Consumer medicine information

Tarka

Trandolapril; Verapamil hydrochloride

BRAND INFORMATION

Brand name

Tarka

Active ingredient

Trandolapril; Verapamil hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tarka.

SUMMARY CMI

TARKA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using TARKA

TARKA contains the active ingredients trandolapril and verapamil hydrochloride. TARKA is used to treat hypertension (high blood pressure).

For more information, see Section 1. Why am I using TARKA in the full CMI.

2. What should I know before I use TARKA

Do not use if you have ever had an allergic reaction to any medicine containing trandolapril (or any other ACE inhibitor), any medicine containing verapamil or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use TARKA in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TARKA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TARKA

  • The usual dosage for TARKA is one tablet daily. The maximum dose of TARKA is one 4/240 mg tablet once daily.

More instructions can be found in Section 4. How do I use TARKA in the full CMI.

5. What should I know while using TARKA

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using TARKA.
  • Have your blood pressure checked when your doctor says, to make sure TARKA is working for you
  • If you feel light-headed or dizzy after taking your first dose of TARKA, or when your dose is increased, tell your doctor immediately.
  • Tell your doctor if you have excessive vomiting and/or diarrhoea while taking TARKA.
Things you should not do
  • Do not take eat grapefruit or drink grapefruit juice whilst taking TARKA.
  • Do not use TARKA to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking TARKA, or lower the dosage, without checking with your doctor.
Driving or using machines
  • TARKA may cause dizziness, light-headedness, or tiredness, in some people. Make sure you know how you react to TARKA; and if you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol
  • Avoid drinking alcohol while you are taking this medicine. You may experience greater blood pressure lowering effects than usual. You may experience worsening dizziness or light-headedness.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using TARKA? in the full CMI.

6. Are there any side effects?

Tell your doctor if the following worry you: dizziness, nausea, vomiting, diarrhoea, indigestion, persistent dry cough, headache, unusual tiredness, aching, tender or weak muscles and taste disturbance.

Tell your doctor immediately or go to your nearest hospital if you experience any serious side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

TARKA®

Active ingredient(s): trandolapril/verapamil hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using TARKA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TARKA.

Where to find information in this leaflet:

1. Why am I using TARKA
2. What should I know before I use TARKA
3. What if I am taking other medicines?
4. How do I use TARKA
5. What should I know while using TARKA
6. Are there any side effects?
7. Product details

1. Why am I using TARKA

TARKA contains two different types of medicines: verapamil hydrochloride in a slow release formulation, and trandolapril in an immediate release formulation.

  • Verapamil belongs to a group of medicines called calcium channel blockers.
    Calcium channel blockers work by opening up blood vessels, which lets more blood and oxygen reach the heart and at the same time lowers high blood pressure.
  • Trandolapril belongs to a group of medicines called Angiotensin Converting Enzyme (ACE) Inhibitors.
    ACE inhibitors work 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 your heart.

TARKA is used to treat hypertension (high blood pressure).

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.

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

Your doctor may have prescribed it for another reason.

There is no evidence that TARKA is addictive.

TARKA should not be given to children under the age of 18, as there have been no studies of its effects in children.

2. What should I know before I use TARKA

Warnings

Do not use TARKA if:

  • you have an allergy to:
    - any medicine containing trandolapril (or any other ACE inhibitor)
    - any medicine containing verapamil.
    - any of the ingredients listed at the end of this leaflet
    Some of the symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.
  • you have experienced symptoms such as wheezing, swelling of the face, lips, mouth, tongue, throat, hands or feet, intense itching or severe skin rashes with previous ACE inhibitor treatment or if you or a member of your family have had these symptoms either spontaneously, or in response to another medicine in the past (a condition called angioedema).
    Taking TARKA could cause this problem to happen again.
  • you are pregnant or planning to become pregnant.
    It may affect your developing baby if you take it during pregnancy.
  • you are breastfeeding
    The active ingredients in TARKA may pass into breast milk and there is a possibility that your baby may be affected.
  • you have severe kidney or liver problems
  • you have certain heart conditions (such as heart failure, a very slow heart rate, heart conduction problems, some irregular heartbeats, or disease of the heart muscle)
  • you have low blood pressure, (hypotension)
  • you are currently being treated with intravenous β-adrenoreceptor antagonists (with the exception of being treated in ICU
  • you undergo treatments where your blood is treated outside your body (extracorporeal treatments), such as haemodialysis with certain membranes, or LDL-apheresis (removal of LDL from your blood)
  • you have a history of angioedema (if you or a member of your family have had wheezing, swelling of the face, lips, mouth, tongue, throat, hands or feet, intense itching or severe skin rashes, either spontaneously, with previous ACE inhibitor treatment or in response to another medicine in the past)
  • you are taking any of the following medications, or medications containing these ingredients:
    - aliskiren (under certain conditions)
    - ivabradine
    - Direct Oral Anticoagulants (DOACs) which thin the blood such as dabigatran (under certain conditions)
    - neutral endopeptidase (NEP) inhibitors such as sacubitril or racecadotril.
    - sacubitril in combination with valsartan

Do not give this TARKA to a child under the age of 18 years.

TARKA's safety and effectiveness in children younger than 18 years have not been established.

Tell your doctor if you:

  • have allergies to any other medicines, foods, preservatives or dyes.
  • have or have had any of the following medical conditions:
    - any other heart problem, including aortic stenosis (narrowing of your aortic valve or aorta - the main artery leaving your heart)
    - blood vessel (circulatory) disease or a stroke
    - liver problems
    - kidney problems, including narrowing of the arteries to your kidneys (called renal artery stenosis) or need dialysis
    - high levels of potassium in your blood
    - recent vomiting or diarrhoea or if you are dehydrated
    - muscle conditions such as Duchenne muscular dystrophy, myasthenia gravis, Lambert-Eaton syndrome
    - connective tissue disease
    - dizzy spells
    - diabetes
  • are of African origin, you may have a higher risk of angioedema.
    In black patients, ACE inhibitors are less effective in lowering blood pressure than in white patients.
  • are taking a diuretic ('fluid' tablets), potassium supplements, on a low-salt diet, or use potassium-salt substitutes.
  • have or are about to have:
    - surgery or general anaesthetic
    - desensitisation treatment for an allergy e.g. to insect stings
    - regular dialysis, blood filtration or similar procedures
    - LDL removed from your blood (LDL-apheresis)
  • have an intolerance to some sugars. TARKA contains sugars (as lactose).

