at increased risk for angioedema.
When involvement of the tongue, glottis or larynx is likely to cause airway obstruction, appropriate therapy, including adrenaline (epinephrine) and oxygen administration, should be carried out promptly or the patient hospitalised. Failing a rapid response, oral/ nasal intubation or securing an airway by surgical means (e.g. cricothyrotomy or tracheostomy) may be necessary, followed by mechanical ventilation. Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.
Intestinal angioedema has also been reported in patients treated with ACE inhibitors. This should be considered in patients on trandolapril presenting with abdominal pain (with or without nausea or vomiting).
As the concomitant inhibition of ACE and neprilysin (neutral endopeptidase, NEP) may increase the risk of angioedema, co-administration of ACE inhibitors and NEP inhibitors, (e.g. sacubitril and racecadotril) is contraindicated (see Section 4.3 Contraindications and Section 4.4 Special warnings and precautions for use).
Patients experiencing angioneurotic oedema must immediately discontinue treatment and be monitored until the oedema resolves.

Patients with renovascular hypertension.

Treatment of renovascular hypertension is by revascularisation. However, ACE inhibitors may be useful while waiting for the revascularisation or when the procedure is not carried out. The risk of severe arterial hypotension and renal insufficiency is increased when patients with prior unilateral or bilateral renal artery stenosis are treated with an ACE inhibitor. Diuretics may further increase the risk. Loss of renal function may occur with only small changes in the serum creatinine, even in patients with unilateral renal artery stenosis. For these patients treatment should be initiated in the hospital under close medical supervision with low doses and careful dose adjustment. Diuretic treatment should be discontinued, and renal function and serum potassium monitored during the early weeks of treatment.

Anaphylactoid reactions and possibly related reactions.

Desensitisation.

Life threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during desensitisation (e.g. against animal venom). These reactions were avoided when ACE inhibitors were temporarily withdrawn, but recurred on inadvertent rechallenge.

Low density lipoprotein (LDL)-apheresis.

Life threatening anaphylactoid reactions have been noted when patients on LDL-apheresis take ACE inhibitors at the same time.

Hypotension.

Hypotension may occur in patients commencing treatment with ACE inhibitors. Excessive hypotension is rarely seen in patients with uncomplicated hypertension but can develop in patients with impaired renal function, in those who are salt/ volume depleted because of renovascular disease, diuretic therapy, vomiting or diarrhoea, and in patients undergoing dialysis (See Section 4.4 Special warnings and precautions for use, Section 4.5 Interaction with other medicines and other forms of interactions and Section 4.8 Adverse effects (undesirable effects)). In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed. This may be associated with syncope, neurological deficits, oliguria and/or progressive azotaemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started at low doses under very close supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased, or diuretic therapy is commenced or increased.
Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident, respectively. In all high risk patients, it is advisable to initiate treatment at lower dosages than those usually recommended for uncomplicated patients.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which usually can be given without difficulty once the blood pressure has increased.

Hypotension post-myocardial infarction.

If hypotension is present, after myocardial infarction, it is recommended that the patient be closely monitored for at least six hours following the initial 0.5 mg dose. Therapy should be initiated after hyponatraemia and/or hypovolaemia (if present) is corrected.

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.
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.

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

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

Cough.

During treatment with an ACE inhibitor, a dry and non-productive cough may occur, which disappears after discontinuation.
A persistent, dry (non-productive), irritating cough has been reported with most of the ACE inhibitors. The frequency of reports has been increasing since cough was first recognised as a side effect of ACE inhibitor therapy. In various studies, the incidence of cough varies between 2% and 15% depending upon the drug, dosage and duration of use.
The cough is often worse when lying down or at night, and has been reported more frequently in women (who account for two-thirds of the reported cases). Patients who cough may have increased bronchial reactivity compared with those who do not. The observed higher frequency of this side effect in nonsmokers may be due to a higher level of tolerance of smokers to cough.
The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins which accumulate because of ACE inhibition. Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor; the reaction may recur but this is not invariably the case. A change to another class of drugs may be required in severe cases.

Hyperkalaemia.

Because ACE inhibitors decrease the formation of angiotensin II and the subsequent production of aldosterone, serum potassium concentrations exceeding 5.5 mEq/L may occur. Hyperkalaemia is more likely in patients with some degree of renal impairment, those treated with potassium sparing diuretics or potassium supplements, potassium containing salt substitutes, the concomitant use of agents to treat hypokalaemia and in those patients taking other active substances associated with increases in serum potassium (e.g. co-trimoxazole also known as trimethoprim/ sulfamethoxazole) concomitantly. Diabetic patients, elderly diabetic patients particularly, and patients with left ventricular dysfunction after myocardial infarction, may be at increased risk of hyperkalaemia. In some patients, hyponatraemia may coexist with hyperkalaemia. It is recommended that patients taking an ACE inhibitor should have serum electrolytes (including potassium, sodium and urea) measured from time to time. This is more important in patients taking diuretics.

Neutropenia/ agranulocytosis.

Agranulocytosis and bone marrow depression (including leucopenia/ neutropenia) have been reported with ACE inhibitors. The risk of neutropenia appears to be dose-and type-related and is dependent on the patient's clinical status. These have mostly occurred in patients with pre-existing impaired renal function, connective tissue diseases such as 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 counts should be considered in patients with collagen vascular disease, renal disease (serum creatinine greater than or equal to 180 micromol/L) and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive.

Dermatological reactions.

Dermatological reactions characterised by maculopapular pruritic rashes and sometimes photosensitivity have been reported rarely with ACE inhibitors. Rare and occasionally severe skin reactions (e.g. lichenoid eruptions, psoriasis, pemphigus-like rash, rosacea, Stevens-Johnson syndrome) have also been reported. A causal relationship is sometimes difficult to assess.
Patients who develop a cutaneous reaction with one ACE inhibitor might not when switched to another drug of the same class, but there are reports of cross reactivity.

Taste disturbances (dysgeusia).

The incidence of taste disturbance was reported to be high (up to 12.5%) with high doses of one ACE inhibitor, but the overall incidence for the class is probably low (< 0.5%). However, the relevant data are scarce and difficult to interpret.
The taste disturbance has been described as a suppression of taste or a metallic sensation in the mouth. The dysgeusia usually occurs in the first few weeks of treatment and may disappear within one to three months despite continued treatment.

Surgery/ anaesthesia.

In patients undergoing major surgery or who require anaesthesia, hypotension due to anaesthetic agents may be greater in patients receiving ACE inhibitors because of interference with compensatory mechanisms associated with the renin angiotensin system. If perioperative hypotension occurs, volume expansion would be required.

Dialysis.

It is not known for certain if trandolapril or trandolaprilat are removed by dialysis. However, it would be expected that dialysis could remove the active moiety, trandolaprilat, from the circulation, resulting in a possible loss of control of blood pressure. Therefore careful monitoring of the patient's blood pressure during dialysis is required and the dosage of Dolapril adjusted if needed.

Valvular stenosis.

Dolapril should not be used in patients with aortic stenosis or outflow obstructions. There has been some concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators, including ACE inhibitors. Vasodilators may tend to drop diastolic pressure, and hence coronary perfusion pressure, without producing the concomitant reduction in myocardial oxygen demand that normally accompanies vasodilatation. The true clinical importance of this concern is uncertain.