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor can discuss with you the risks and benefits involved.

3. What if I am taking other medicines?

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

Some medicines may interfere with TARKA and affect how it works. Please tell your doctor if you are taking any of the following:

  • Medicines used to treat heart problems or high blood pressure:
    - Beta-blockers e.g. atenolol, propranolol, metoprolol, etc
    - Diuretics (also called fluid tablets)
    - Angiotensin II receptor blockers (also called ARBs, A2RAs, or sartans)
    - Aliskiren
    - Ivabradine
    - Digoxin
    - neutral endopeptidase (NEP) inhibitors such as sacubitril or racecadotril
    - Any other medicines used to control an irregular heartbeat e.g. quinidine, flecainide, amiodarone, disopyramide, procainamide
    - Any other medicines used to control high blood pressure
  • Medicines used to treat or prevent blood clots (sometimes referred to as "blood thinners")
    - Direct Oral Anticoagulants (DOACs) which thin the blood such as dabigatran
    - aspirin, heparin
  • Medicines used to lower cholesterol
    - Statins such as atorvastatin, simvastatin or lovastatin
  • Medicines used to treat or prevent gout
    - Colchicine, sulfinpyrazone, allopurinol
  • Medicines used to lower blood glucose:
    - Anti-diabetic medicines such as insulin and any oral hypoglycaemic medicines, including metformin, glibenclamide or vildagliptin
  • Medicines used to treat psychological problems
    - Any medicines used to treat depression, anxiety, or psychosis; such as imipramine, buspirone, midazolam, lithium or tricyclic antidepressants.
  • Medicines used to treat epilepsy or seizures:
    - Phenytoin, carbamazepine, phenobarbital (phenobarbitone)
  • Medicines used to treat or prevent organ transplant rejection (immunosuppressants):
    - Such as ciclosporin, everolimus, sirolimus, tacrolimus and temsirolimus
  • Medicines used to treat infections or tuberculosis
    - Such as erythromycin, clarithromycin, telithromycin or rifampicin
    - Co-trimoxazole (trimethoprim and sulfamethoxazole)
  • Medicines used in the treatment of Human Immunodeficiency Virus (HIV):
    - Such as ritonavir
  • Medicines used in surgical procedures such as:
    - General anaesthetics used for inducing sleep
    - Muscle relaxants, including dantrolene
  • Medicines used to treat pain and inflammation (such as arthritis) or fever:
    - Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, diclofenac, meloxicam, indometacin, celecoxib
    - Injectable gold
  • Other medicines that may react with TARKA:
    - Potassium supplements, or large amounts of salt
    - Potassium - containing salt substitutes in your food (check the label)
    - Sympathomimetics - these may be found in some decongestants, cough / cold remedies and asthma medicines
    - Theophylline, a medicine used to treat asthma
    - Doxorubicin and cytostatic medicines, used to treat certain cancers
    - Cimetidine and other antacids, medicines commonly used to treat stomach ulcers and reflux
    - Neuromuscular blocking agents such as vecuronium

Avoid grapefruit juice, as this may increase the blood levels of verapamil.

This is not a complete list of medicines which may interfere with TARKA.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking TARKA. You may need to use different amounts of your medicine or take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TARKA.

4. How do I use TARKA

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

They may differ from the information contained in this leaflet. Your doctor will tell you how many tablets you will 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.

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

How much to take

  • The usual dosage for TARKA is one tablet daily.
  • The maximum dose of TARKA is one 4/240 mg tablet once daily.

When to take TARKA

  • Take TARKA at about the same time each day.
    Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
    TARKA should ideally be taken in the morning with or after food.
  • If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of TARKA.
  • Continue taking your medicine for as long as your doctor or pharmacist tells you.
    TARKA helps control your blood pressure, but it does not cure it.

How to take TARKA

  • Swallow the tablets whole with a full glass of water.
  • Do not crush or chew TARKA tablets.

If you forget to use TARKA

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 getting an unwanted side effect.

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

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

If you use too much TARKA

If you think that you have used too much TARKA, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose may include: a slow heartbeat, palpitations, chest pain, anxiety, feeling faint, dizzy or light-headed, and collapsing.

5. What should I know while using TARKA

Things you should do

  • Have your blood pressure checked when your doctor says, to make sure TARKA is working for you.
  • Drink plenty of water when you are using TARKA, especially if you sweat a lot (e.g. during hot weather or exercise).
    If you do not drink enough water while taking TARKA, you may feel faint or light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking TARKA.
  • Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.
  • If you are going to have surgery, tell the surgeon that you are taking this medicine.
  • Visit your doctor regularly so that they can check on your progress.
    Your doctor may ask you to have blood tests to check your liver from time to time to make sure the medicine is working and to prevent unwanted side effects.
  • If you are about to receive any dialysis, desensitisation treatment for an allergy e.g. to insect stings, or about to have LDL removed from your blood (LDL-apheresis), tell your doctor that you are taking this medicine.

Call your doctor straight away if you:

  • feel light-headed or dizzy after taking your first dose of TARKA, or when your dose is increased
  • have excessive vomiting and/or diarrhoea while taking TARKA.
    The loss of water and salt from your body may cause your blood pressure to drop too much.
  • become pregnant while you are taking this medicine

Remind any doctor, dentist or pharmacist you visit that you are using TARKA.

Things you should not do

  • Do not take eat grapefruit or drink grapefruit juice whilst taking TARKA.
  • Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking TARKA, 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 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TARKA affects you.

TARKA may cause dizziness, light-headedness, or tiredness, in some people. Make sure you know how you react to TARKA; and if you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Avoid drinking alcohol while you are taking this medicine.

You may experience greater blood pressure lowering effects than usual. You may experience worsening dizziness or light-headedness.