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, and rarely with acute renal failure and/or death.
In clinical studies with ACE inhibitors 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 treatment. ACE inhibitors should be avoided in patients with known or suspected renal artery stenosis. When an ACE inhibitor is given to a patient with stenosis of the renal artery supplying a solitary kidney or with bilateral renal artery stenosis, acute renal insufficiency may occur. ACE inhibition may also cause a decrease in renal function in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces the pressure in the afferent glomerular arteriole, and transglomerular hydrostatic pressure is then maintained by angiotensin II induced constriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration pressure falls and renal failure may result. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors.
Some hypertensive patients with no apparent pre-existing renovascular disease have developed increases in blood urea nitrogen and serum creatinine which are usually minor and transient. This is more likely to occur in patients with pre-existing renal impairment or in those on diuretics. Dosage reduction of the ACE inhibitor and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function. 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 usage of another class of antihypertensive agent would be preferable. Patients with unilateral renal artery disease present a special problem, as deterioration of function may not be apparent from measurement of blood urea and serum creatinine.
Some ACE inhibitors, including trandolaprilat, 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 an NSAID.

Use in hepatic impairment.

As trandolapril is a prodrug metabolised in the liver to its active moiety, particular caution and close monitoring should be applied to patients with impaired hepatic function. The metabolism of the parent compound and, therefore, the formation of the bioactive metabolite trandolaprilat may be diminished, resulting in markedly elevated plasma levels of the parent compound (due to the reduced activity of the esterases in the liver). Dolapril therapy should be initiated with the 0.5 mg dose in this case (see Section 4.2 Dosage and method of administration).

Use in renal impairment.

See Section 4.2 Dose and method of administration.

Use in the elderly.

A pharmacokinetic study of trandolapril in hypertensive patients aged over 65 years with normal renal function for their age shows that no dosage adjustment is necessary. In patients with impaired renal function, impaired hepatic function and in sodium deficient patients, the starting dose should be reduced to 0.5 mg daily.

Paediatric use.

The safety and efficacy of Dolapril have not been established in children. Interaction studies have only been performed in adults.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

NEP inhibitors.

Co-administration of ACE inhibitors and NEP inhibitors e.g. sacubitril (available as fixed-dose combination with valsartan) and racecadotril, is contraindicated as the concomitant inhibition of ACE and neprilysin (neutral endopeptidase, NEP) may increase the risk of angioedema (see Section 4.3 Contraindications and Section 4.4 Special warnings and precautions for use).

Diuretics.

When a diuretic is added to the therapy of a patient receiving an ACE inhibitor, the antihypertensive effect is usually additive. Patients receiving diuretics, especially those in whom diuretic therapy was recently instituted or those with intravascular volume depletion, may sometimes experience an excessive reduction of blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects may be minimised by discontinuing the diuretic and ensuring adequate hydration and salt intake prior to commencing ACE inhibitor therapy. If it is not possible to discontinue the diuretic, the starting dose of the ACE inhibitor should be reduced and the patient closely observed for several hours following the initial dose of the ACE inhibitor and until the blood pressure has stabilised. The combined use of the three classes of drugs, thiazides, an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist) and an anti-inflammatory drug (NSAID or COX-2 inhibitor) all at the same time increases the risk of renal impairment (see Section 4.4 Special warnings and precautions for use).
Combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension.

Angiotensin II receptor blockers, aliskiren.

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 high frequency of adverse events such a hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS acting agent.

Lithium.

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. These drugs should be co-administered 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.

Agents affecting serum potassium.

ACE inhibitors can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. The concomitant therapy of an ACE inhibitor with a potassium sparing diuretic (e.g. spironolactone, triamterene or amiloride), potassium supplement or potassium containing salt substitute can increase the risk of hyperkalaemia. Therefore, if coadministration is indicated, they should be used with caution and the patient's serum potassium should be monitored frequently.

Co-trimoxazole (trimethoprim/sulfamethoxazole).

Patients taking concomitant co-trimoxazole (trimethoprim sulfamethoxazole) may be at increased risk for hyperkalaemia (See Section 4.4 Special warnings and precautions for use).

Nonsteroidal anti-inflammatory drugs.

Drugs with prostaglandin synthetase inhibitory properties (e.g. indomethacin) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors and may increase the risk of hyperkalaemia. As with all antihypertensives, NSAIDs (including aspirin used in higher doses as an anti-inflammatory drug e.g. for pain relief) may reduce the antihypertensive effects of trandolapril.
NSAIDs including aspirin, unless aspirin is used in lower doses as a platelet aggregation inhibitor, should be avoided with ACE inhibitors in patients with heart failure.
Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with trandolapril. The combined use of the three classes of drugs, thiazides, an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist) and an anti-inflammatory drug (NSAID or COX-2 inhibitor) all at the same time increases the risk of renal impairment (see Section 4.4 Special warnings and precautions for use).

Agents affecting sympathetic activity.

Agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neurone blocking agents may be used with caution. Beta-adrenergic blocking drugs will increase the antihypertensive effect of ACE inhibitors, and therefore the patient will need to be closely supervised.
The antihypertensive effects of ACE inhibitors may be reduced by sympathomimetics. Patients should be carefully monitored.

Alcohol.

Alcohol increases the bioavailability of ACE inhibitors and the risk of hypertension.

Antacids.

As antacids decrease the bioavailability of ACE inhibitors, it is recommended that these products are taken separately.

Antidiabetic agents.

Concomitant use of antidiabetic medicines (insulin or oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycaemia. Therefore, blood glucose should be closely monitored in diabetics treated with a hypoglycaemic agent and trandolapril, particularly when starting or increasing the dose of ACE inhibitor or in patients with impaired renal function.

Mammalian Target of Rapamycin (mTOR) Inhibitors.

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

Others.

No pharmacokinetic interaction has been noted when trandolapril was combined with digoxin, furosemide (frusemide) or nifedipine. No modification of the anticoagulant properties of warfarin has been observed following simultaneous administration with trandolapril.
The effects of certain anaesthetics may be enhanced by ACE inhibitors.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide may increase the risk of leucopenia, if used concomitantly with ACE inhibitors.
As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.
No clinically significant interaction has been found between trandolaprilat (trandolapril active metabolite) and cimetidine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproduction toxicity studies showed effects on renal development in offspring with increased incidence of renal pelvic dilation; this was seen at doses of 10 mg/kg/day and above in the rat but these changes did not affect the normal development of the offspring. Fertility of male and female rats was unaffected following oral administration of trandolapril at doses of up to 100 mg/kg/day.
(Category D)
As with all ACE inhibitors, Dolapril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with trandolapril and avoided during treatment.
If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment.
If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
The use of Dolapril is contraindicated in pregnancy. Pregnancy should be excluded before start of treatment and avoided during treatment. There are no adequate and well controlled studies of ACE inhibitors in pregnant women, but foetotoxicity is well documented in animal models. Data however show that ACE inhibitors cross the human placenta. Post marketing 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. As with all ACE inhibitors, Dolapril must not be used in pregnancy.
A historical cohort study in over 29,000 infants born to non-diabetic 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. When ACE inhibitors have been used during the second and third trimesters of pregnancy, there have been reports of foetal hypotension, renal failure, skull hypoplasia and death.
Oligohydramnios has been reported, presumably resulting from decreased foetal renal function. Oligohydramnios has been associated with foetal limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation. Prematurity and patent ductus arteriosus have been reported, however it is not clear whether these events were due to ACE inhibitor exposure or to the mother's underlying disease.
Infants exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia. If such complications arise, appropriate medical treatment should be initiated to support blood pressure and renal perfusion.

Ingestion of a single 10 mg dose of trandolapril in rats resulted in small amounts of trandolapril and its metabolites in breast milk. There is also evidence that other ACE inhibitors are excreted in rat breast milk, hence Dolapril must not be given to breastfeeding women. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

4.8 Adverse Effects (Undesirable Effects)

The adverse events reported are usually mild to moderate. The type and frequency of adverse events reported for elderly patients are similar to those reported for young patients. Clinical studies did not reveal any adverse effects due specifically to trandolapril except those believed to be a class effect due to ACE inhibition.

Patients with hypertension.

Trandolapril has been evaluated for safety in more than 1,900 patients with hypertension, including 448 treated for one year or more. Of these patients, 7.8% were at least 65 years old.
In long-term studies, 1,049 patients were exposed to trandolapril, either alone or in combination with diuretics and/or calcium channel inhibitors, for a mean duration of 45 weeks.