Looking after your medicine

  • Keep your tablets in the pack until it is time to take them.
    If you take the tablets out of the blister pack, they may not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

6. Are there any side effects?

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

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

If you are over 65 years of age you may have an increased chance of getting side effects. Report any side effects to your doctor promptly.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

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

Less serious side effects

Less serious side effectsWhat to do
  • persistent dry cough
  • taste disturbance
  • constipation
  • nausea, vomiting, diarrhoea or stomach upset/stomach pains
  • dizziness, light-headedness or vertigo
  • headache
  • unusual tiredness or weakness
  • aching, tender, or weak muscles not caused by exercise
  • flushing
  • excessive sweating
Speak to your doctor if you have any of these less serious side effects and they worry you.
This list includes the more common side effects of your medicine.

Serious side effects

Serious side effectsWhat to do
  • slow, fast, or irregular heart beat
  • shortness of breath (sometimes with tiredness, weakness and reduced ability to exercise), which may occur together with swelling of the feet and legs due to fluid build up
  • fever, upper stomach pain, feeling generally unwell
  • symptoms of sunburn which may occur more quickly than normal, severe blisters, skin rash, itching or flaking skin
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • tremor
Tell your doctor straight away, if you notice any of these serious side effects.
The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Very Serious side effects

Very Serious side effectsWhat to do
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • severe dizziness and confusion with visual disturbances and speech problems
  • rapid, shallow breathing, cold clammy skin, a rapid, weak pulse, dizziness, weakness and fainting
  • chest pain, fainting, collapse
Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of these very serious side effects.
This list includes very serious side effects. You may need urgent medical attention. These side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What TARKA contains

Active ingredient
(main ingredient)
  • TARKA 2/180 contains 2 mg of trandolapril and 180 mg of slow release verapamil hydrochloride as the active ingredients.
  • TARKA 4/240 contains 4 mg of trandolapril and 240 mg of slow release verapamil hydrochloride as the active ingredients.
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • docusate sodium
  • hyprolose
  • hypromellose
  • iron oxide black
  • iron oxide red
  • iron oxide yellow
  • lactose monohydrate
  • macrogol 400
  • macrogol 6000
  • magnesium stearate
  • povidone
  • colloidal anhydrous silica
  • sodium alginate
  • sodium stearylfumarate
  • maize starch
  • purified talc
  • titanium dioxide
Potential allergensTARKA contains sugars as lactose.

Do not take this medicine if you are allergic to any of these ingredients.

What TARKA looks like

TARKA comes in two types of tablets:

TARKA 2/180 - pink, oval, film coated tablets, marked with the numbers "182" on one side. The 2/180 mg strength is available in boxes of 28 tablets. (AUST R 104663)

TARKA 4/240 - red-brown, oval, film coated tablets, marked with the numbers "244" on one side. The 4/240 mg strength is available in boxes of 28 tablets. (AUST R 104664)

Who distributes TARKA

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in October 2023.

TARKA® is a Viatris company trade mark

TARKA_cmi\Oct23/00

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Tarka

Active ingredient

Trandolapril; Verapamil hydrochloride

Schedule

S4

 

1 Name of Medicine

Trandolapril/verapamil hydrochloride.

2 Qualitative and Quantitative Composition

Tarka 2/180 contains trandolapril 2 mg and verapamil 180 mg modified release as the active ingredients in pink, oval, film coated tablets. Tarka 2/180 also contain 107.00 mg lactose monohydrate.
Tarka 4/240 contains trandolapril 4 mg and verapamil 240 mg modified release as the active ingredients in red-brown, oval, film coated tablets. Tarka 4/240 also contain 110.37 mg lactose monohydrate.

Excipients with known effect.

Contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tarka 2/180 are pink, oval, film coated tablets embossed with '182' on one face.
Tarka 4/240 are red-brown, oval, film coated tablets embossed with '244' on one face.

4 Clinical Particulars

4.1 Therapeutic Indications

Tarka is indicated for the treatment of hypertension. Treatment should not be initiated with this fixed dose combination.

4.2 Dose and Method of Administration

The product should be swallowed whole with water ideally in the morning with or after food.

Adults.

The usual dosage is one tablet daily. The maximum dose of Tarka is 4/240 mg once daily.

Elderly.

Tarka has been studied in a limited number of elderly hypertensive patients only. Pharmacokinetic data show that the systemic availability of Tarka is higher in elderly compared to younger hypertensives. Some elderly patients might experience a more pronounced blood pressure lowering effect than others.

Children.

Tarka has not been studied in children and adolescents, therefore, use in this age group is not recommended.

Angina.

The safety and efficacy of Tarka has not been evaluated in the treatment of angina.

4.3 Contraindications

Tarka is contraindicated in:
Patients who are hypersensitive to trandolapril or any other ACE inhibitor, or to verapamil hydrochloride, or to any of the inactive ingredients.
Use in children and adolescents (< 18 years).
Patients concomitantly treated with intravenous β-adrenoreceptor antagonists (exception: intensive care unit; see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Because of the trandolapril component, Tarka is contraindicated in:
Pregnancy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Severe renal impairment (creatinine clearance < 30 mL/min).
Dialysis.
Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Liver cirrhosis with ascites.
Patients with a history of hereditary and/or idiopathic angioedema, or angioedema associated with previous treatment with an angiotensin converting enzyme inhibitor.
Hereditary/idiopathic angioedema.
Concomitant use with neprilysin (neutral endopeptidase, NEP) inhibitors such as sacubitril and racecadotril (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions 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 apheresis 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 polysulphone PSF) for haemodialysis.
Because of the verapamil hydrochloride component, Tarka is contraindicated in:
Severe left ventricular dysfunction (see Section 4.4 Special Warnings and Precautions for Use).
Hypotension (less than 90 mmHg systolic pressure) or cardiogenic shock.
Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).
Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see Section 4.4 Special Warnings and Precautions for Use). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil hydrochloride is administered.
Heart failure with reduced ejection fraction of less than 35%, and/or pulmonary wedge pressure above 20 mmHg.
Patients concomitantly administered ivabradine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Simultaneous initiation of treatment with dabigatran etexilate and oral verapamil (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Treatment initiation with oral verapamil in patients following major orthopaedic surgery who are already treated with dabigatran etexilate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Combination product (Tarka).

Tarka is a combination of verapamil and trandolapril. Adverse events may result from either component of this medicine (see Section 4.4 Special Warnings and Precautions for Use, Trandolapril component; Section 4.4 Special Warnings and Precautions for Use, Verapamil component).

Renal impairment.

The combination product Tarka has not been evaluated in patients with impaired renal function, however, information on the individual components is provided (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Trandolapril component; Section 5.2 Pharmacokinetic Properties, Verapamil component).

Hepatic impairment.

The combination product Tarka has not been evaluated in patients with impaired hepatic function, however, information on the individual components is provided (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Trandolapril component; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Verapamil component).

Lactose.

Tarka contains lactose monohydrate, therefore, patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine.

Trandolapril component.

Angioedema.

Severe life-threatening angioedema has been reported with most of the ACE inhibitors. The overall incidence is approximately 0.1% to 0.2%. There seems to be no sex difference in the incidence of angioedema, or in the predisposition to angioedema, in patients with heart failure or hypertension. ACE inhibitors have been shown to cause a higher rate of angioedema in black patients than in non-black patients. 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 involving the tongue, glottis or larynx requires immediate subcutaneous administration of 0.3-0.5 mL of adrenaline (epinephrine) solution (1:1000) along with other therapeutic measures as appropriate.
Where 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.
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 intervals.
There are case reports where changing the patient over to another ACE inhibitor was followed by a 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).
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).
Patients receiving coadministration of an ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or vildagliptin may be at increased risk for angioedema.
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; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of trandolapril therapy. If treatment with sacubitril/valsartan is stopped, trandolapril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients experiencing angioneurotic oedema must immediately discontinue treatment and be monitored until the oedema resolves.

Anaphylactoid reactions during desensitisation.

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

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 that 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 Interactions with Other Medicines and Other Forms of Interactions; 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 postmyocardial infarction.

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

Use in renal impairment.

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 is 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 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 trandolapril have been associated with the occurrence of proteinuria (up to 0.7%) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium sparing diuretics or high doses of other diuretics, limited cardiac reserve, or treatment with a non-steroidal anti-inflammatory drug.

Proteinuria.

Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.

Combination with angiotensin II receptor blockers or 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 higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

As trandolapril is a pro-drug metabolised in the liver to its active moiety, particular caution and close monitoring should be applied to patients with impaired liver 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).

Cough.

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% to 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 2/3 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 non-smokers 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 that 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 the 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, in those consuming potassium-containing salt substitutes and in those patients taking other active substances associated with increases in serum potassium (e.g. co-trimoxazole also known as trimethoprim/sulfamethoxazole) concomitantly. Diabetics, and particularly elderly diabetics and/or those having 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 leukopenia/ neutropenia) have been reported with ACE inhibitors. The risk of neutropenia appears to be dose and type-related and is dependent in 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 leukopenia and neutropenia have been single, transient occurrences without any associated clinical symptoms. In addition, data to establish a causal relationship are currently lacking.
It is recommended that periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease, renal disease (serum creatinine ≥ 180 micromol/L) and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive.

Dermatological reactions.

Dermatological reactions characterised by maculo-papular 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 1-3 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 trandolapril adjusted if needed.

Valvular stenosis.

Trandolapril 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.

LDL apheresis.

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

Verapamil component.

Heart failure.

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary oedema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g. ejection fraction less than 30%, pulmonary wedge pressure above 20 mmHg, or severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Acute myocardial infarction.

Use with caution in patients with acute myocardial infarction complicated by bradycardia, marked hypotension, or left ventricular dysfunction.

Hypotension.

Occasionally, the pharmacological action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine).

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a co-existing accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see Section 4.3 Contraindications).
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Atrioventricular block.

Verapamil affects the AV and SA nodes and prolongs AV conduction time. Use with caution as development of second- or third-degree AV block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block requires discontinuation in subsequent doses of verapamil hydrochloride and institution of appropriate therapy, if needed.
Verapamil hydrochloride affects the AV and SA nodes and may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients.
Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately.
In studies using Isoptin SR, prolongation of PR interval values of 0.21 to 0.22 sec occurred in 59 of 3,670 patients (= 1.6%) and to 0.23 to 0.28 sec in 4 patients whose PR intervals had been normal before treatment (0.1 to 0.2 sec). Second or third degree AV block was not observed. Higher degrees of AV block, however, were infrequently (0.8%) observed.

Patients with hypertrophic cardiomyopathy (IHSS).

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen: three patients died in pulmonary oedema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary oedema and/or severe hypotension; abnormally high (over 20 mmHg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients.
Concomitant administration of quinidine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary oedema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

Use in hepatic impairment.

Since verapamil is highly metabolised by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours, hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see Section 4.9 Overdose) should be carried out.

Elevated liver enzymes.

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge. Half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain), in addition to elevations of SGOT (AST), SGPT (ALT) and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Use in patients with impaired neuromuscular transmission.

Verapamil should be used with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).
It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Use in renal impairment.

About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by haemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see Section 4.9 Overdose).

Use in the elderly.

Pharmacokinetic data show that the systemic availability of both components of Tarka is higher in elderly compared with young hypertensives. Some elderly patients might experience a more pronounced blood pressure lowering effect than others. Evaluation of the renal function at the beginning of treatment is recommended as is careful monitoring of blood pressure when commencing treatment with Tarka 2/180.

Paediatric use.

No data available.

Carcinogenicity and mutagenicity.

Carcinogenicity studies with the trandolapril/ verapamil combination have not been performed.

Trandolapril.

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 in long-term rat (24 months, up to 8 mg/kg/day) or mouse (18 months, up to 25 mg/kg/day) studies with trandolapril.

Verapamil.

An 18 month toxicity study in rats, at a low multiple (sixfold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses up to 120 mg/kg/day, approximately 12 times the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day).
Neither trandolapril nor verapamil (either alone or in combination) were genotoxic in standard test batteries for gene mutations and chromosomal damage.

Effects on laboratory tests.