More common reactions.

The most common adverse events (> 1%) are detailed in Table 1.

Less common reactions.

Less frequent adverse events (0.1 to 1%), possibly/ probably related to treatment, included the following.

Body as a whole.

Abnormal feeling, abdominal pain.

Cardiovascular.

Hypotension, palpitation, chest pain, syncope, tachycardia, arrhythmias, angina pectoris, myocardial infarction, transient ischaemic attacks, cerebral haemorrhage, angioedema.

Digestive system.

Nausea, gastrointestinal disorder, vomiting, constipation, dry mouth.

Metabolic and nutritional.

Gout.

Musculoskeletal.

Cramps.

Nervous system.

Depression, insomnia, decreased libido, paraesthesia, somnolence.

Respiratory.

Dyspnoea.

Skin and appendages.

Non-specific skin disorder, pruritus.

Urogenital.

Impotence, deterioration of renal function, acute renal failure.

Hepatic.

There have been reports of individual incidents of cholestatic jaundice, hepatitis, pancreatitis and ileus connected with the use of ACE inhibitors.

Hypersensitivity.

Allergic hypersensitivity reactions such as pruritus and rash have been reported. Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like efflorescences and alopecia, which may be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA (antinuclear antibody) titres have been occasionally reported with ACE inhibitor treatment.

Other.

In very rare cases, angioedema has occurred (see Section 4.4 Special warnings and precautions for use).

Patients with acute myocardial infarction (TRACE study).

Adverse reactions related to trandolapril occurring at a rate greater than that observed in placebo treated patients with left ventricular dysfunction are shown in Table 2. The incidences represent the experiences from the TRACE study. Despite the use of a forced titration regimen to ensure that the highest possible dose (to a maximum of 4 mg) was used, observed reactions were those normally seen with ACE inhibitors. The follow-up time was between 24 and 50 months for this study.

Reactions from postmarketing surveillance or phase IV clinical trials.

Significant adverse events seen with trandolapril are listed below by body system:

Infections and infestations.

Bronchitis.

Blood and lymphatic system disorders.

Agranulocytosis, leukopenia.

Immune system disorders.

Allergic hypersensitivity reactions including pruritus and rash.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Nausea, Vomiting, abdominal pain, diarrhoea, dry mouth, pancreatitis.

Skin and subcutaneous tissue disorders.

Angioedema, alopecia, sweating.

General disorders and administration site conditions.

Fever.

Investigations.

Increases in BUN and serum creatinine, decreased platelets, elevated liver enzymes (including SGOT and SGPT).
The following adverse events have been reported with ACE inhibitors as a class.

Blood and lymphatic system disorders.

Pancytopenia.

Nervous system disorders.

Transient ischaemic attacks.

Cardiac disorders.

Angina pectoris, myocardial infarction, A-V block, bradycardia, cardiac arrest, tachycardia.

Vascular disorders.

Cerebral haemorrhage.

Skin and subcutaneous tissue disorders.

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders.

Myalgia.

Investigations.

Decreased haemoglobin, decreased haematocrit.

Gastrointestinal disorders.

Intestinal angioedema.

Clinical laboratory test findings.

In some cases, an elevation of urea and plasma creatinine has been observed in patients treated with trandolapril. This increase is most frequently found when Dolapril is prescribed with diuretics or renal insufficiency, or severe heart failure or renovascular hypertension are present.
Hyperkalaemia has rarely been observed in patients treated with trandolapril. No other electrolyte disturbances nor changes in plasma lipids (total cholesterol, HDL, LDL, VLDL) or glucose tolerance have been observed in patients.
In some cases, an increase in alkaline phosphatase and transaminases has been reported.
Decreased haemoglobin, haematocrit, platelets and white cell count and individual cases of agranulocytosis or pancytopenia have been reported with ACE inhibitor treatment; also evaluate liver enzymes and serum bilirubin. Haemolytic anaemia has been reported in some patients with a congenital deficiency concerning G6PDH (glucose-6-phosphate dehydrogenase) during treatment with ACE inhibitors.
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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dolapril has a duration of action greater than 24 hours and should not be administered at intervals of less than 24 hours. Monitoring of trough blood pressure should be done initially to ensure that control lasts over the dosing period. Should daily doses of more than one capsule be required, they should be administered together as a single daily dose. Since there is no clinically significant effect of food on the absorption of trandolapril, the capsules may be taken before, during or after a meal.