Haematology.

Low white cells, low neutrophils, low lymphocytes and low platelets.

Serum electrolytes.

Hyperkalaemia, hyponatraemia.

Renal function tests.

Increased creatinine, BUN.

Liver function tests.

Increased SGOT, SGPT, LDH, alkaline phosphatase and/or serum bilirubin.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The section below summarises potential drug interactions between the components of Tarka and other therapeutic agents.
In vitro metabolic studies indicate that verapamil hydrochloride is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil, therefore, patients should be monitored for drug interactions. Coadministration of verapamil and a drug primarily metabolised by CYP3A4 or being a P‐gp substrate may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.

NEP inhibitors.

Trandolapril component.

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; Section 4.4 Special Warnings and Precautions for Use).

Ivabradine.

Verapamil component.

Concomitant administration of verapamil and ivabradine is contraindicated. Ivabradine use in combination with verapamil is associated with increased plasma concentrations of ivabradine and additional heart rate lowering effects (see Section 4.3 Contraindications).

Dabigatran.

Verapamil component.

Use of dabigatran with verapamil may increase the bioavailability of dabigatran. Verapamil sustained release: increased dabigatran (Cmax up to 90% and AUC up to 70%). When co-administered with oral verapamil, the dose of dabigatran may need to be reduced (refer to dabigatran Product Information for dabigatran dosing instructions) as the risk of bleeding may increase.
No meaningful interaction was observed when verapamil was given 2 hours after dabigatran etexilate (increase of Cmax by about 10% and AUC by about 20%).
Close clinical surveillance is recommended when verapamil is combined with dabigatran etexilate and particularly in the occurrence of bleeding, notably in patients having mild to moderate renal impairment.
Simultaneous initiation of treatment with dabigatran etexilate and oral verapamil is contraindicated (see Section 4.3 Contraindications).
Treatment initiation with oral verapamil in patients following major orthopaedic surgery who are already treated with dabigatran etexilate is contraindicated (see Section 4.3 Contraindications).

Other direct oral anticoagulants (DOACs).

Use of DOACs with verapamil may increase the absorption of DOACs since they are P-glycoprotein (P‐gp) substrates. If applicable, coadministration with verapamil may also reduce elimination of DOACs which are metabolised by CYP3A4, and this may increase the systemic bioavailability of DOACs.
When co-administered with oral verapamil, the dose of DOAC may need to be reduced (refer to DOAC Product Information for DOAC dosing instructions) as the risk of bleeding may increase especially in patients with further risk factors.

Heparin.

Trandolapril component.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Intravenous beta-blockers.

Intravenous beta-blockers should not be administered during treatment with Tarka (see Section 4.3 Contraindications). The combination of verapamil with beta-blockers may provide a strong AV-conduction disturbance, which in some cases may lead to severe bradycardia: serious cardiodepression may also arise.

Beta-blockers.

Verapamil component.

Concomitant therapy with beta-adrenergic blockers and verapamil component may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contractility and induction of heart failure and potentiated hypotension. The addition of beta-blocker therapy (ophthalmic or oral) to patients on verapamil, including Tarka should be done only with caution, and close monitoring.

Trandolapril component.

Beta adrenergic blocking drugs will increase the anti-hypertensive effect of ACE inhibitors, therefore, the patient will need to be closely supervised.

Antihypertensive agents.

Verapamil component.

Verapamil administered concomitantly with oral antihypertensive agents (e.g. vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored.

Concomitant diuretic therapy.

Trandolapril component.

As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Tarka. The possibility of exacerbation of hypotensive effects with Tarka may be minimised by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Tarka. If it is not possible to discontinue the diuretic, the starting dose of Tarka should be reduced.

Agents affecting serum potassium.

Trandolapril component.

Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium sparing diuretics (spironolactone, triamterene or amiloride), potassium supplements or potassium containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalaemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium.

Co-trimoxazole (trimethoprim/sulfamethoxazole).

Trandolapril component.

Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use).

Combination with angiotensin II receptor blockers or 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 higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

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

Trandolapril component.

The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at 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.

Alpha-blockers.

Verapamil component.

Additive hypotensive effect (e.g. prazosin, terazosin). Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Verapamil has been reported to cause the elevation of prazosin plasma levels.

Antiarrhythmics.

Verapamil component.

When combined with antiarrhythmic drugs, mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension) may occur.

Quinidine.

Verapamil component.

In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Pulmonary oedema may occur in patients with hypertrophic obstructive cardiomyopathy with concomitant use of verapamil and quinidine. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Antiasthmatics.

Theophylline.

Verapamil component.

Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline.

Anticonvulsants.

Carbamazepine.

Verapamil component.

Verapamil may increase carbamazepine concentrations during combined therapy producing carbamazepine side effects such as diplopia, headache, ataxia or dizziness.
Phenytoin.

Verapamil component.

Verapamil therapy may alter plasma levels of phenytoin.

Antidiabetics.

Trandolapril component.

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.
Vildagliptin.

Trandolapril component.

Patients taking concomitant vildagliptin may be at increased risk for angioedema.

Anti-infectives.

Rifampicin.

Verapamil component.

Blood pressure lowering effect may be reduced.
Erythromycin, clarithromycin and telithromycin.

Verapamil component.

Erythromycin, clarithromycin and telithromycin therapy may increase serum levels of verapamil.

Barbiturates.

Phenobarbital (phenobarbitone).

Verapamil component.

Phenobarbital (phenobarbitone) therapy may increase verapamil clearance.

Benzodiazepines and other anxiolytics.

Midazolam.

Verapamil component.

Verapamil therapy may increase serum levels of midazolam.

Cardiac glycosides.

Digoxin.

Verapamil component.

Clinical use of verapamil in digitalised patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin level by 50-75% during the first week of therapy, and this can result in digoxin toxicity. Maintenance digoxin doses should be reduced when Tarka is administered and the patient should be carefully monitored to avoid over or underdigitalisation. Whenever overdigitalisation is suspected, the daily dose of digoxin should be reduced or temporarily discontinued. Upon discontinuation of any verapamil containing regime including Tarka, the patient should be reassessed to avoid underdigitalisation.

H2-receptor antagonists.

Cimetidine.

Verapamil component.

Possible elevation of verapamil plasma levels.

Immunologics/ immunosuppressants.

Ciclosporin.

Trandolapril component.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Verapamil component.

Verapamil therapy may increase serum levels of ciclosporin.
Mammalian target of rapamycin (mTOR) inhibitors.

Trandolapril component.

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

Verapamil component.

Verapamil therapy may increase serum levels of everolimus and sirolimus.
Tacrolimus.

Verapamil component.

Verapamil therapy may increase serum levels of tacrolimus.

Inhalation anaesthetics.

Verapamil component.

Animal experiments have shown that inhalation anaesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anaesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.

Trandolapril component.

The effects of certain anaesthetics may be enhanced by ACE inhibitors.

Lipid lowering agents.

HMG-CoA reductase inhibitors.

Verapamil component.

Treatment with HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG-CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.
Verapamil may increase serum levels of HMG-CoA reductase inhibitors primarily metabolised by CYP3A enzymes (e.g. simvastatin and atorvastatin). Similarly, verapamil concentrations may be increased by atorvastatin. Consider using caution when these HMG-CoA reductase inhibitors and verapamil are concomitantly administered. The concomitant administration of verapamil and high doses of simvastatin has been reported to increase the risk of myopathia/ rhabdomyolysis.
Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil.

Metformin.

Co-administration of verapamil with metformin may reduce the efficacy of metformin.

Lithium.

Verapamil component.

Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy, with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.

Trandolapril component.

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 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.

HIV antiviral agents.

Verapamil component.

Due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or the dose of verapamil may be decreased.

Sulfinpyrazone.

Verapamil component.

Blood pressure lowering effect may be reduced.

Neuromuscular blocking agents.

Verapamil component.

Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarising). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Nitrates.

Verapamil component.

Verapamil has been given concomitantly with short and long acting nitrates without any undesirable drug interactions. The pharmacological profile of both drugs and the clinical experience suggest beneficial interactions.

NSAIDs.

Trandolapril component.

Drugs with prostaglandin synthetase inhibitory properties (e.g. indometacin) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors and may increase the risk of hyperkalaemia. As with all antihypertensives, NSAIDs may reduce the antihypertensive effects of trandolapril. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with trandolapril. Furthermore, it has been described that NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with compromised renal function.
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. The concomitant use of aspirin with verapamil can increase the side effect profile of aspirin (may increase the risk of bleeding).

Antineoplastics.

Doxorubicin.

Verapamil component.

Caution should be used when oral verapamil is administered in combination with doxorubicin due to the potential for increased doxorubicin levels.

Colchicine.

Verapamil component.

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. Combined use is not recommended.

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 including trandolapril.

Dantrolene.

Verapamil component.

Hyperkalaemia and myocardial depression have been reported in a coronary artery disease patient treated with verapamil following administration of dantrolene. Combined use of verapamil and dantrolene is not recommended.

Sodium.

For Tarka 240 mg/4 mg tablets: the medicinal product contains 1.6 mmol (or 37.3 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.
For Tarka 180 mg/2 mg tablets: the medicinal product contains 1.2 mmol (or 28.0 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

General.

Ethanol (alcohol).

Verapamil component.

Verapamil may inhibit the metabolism of alcohol increasing its CNS depressant effects. Ethanol increases the risk of hypotension.

Trandolapril component.

Alcohol increases the bioavailability of ACE inhibitors.
Antacids.

Trandolapril component.

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

Verapamil component.

Grapefruit juice may increase the plasma levels of verapamil and, therefore, grapefruit and its juice should not be taken with Tarka.

Other.

Trandolapril component.

Anaphylactoid reactions to high flux polyacrylonitrile membranes used in haemodialysis have been reported in patients treated with ACE inhibitors. As with other antihypertensives of this chemical class, this combination should be avoided when prescribing ACE inhibitors to renal dialysis patients.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide may increase the risk of leukopenia if used concomitantly with ACE inhibitors.
Agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neurone blocking agents) may be used with caution.
The antihypertensive effects of ACE inhibitors may be reduced by sympathomimetics. Patients should be carefully monitored.
As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension.
No pharmacokinetic interaction has been noted when trandolapril was combined with, furosemide or nifedipine. No modification of the anticoagulant properties of warfarin has been observed following simultaneous administration with trandolapril.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The potential effect of the trandolapril/ verapamil combination on fertility has not been evaluated in animal studies.

Trandolapril.

Reproduction studies in rats with trandolapril did not show any impairment of fertility at oral doses up to 100 mg/kg/day (600 mg/m2/day), which is ca. 200 times the maximum clinical dose based on body surface area. 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.

Verapamil.

Reproduction studies in female rats with verapamil at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.
(Category D)
As with all ACE inhibitors, Tarka should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Tarka 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.
Tarka is contraindicated during pregnancy, as it carries the potential to produce foetal hypoxia associated with maternal hypotension (due to the verapamil component) and may, during the second and third trimesters, cause a range of abnormalities (renal dysfunction and oligohydramnios due to the trandolapril component). These effects can be associated with foetal death in utero.

Trandolapril.

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. 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. As with all ACE inhibitors, when pregnancy is detected, Tarka should be discontinued.
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 limit contractures, craniofacial deformities, hypoplasic 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.

Verapamil.

Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and six (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded foetal growth and development, probably because of adverse maternal effects reflected in the reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. Verapamil hydrochloride crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil may inhibit contractions if used at the end of the pregnancy. Also, foetal bradycardia and hypotension cannot be excluded, based on the pharmacological properties.
 The use of Tarka is contraindicated in breastfeeding.
Verapamil and trandolapril or its metabolites are excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil and trandolapril, nursing should be discontinued while Tarka is administered. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on Ability to Drive and Use Machines

Depending on individual susceptibility, the patient's ability to drive a vehicle or operate machinery may be impaired due to blood pressure lowering effects of Tarka, especially in the initial stages of treatment, or when changing over from another drug. Therefore, after the first dose it is not advisable to drive or operate machinery for several hours.
Tarka may increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8 Adverse Effects (Undesirable Effects)

The listed ADRs have been reported during the clinical phase, the post-marketing surveillance or the phase IV clinical trials.