Hypertension.

The usual starting dose is one 1 mg capsule once daily. Maximum response is usually achieved within two to four weeks.
Some patients not responding to 1 mg once daily may respond to 2 mg once daily. An alternative to increasing the dose is to add a calcium channel blocker or diuretic (see Section 4.5 Interactions with other medicines and other forms of interactions).
The maximum daily dose of Dolapril should not exceed 4 mg.

Left ventricular dysfunction postmyocardial infarction.

(See Section 4.4 Special warnings and precautions for use, Hypotension.)
Following a myocardial infarction, therapy may be initiated as early as on the third day using an aggressive titration dose regimen. After a 0.5 mg test dose, treatment should commence with 1 mg once daily for the next three days. The dose should then be increased to 2 mg for a further four weeks. After the initial four week treatment, the dose should be increased to a maximum daily dose of 4 mg once daily and maintained at that level subject to tolerability, such as symptomatic hypotension.

Use in elderly hypertensive patients.

In patients older than 65 years with normal renal and hepatic function, there is no need to reduce the dose of trandolapril.

Diuretic treated or severely salt depleted patients.

As with other ACE inhibitors, in cases of prior diuretic treatment it is advisable either to discontinue the diuretic at least three days before starting treatment with trandolapril, or commence with 0.5 mg daily. If diuretic treatment is continued, plasma creatinine levels should be monitored.

Renal insufficiency.

If creatinine clearance is less than 10 mL/minute, treatment should be initiated and maintained at 0.5 mg daily. Patients with clearance rates greater than 10 mL/minute but less than or equal to 50 mL/minute should be initiated on 0.5 mg daily. The dose may be increased according to patient response, to a maximum daily dose of 1 mg.

Hepatic insufficiency.

Treatment should be initiated at 0.5 mg daily and adjusted according to therapeutic response.

Cardiac failure.

In hypertensive patients who also have congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients, therapy should be started at a dose of Dolapril 0.5 mg once daily under close medical supervision.

4.7 Effects on Ability to Drive and Use Machines

Ability to concentrate and react, and thus ability to drive or operate machinery, may be impaired due to the blood pressure lowering effects of ACE inhibitors. This may occur mainly during initiation of treatment, when changing over from other medication or during concomitant use of alcohol. Therefore after the first dose or subsequent increases in dose, it is not advisable to drive or operate machinery for several hours.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia).
In clinical trials, trandolapril doses of up to 16 mg have been administered and were well tolerated. There is no experience with overdosage. Symptoms expected with ACE inhibitors are severe hypotension, shock, stupor, bradycardia, electrolyte disturbance and renal failure. In the event of overdosage following recent ingestion, consideration should be given to emptying the stomach contents. Blood pressure should be monitored and, if hypotension develops, volume expansion should be considered.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Dolapril capsules come in four strengths and contain 0.5 mg, 1 mg, 2 mg or 4 mg of trandolapril.
The capsules also contain the following excipients: povidone, lactose monohydrate, maize starch, croscarmellose sodium and sodium stearylfumarate. The capsule shells contain titanium dioxide, gelatin, TekPrint SW-9008 Black Ink, brilliant blue FCF (1 mg and 2 mg), erythrosine (1 mg and 2 mg), allura red AC (1 mg and 2 mg) and sunset yellow FCF (1 mg only).
The capsules are gluten free.

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

Dolapril capsule is available in Aluminium/Aluminium blister packs of 28 capsules.

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