Reactions during clinical trials with fixed dose combination product Tarka (or the combination of verapamil + trandolapril).

Adverse events (regardless of causality) which were observed in more than 1% of patients (regardless of causality) in the double blind phase of eight Tarka pivotal phase II and III clinical studies (MPF/K9007, MPF/K9301, TV-031-HTN, TV-50-HTN, TV-51-HTN, VT 020, VT 067 and VT 082), or in the open label long-term phase of TV-031-HTN, are depicted in Table 1. Within each system organ class, the reactions are ranked under headings of frequency.
The following convention is used for the frequencies: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). When frequency cannot be estimated from the available data, category frequency: not known (cannot be estimated from the available data) applies.
Additional significant adverse events seen with verapamil hydrochloride are listed by body system. See Table 2.
Additional significant adverse events seen with trandolapril are listed by body system. See Table 3.
The following adverse events have been reported with ACE inhibitors as a class. See Table 4.

Reporting suspected adverse effects.

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

4.9 Overdose

Symptoms.

The highest dose used in clinical trials was 16 mg of trandolapril which produced no signs or symptoms of intolerance. During overdose with Tarka, the following symptoms may occur due to the verapamil hydrochloride component: hypotension, bradycardia, AV block and asystole, negative inotropy and acute respiratory distress syndrome. Fatalities have occurred as a result of overdose.
During overdose with Tarka, the following symptoms may occur due to the ACE inhibitor component: severe hypotension, shock, stupor, bradycardia, electrolyte disturbance, renal failure, hyperventilation, tachycardia, palpitations, dizziness, anxiety, and cough.

Treatment.

After ingestion of an overdose of trandolapril/ verapamil tablets, total intestinal lavage should be considered. Further absorption of verapamil present in the gastrointestinal tract should be prevented by gastric lavage, administration of an absorbent (activated charcoal) and a laxative.
Except for general measures (maintenance of an adequate circulation volume with plasma or plasma replacements) against severe hypotension (e.g. shock), inotropic support with dopamine, dobutamine or isoprenaline can also be administered.
Treatment of Tarka overdose should be mainly supportive. Treatment of overdose of the verapamil hydrochloride component includes administration of parenteral calcium. Beta-adrenergic stimulation and gastrointestinal irrigation have been used in the treatment of verapamil hydrochloride overdose. Due to the potential for delayed absorption of the sustained release product, patients may require observation and hospitalisation for up to 48 hours. Verapamil hydrochloride cannot be removed by haemodialysis.
The recommended treatment of trandolapril overdose is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. If ingestion is recent, take measures to eliminate trandolapril (e.g. emesis, gastric lavage, administration of absorbents and sodium sulfate). It is not known whether trandolapril (or the active metabolite, trandolaprilat) can be removed via haemodialysis. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Trandolapril.

Trandolapril is a long acting, highly lipophilic, non-peptide, angiotensin converting enzyme (ACE) inhibitor with a carboxyl group but without a sulphydryl group. Trandolapril suppresses the plasma renin-angiotensin-aldosterone system. Renin is an endogenous enzyme synthesised by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE), a peptidyldipeptidase, to angiotensin II. Angiotensin II is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity.
Another function of the converting enzyme is to degrade the potent vasodepressive kinin peptide, bradykinin, to inactive metabolites. Therefore inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin system, which contributes to peripheral vasodilation by activating the prostaglandin system. It is possible that this mechanism is involved in the hypotensive effects of ACE inhibitors and is responsible for certain side effects. In patients with hypertension, administration of ACE inhibitors results in a reduction of supine and standing blood pressure to about the same extent with no compensatory increase in heart rate. Peripheral arterial resistance is reduced with either no change or an increase in cardiac output. There is an increase in renal blood flow and glomerular filtration rate is usually unchanged. Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long-term therapy. Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure.
The antihypertensive effect of trandolapril sets in one hour post-dose and lasts for up to 48 hours, but trandolapril does not interfere with the circadian blood pressure pattern.
Trandolapril 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 70-80% for a 48-hour period after a dose. Thus, at steady state, the antihypertensive effect of trandolapril is maintained for up to 48 hours after a dose. Trandolapril is, however, administered as a single daily dose to achieve and maintain effective steady-state levels.

Verapamil.

Verapamil hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verapamil hydrochloride is present as a racemic mixture and different activities reside in the two enantiomers. The pharmacological action of verapamil is due to inhibition of the influx of calcium ions through the slow channels of the cell membrane of vascular smooth muscle cells and of the conductile and contractile cells in the heart. Verapamil reduces arterial pressure, both at rest and at a given level of exercise, by dilating peripheral arterioles. This reduction in total peripheral resistance (afterload) reduces myocardial oxygen requirements and energy consumption. Verapamil reduces myocardial contractility. The negative inotropic activity of verapamil can be compensated by the reduction in total peripheral resistance. The cardiac index will not be decreased except in patients with pre-existing left ventricular dysfunction.
Verapamil does not interfere with sympathetic regulation of the heart because it does not block the beta-adrenergic receptors. Asthma and similar conditions, therefore, are not contraindications to verapamil.

Tarka.

Neither animal studies nor healthy volunteer studies could demonstrate pharmacokinetic or renin angiotensin system interactions between verapamil and trandolapril. The observed synergistic activity of these two drugs must therefore be due to their complementary pharmacodynamic actions.
In clinical trials, Tarka was more effective in reducing high blood pressure than either drug alone.
Tarka does not adversely influence glucose, insulin or lipid parameters in patients with hypertension and type II (non-insulin dependent) diabetes mellitus with or without elevated cholesterol and/or triglyceride levels.
Tarka reduces proteinuria to a greater extent than the individual components in patients with diabetic or non-diabetic proteinuria.

Clinical trials.

In controlled clinical trials, once daily doses of Tarka (trandolapril 4 mg/ verapamil SR 240 mg or trandolapril 2 mg/ verapamil SR 180 mg), decreased placebo-corrected seated pressure (systolic/ diastolic) 24 hours after dosing by about 7-12/ 6-8 mmHg. Each of the components of Tarka added to the antihypertensive effect. Treatment effects were consistent across age groups (< 65, ≥ 65 years), and gender (male, female). Blood pressure reductions were significantly greater for the Tarka combinations than for either of the respective components used alone. The antihypertensive effects of Tarka have continued during therapy for at least 1 year.
The tabulated results of the pivotal studies involving Tarka 2/180 and Tarka 4/240 are presented in Tables 5 and 6, respectively.

5.2 Pharmacokinetic Properties

Trandolapril.

Orally administered trandolapril is absorbed rapidly. Bioavailability is 40-60% and independent of the presence of food. The time to peak plasma concentration is about 30 minutes to two hours.
Trandolapril disappears very rapidly from plasma and its half-life is less than one hour. It is hydrolysed in plasma to form trandolaprilat, a specific ACE inhibitor. The time to peak plasma concentration of trandolaprilat is four to six hours and the amount of trandolaprilat formed is independent of food intake. Plasma protein binding of trandolaprilat is 94%. Trandolaprilat binds with great affinity to ACE and this is a saturable process. Most of the circulating trandolaprilat binds to albumin in a nonsaturable process. Steady state of trandolaprilat, after multiple once daily dosing is reached after about four days in healthy volunteers as well as in younger and elderly hypertensive patients. The effective elimination half-life is 22 hours and the terminal half-life of elimination is between 47 and 98 hours depending on dose. This terminal phase probably represents binding/ dissociation kinetics of the trandolapril/ ACE complex.
Ten to fifteen percent of an administered trandolapril dose is excreted as unchanged trandolaprilat in urine. Following oral administration of radioactive labelled trandolapril, 33% of radioactivity is recovered in urine and 66% in faeces.
The renal clearance of trandolaprilat shows a linear correlation with creatinine clearance. The trandolaprilat plasma concentration is significantly higher in patients whose creatinine clearance is < 30 mL/min. Therefore, if treatment with Tarka is desirable, it is recommended that the trandolapril dose should be established before starting Tarka. Once the trandolapril dose has been established, the Tarka formulation consistent with the established trandolapril dose should be selected. Following repeated administration to patients with chronic renal dysfunction, steady state is, however, also reached after four days, independently of the extent of kidney function impairment. The trandolapril plasma concentration may be 10 times higher in patients with liver cirrhosis than in healthy volunteers. The plasma concentration and renal extraction of trandolaprilat are also increased in cirrhotic patients, albeit to a lesser extent. Trandolapril(at) kinetics are unchanged in patients with compensated hepatic dysfunction.

Verapamil.

About 90% of orally administered verapamil is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. The presence of food has no effect on the bioavailability of verapamil.
The mean time to peak plasma concentration is 4 to 15 hours*. The peak plasma concentration of norverapamil is attained about 5 to 15 hours* post-dose. Steady state after multiple once daily dosing is reached after three to four days. Plasma protein binding of verapamil is about 90%.
The mean elimination half-life in single dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration.
Metabolite excretion is in the urine (70%) and in the faeces (16%). Norverapamil is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacological activity of verapamil and accounts for 6% of excreted drug. The steady-state plasma concentrations of norverapamil and verapamil are similar. Verapamil kinetics are not altered by renal function impairment. The bioavailability and elimination half-life of verapamil are increased in patients with liver cirrhosis. Verapamil kinetics are, however, unchanged in patients with compensated hepatic dysfunction. Kidney function has no effect on verapamil elimination.
(*Verapamil Filmtab).

Tarka.

As there are no known kinetic interactions between verapamil and trandolapril or trandolaprilat, the single agent kinetic parameters of these two drugs apply to the combination product as well.

Special populations.

Ethnic differences.

In black patients, ACE inhibitors are less effective in lowering blood pressure than in white patients.

5.3 Preclinical Safety Data

Genotoxicity.

See Section 4.4 Special Warnings and Precautions for Use.

Carcinogenicity.

See Section 4.4 Special Warnings and Precautions for Use.

6 Pharmaceutical Particulars

6.1 List of Excipients

Maize starch, lactose monohydrate, povidone, hypromellose, sodium stearylfumarate, microcrystalline cellulose, sodium alginate, magnesium stearate, hyprolose, macrogol 400, macrogol 6000, purified talc, colloidal anhydrous silica, docusate sodium, titanium dioxide, iron oxide red CI 77491, iron oxide yellow CI 77492, iron oxide black CI 77499.

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

Tarka 2/180: Packed in PVC/PVDC/aluminium blister packs of 14*, 28, 30*, 50*, 56*, 98*, 280*.
Tarka 4/240: Packed in PVC/PVDC/aluminium blister packs of 14*, 28, 30*, 50*, 56*, 98*, 280*.
*Not currently marketed in Australia.

Australian Register of Therapeutic Goods (ARTG).

AUST R 104663 - Tarka 2/180 trandolapril 2 mg and verapamil hydrochloride 180 mg tablet blister pack.
AUST R 104664 - Tarka 4/240 trandolapril 4 mg and verapamil hydrochloride 240 mg tablet blister pack.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Trandolapril is a white or almost white, crystalline substance that is soluble in chloroform, dichloromethane and methanol. It is slightly soluble in water and sparingly soluble in hydrochloric acid.
Verapamil hydrochloride is an almost white, crystalline powder, practically free of odour, with a bitter taste. It is soluble in water, freely soluble in chloroform, sparingly soluble in alcohol and practically insoluble in ether.

Chemical structure.

Trandolapril.


Chemical name: (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3- phenylpropyl]amino]propanoyl]octahydro-1H-indole-2-carboxylic acid. C24H34N2O5, MW: 430.54.

Verapamil.


Chemical name: benzeneacetonitrile, α-[3-[{2-(3,4-dimethoxyphenyl)ethyl}methylamino] propyl]-3,4- dimethoxy-α -(1-methylethyl) monohydrochloride. C27H38N2O4.HCl, MW: 491.08.

CAS number.

Trandolapril: 87679-37-6.
Verapamil: 152-11-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes