Consumer medicine information

Cadivast

Amlodipine; Atorvastatin

BRAND INFORMATION

Brand name

Cadivast

Active ingredient

Amlodipine; Atorvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cadivast.

SUMMARY CMI

CADIVAST®

Consumer Medicine Information (CMI) summary

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

1. Why am I taking CADIVAST?

CADIVAST contains the active ingredient amlodipine besilate and atorvastatin calcium trihydrate. It is used to treat high blood pressure and high cholesterol (fat in the blood) and angina (a certain type of chest pain). CADIVAST is also used to help reduce the risk of having a heart attack or stroke in people who have high blood pressure and coronary heart disease (CHD) or who are at risk of CHD (for example, if they have diabetes, a history of stroke, or small blood vessel disease). For more information, see Section 1. Why am I taking CADIVAST? in the full CMI.

2. What should I know before I take CADIVAST?

Do not use if you have ever had an allergic reaction to CADIVAST 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 take CADIVAST? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CADIVAST 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 take CADIVAST?

CADIVAST is taken once a day. Your doctor will decide which strength is suitable for you. More instructions can be found in Section 4. How do I take CADIVAST? in the full CMI.

5. What should I know while taking CADIVAST?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking CADIVAST.
  • Follow the directions from your doctor about regular testing.
Things you should not do
  • Do not stop taking this medicine suddenly.
  • Do not take CADIVAST to treat any other conditions unless your doctor tells you to.
Driving or using machines
  • Be careful driving or operating machinery until you know how CADIVAST affects you.
  • CADIVAST may cause dizziness or drowsiness in some people and affect alertness.
Drinking alcohol
  • Avoid drinking large quantities of alcohol.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the pack until it is time to take them.
  • Keep CADIVAST where children cannot reach it.

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

6. Are there any side effects?

Speak to your doctor if you have any of these: headache; flushing; dizziness; tiredness or weakness; drowsiness or sleepiness; stomach pain or nausea (feeling sick); constipation, diarrhoea, wind; heartburn, indigestion; urine infection; stuffy or runny nose; nose bleeds; rash. Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you have any of these: symptoms of allergy such as skin rash, itching, swelling of the face, lips, mouth, throat or neck which may cause difficulty in swallowing and breathing; shortness of breath; unexpected muscle pain, tenderness or weakness not caused by exercise (particularly if you also feel unwell or have a fever); changes in heart beat either fast, slow or irregular; chest pain; sudden severe headache which may be accompanied by nausea, vomiting, loss of sensation, tingling in any part of the body or ringing in the ears; severe blisters and bleeding of the lips, eyes, mouth, nose or genitals; severe upper stomach pain often with nausea and vomiting. 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

CADIVAST®

Active ingredient(s): amlodipine (as besilate) and atorvastatin (as calcium trihydrate)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking CADIVAST?

CADIVAST contains the active ingredient amlodipine and atorvastatin.

Amlodipine belongs to a group of medicines called calcium channel blockers. They work by relaxing your blood vessels, making it easier for your heart to pump blood around the body and help increase the supply of blood and oxygen to your heart. Calcium channel blockers do not change the amount of calcium in your blood or bones.

Atorvastatin belongs to a group of medicines called statins. It works by reducing the amount of cholesterol made by the liver. It reduces the 'bad' cholesterol and can raise the 'good' cholesterol. Atorvastatin also helps to protect you from a heart attack or stroke.

CADIVAST may be used alone, or in combination with other medicines, to treat your condition.

CADIVAST is used to treat:

  • high blood pressure and high cholesterol (fat in the blood)
  • angina (a certain type of chest pain)
  • people who have high blood pressure and coronary heart disease (CHD) or who are at risk of CHD (for example, if they have diabetes, a history of stroke, or small blood vessel disease). In these people, CADIVAST is used to help reduce the risk of having a heart attack or stroke.

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

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

Use in children

There is not enough information to recommend the use of this medicine for children.

Use in the elderly

If you are 65 years or older, you should be especially careful while taking CADIVAST. Report any side effects promptly to your doctor.

Some people in this age group may be more likely to experience side effects such as swelling of the feet and ankles, muscle cramps and dizziness.

What is high blood pressure?

There are usually no symptoms of high blood pressure (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.

What is cholesterol?

Everyone has cholesterol in their blood. It is a type of blood fat needed by the body for things such as building cell lining, making bile acids (which help to digest food) and some hormones. However, too much cholesterol can be a problem.

Cholesterol is present in many foods and is also made in your body by the liver. If your body makes too much cholesterol or you take too much cholesterol in your diet, then your level becomes too high.

High cholesterol is more likely to occur with certain diseases or if you have a family history of high cholesterol.

There are different types of cholesterol. LDL, or low-density lipoprotein, is the 'bad' cholesterol that can block your blood vessels. HDL, or high-density lipoprotein, is the 'good' cholesterol that is thought to remove the 'bad' cholesterol from the blood vessels.

When you have high levels of 'bad' cholesterol in your blood, it may begin to 'stick' to the inside of your blood vessels instead of being carried to the parts of the body where it is needed. Over time, this can form hard areas, also called plaque, on the walls of your blood vessels, making it more difficult for the blood to flow. Sometimes, the plaque can detach from the vessel wall and float in the bloodstream; it can then reach a smaller vessel and completely block it. This blocking of your blood vessels can lead to several types of blood vessel disease, heart attack, angina and stroke.

There is another type of blood fat called triglyceride that is a source of energy. However, high levels of triglyceride can be associated with a low level of 'good' cholesterol and may increase your risk of heart disease.

In some patients, CADIVAST is used to treat high cholesterol and high triglycerides together.

In most people, there are no symptoms of abnormal cholesterol or triglyceride levels. Your doctor can measure your levels with a simple blood test.

What is angina?

Angina is a pain or uncomfortable feeling in the chest, often spreading to the arms or neck, and sometimes to the shoulders and back. The pain of angina is due to a shortage of oxygen to the heart. CADIVAST is used to treat chronic angina.

2. What should I know before I take CADIVAST?

Warnings

Do not take CADIVAST if you:

  • are allergic to any medicine containing amlodipine
  • are allergic to any medicine containing atorvastatin
  • are allergic to any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin.
    Always check the ingredients to make sure you can take this medicine.
  • have active liver disease
  • are pregnant or intend to become pregnant
  • are breastfeeding or intend to breastfeed
  • are taking the antibiotic fusidic acid hemihydrate which is used to treat infections
  • are taking the antivirals glecaprevir/pibrentasvir for the treatment of hepatitis C.

Do not give this medicine to children.

Safety and effectiveness in children have not been established.

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 you are not sure whether you should start taking this medicine, talk to your doctor.

Check with your doctor if you:

  • have or have had any of the following medical conditions:
    - heart disease such as heart failure
    - liver problems
    - kidney problems
    - muscle pain, tenderness or weakness from other medicines used to treat cholesterol or triglycerides
    - vision problems, eye muscle weakness and drooping eyelid
    - breathing problems
    - a type of stroke called a haemorrhagic stroke or a type of stroke called a lacunar stroke.
    If you have had one of these strokes before, this medicine may increase the risk of you having a haemorrhagic stroke.
  • have allergies to any other medicines, foods, preservatives or dyes
  • take medicines for any other condition
  • Tell your doctor if you are consuming alcohol regularly.

Your doctor will ask you to have your liver function tested before you start to take CADIVAST.

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

Do not take this medicine if you are pregnant or intend to become pregnant.

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

If you are a woman of child-bearing age and are taking this medicine, use a proven method of birth control to avoid pregnancy.

This medicine may affect your developing baby if you take it during pregnancy.

Do not take this medicine if you are breastfeeding or intend to breastfeed.

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

This medicine may pass into breast milk and there is a possibility that your baby may be affected.

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

If you have not told your doctor about any of the above, tell him/her before you start taking CADIVAST.

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 CADIVAST and affect how it works.

You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking:

  • other calcium channel blockers. These medicines include amlodipine which is also in CADIVAST; other calcium channel blockers include medicines with the active ingredient felodipine or nifedipine.
  • other statins. These medicines include atorvastatin which is also in CADIVAST. Other statins include medicines with active ingredient fluvastatin, pravastatin, rosuvastatin, simvastatin or simvastatin containing medicines.

Check with your doctor or pharmacist if you are unsure.

Tell your doctor or pharmacist if you are taking any of the following:

  • digoxin, a medicine used to treat some heart problems
  • the antibiotics erythromycin, clarithromycin, rifampicin or fusidic acid hemihydrate
  • phenytoin, a medicine used to treat epilepsy (seizures)
  • oral contraceptives for birth control
  • other medicines to treat high cholesterol or triglycerides (fats)
  • other medicines to treat high blood pressure
  • some medicines to treat low potassium
  • ciclosporin, tacrolimus, sirolimus or everolimus, medicines used to suppress the immune system
  • temsirolimus, a medicine used to treat kidney cancer
  • some medicines used to treat some fungal infections, such as ketoconazole or itraconazole
  • protease inhibitors for the treatment of HIV infections and/or Hepatitis C, such as efavirenz, fosamprenavir, ritonavir, boceprevir, telaprevir, tipranavir/ritonavir, elbasvir/grazoprevir and simprevir
  • HCV non-structural protein 5A (NS5A)/5B (NS5B) inhibitors such as daclatasvir and ledipasvir
  • letermovir
  • diltiazem, a medicine used to treat angina
  • antacids, medicines used to treat reflux or ulcers
  • spironolactone, a medicine used to treat high blood pressure and certain types of swelling
  • vitamin B3
  • colchicine, a medicine used to treat a disease with painful swollen joints caused by uric acid crystals
  • ticagrelor, a medicine used to prevent blood clots.

It is also possible that CADIVAST may be affected by some medicines used to treat heart palpitations (or arrhythmias) and St John's Wort.

If you have not told your doctor about any of the above, tell him/her before you start taking CADIVAST.

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

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

4. How do I take CADIVAST?

How much to take

  • CADIVAST is taken once a day.
  • Your doctor will decide which strength is suitable for you.
    This will depend on your blood pressure, cholesterol and triglyceride levels.
  • Your doctor may need to adjust your dose after your blood pressure and the fat levels in your blood have been checked. It is important that you keep your appointments to have these tests done.
  • If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.
  • Follow the instructions provided and use CADIVAST until your doctor tells you to stop.

When to take CADIVAST

  • Take your medicine 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.
  • CADIVAST can be taken with or without food.

How to take CADIVAST

  • Swallow the tablets whole with a full glass of water.
  • Do not crush or chew the tablets.
  • Take CADIVAST exactly as your doctor has prescribed.
  • Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.
  • Your doctor may discuss with you the need to be on a diet. Follow your agreed diet plan carefully.

How long to take CADIVAST

Take CADIVAST every day and continue taking it for as long as your doctor tells you.

This medicine helps to lower cholesterol levels and blood pressure and control the symptoms of angina but it does not cure your condition.

It is important to keep taking your medicine even if you feel well. If you stop taking CADIVAST, your blood pressure and cholesterol levels may rise again.

If you forget to take CADIVAST

CADIVAST should be taken regularly at the same time each day.

If you miss your dose at the usual time and it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much CADIVAST

If you think that you or anyone else may have taken too much CADIVAST, urgent medical attention may be needed.

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.

Keep telephone numbers of these facilities handy.

Symptoms of an overdose may include dizzy, lightheaded or faint and have an irregular heartbeat.

5. What should I know while taking CADIVAST?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking CADIVAST.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
    It may affect other medicines used during surgery.
  • If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.
  • Keep all of your doctor's appointments so that your progress can be checked.
  • Your cholesterol and triglyceride levels and your liver function tests need to be checked regularly while you are taking this medicine.
  • A regular blood test to check an enzyme called creatine kinase (CK) may be needed. CK in your blood can rise after muscle injury which can be caused by medicines used to treat cholesterol or triglycerides, such as CADIVAST.
    This helps to make sure that CADIVAST is working and to avoid some possible side-effects.
  • Your blood pressure may also be checked regularly.

Call your doctor straight away if you:

  • become pregnant while taking this medicine.

Remind any doctor, dentist or pharmacist you visit that you are taking CADIVAST.

Things you should not do

  • Do not take CADIVAST to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
    If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

  • Avoid eating large quantities of grapefruit or drinking large quantities of grapefruit juice.
    Grapefruit juice contains one or more components that alter the metabolism of some medicines, including CADIVAST.
    Drinking very large quantities (over 1.2 litres) of grapefruit juice each day while taking CADIVAST increases your chance of getting side effects.
  • 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 CADIVAST affects you.

CADIVAST may cause dizziness or drowsiness in some people and affect alertness.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Avoid drinking large quantities of alcohol. Tell your doctor if you drink alcohol.

Drinking large quantities of alcohol while taking CADIVAST may increase your chance of getting liver problems.

Excessive alcohol intake can raise your cholesterol levels or affect your liver function, which could increase the chance of you getting unwanted side effects.

Your doctor may discuss with you whether you should reduce the amount of alcohol you drink.

Lifestyle measures that help reduce heart disease risk

By following these simple measures, you can further reduce the risk from heart disease.

  • Quit smoking and avoid second-hand smoke. Smoking increases the risk of you suffering from heart problems. Your doctor may advise you to stop smoking.
  • Limit alcohol intake.
  • Enjoy healthy eating by:
    - eating plenty of vegetables and fruit
    - reducing your saturated fat intake (eat less fatty meats, full fat dairy products, butter, coconut and palm oils, most take-away foods, commercially-baked products)
    - reducing your salt intake. Your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake, avoid using salt at the table or in cooking.
  • Be active. Progress, over time, to at least 30 minutes of moderate-intensity physical activity on 5 or more days each week. Can be accumulated in shorter bouts of 10 minutes duration. If you have been prescribed anti-angina medicine, carry it with you when being physically active.
  • Regular exercise can help lower your cholesterol levels and blood pressure and can strengthen your heart. It is important not to overdo it. Before commencing regular exercise, you should consult your doctor who will suggest the most suitable exercise for you. If you experience any discomfort when exercising, see your doctor.
  • Maintain a healthy weight. While you are taking CADIVAST, you may need to follow a diet plan agreed to with your doctor. This may include measures to lose some weight.
  • Discuss your lifestyle and lifestyle plans with your doctor.
  • For more information and tools to improve your heart health, call Heartline, the Heart Foundation's national telephone information service, on 1300 36 27 87 (local call cost).

Know warning signs of heart attack and what to do:

  • Tightness, fullness, pressure, squeezing, heaviness or pain in your chest, neck, jaw, throat, shoulders, arms or back.
  • You may also have difficulty breathing, or have a cold sweat or feel dizzy or light headed or feel like vomiting (or actually vomit).
  • If you have heart attack warning signs that are severe, get worse or last for 10 minutes even if they are mild, call triple zero (000). Every minute counts.

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 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.

Heat and dampness can destroy some medicines.

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 you no longer need to take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

6. Are there any side effects?

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.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Less serious side effects

Less serious side effectsWhat to do
  • headache
  • flushing
  • dizziness
  • tiredness or weakness
  • drowsiness or sleepiness
  • stomach pain or nausea (feeling sick)
  • constipation, diarrhoea, wind
  • heartburn, indigestion or wind
  • urine infection
  • stuffy or runny nose
  • nose bleeds
  • rash
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. They are usually mild and short-lived.

Serious side effects

Serious side effectsWhat to do
  • swelling of the ankles, feet, face or hands
  • muscle and joint pain, muscle weakness, especially in the forearms, thighs, hips, shoulders, neck, and back
  • vision problems, eye muscle weakness and drooping eyelid
  • difficulty climbing stairs or standing up from a chair
  • difficulty lifting arms over the head
  • falling and difficulty getting up from a fall
  • symptoms of liver disease such as itching, yellowing of the skin and eyes and dark coloured urine
  • feeling weak and tired, excessively thirsty and passing more urine
  • dizziness or lightheadedness on standing up from a sitting or lying position
  • problems with breathing, including shortness of breath, persistent cough and fever
  • eye pain or change in vision
  • changes in mood, feeling anxious or nervous
Call your doctor straight away if you notice any of these serious side effects. This list includes serious side effects that may require medical attention.

Very serious side effects

Very serious side effectsWhat to do
  • symptoms of allergy such as skin rash, itching, swelling of the face, lips, mouth, throat or neck which may cause difficulty in swallowing and breathing
  • shortness of breath
  • unexpected muscle pain, tenderness or weakness not caused by exercise, particularly if you also feel unwell or have a fever
  • tingling in the hands or feet
  • changes in heart beat either fast, slow or irregular
  • chest pain associated with exertion (angina) that lasts longer, is more severe or occurs more often
  • chest pain
  • sudden severe headache, which may be accompanied by nausea, vomiting, loss of sensation, tingling in any part of the body or ringing in the ears
  • severe blisters and bleeding of the lips, eyes, mouth, nose or genitals
  • severe upper stomach pain, often with nausea and vomiting
Call your doctor straight away, or go straight to the Emergency Department 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 or hospitalisation.

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.

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

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 CADIVAST contains

Active ingredient
(main ingredient)		amlodipine besilate 5 mg or 10 mg and atorvastatin calcium trihydrate 10 mg, 20 mg, 40 mg or 80 mg per tablet
Other ingredients
(inactive ingredients)
  • colloidal anhydrous silica
  • sodium carbonate
  • microcrystalline cellulose
  • arginine
  • pregelatinised maize starch
  • croscarmellose sodium
  • hyprolose
  • magnesium stearate
  • OPADRY AMB complete film coating system OY-B-28920 White (ARTG PI No: 4271) [5 mg/ 10 mg, 5 mg/20 mg, 5 mg/40 mg and 5 mg/80 mg]
  • OPADRY AMB aqueous moisture barrier coating system 80W10932 BLUE (ARTG PI No: 106951) [10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg and 10 mg/80 mg]
Potential allergensSoya bean products

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

What CADIVAST looks like

CADIVAST 5/10 mg tablet: A white to off-white, film-coated, oval, biconvex tablet debossed with “AA 4” on one side of the tablet and “M” on the other side. (AUST R 199213)

CADIVAST 5/20 mg tablet: A white to off-white, film-coated, round, biconvex tablet debossed with “AA 5” on one side of the tablet and “M” on the other side. (AUST R 199222)

CADIVAST 5/40 mg tablet: A white to off-white, film-coated, capsule shaped, biconvex tablet debossed with “AA 6” on one side of the tablet and “M” on the other side. (AUST R 199214)

CADIVAST 5/80 mg tablet: A white to off-white, film-coated, oval, biconvex tablet debossed with “AA 7” on one side of the tablet and “M” on the other side. (AUST R 199210)

CADIVAST 10/10 mg tablet: A blue, film-coated, barrel shaped, biconvex tablet debossed with “AA 8” on one side of the tablet and “M” on the other side. (AUST R 199215)

CADIVAST 10/20 mg tablet: A blue, film-coated, oval, biconvex tablet debossed with “AA 9” on one side of the tablet and “M” on the other side. (AUST R 199223)

CADIVAST 10/40 mg tablet: A blue, film-coated, round, biconvex tablet debossed with “AA 10” on one side of the tablet and “M” on the other side. (AUST R 199225)

CADIVAST 10/80 mg tablet: A blue, film-coated, capsule shaped, biconvex tablet debossed with “AA 11” on one side of the tablet and “M” on the other side. (AUST R 199217)

CADIVAST is available in bottles of 30 tablets.

Who distributes CADIVAST

Alphapharm Pty Ltd trading as Viatris
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 January 2024.

CADIVAST® is a Viatris company trade mark

CADIVAST_cmi\Jan24/01

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Cadivast

Active ingredient

Amlodipine; Atorvastatin

Schedule

S4

 

1 Name of Medicine

Amlodipine (as besilate) and atorvastatin (as calcium trihydrate).

2 Qualitative and Quantitative Composition

The Cadivast tablets contain 5 or 10 mg amlodipine (as amlodipine besilate) and 10, 20, 40, or 80 mg atorvastatin (as atorvastatin calcium trihydrate).

Excipients with known effect.

Soya bean products.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cadivast 5/10 tablets.

A white to off-white, film-coated, oval, biconvex tablet debossed with "AA 4" on one side of the tablet and "M" on the other side.

Cadivast 5/20 tablets.

A white to off-white, film-coated, round, biconvex tablet debossed with "AA 5" on one side of the tablet and "M" on the other side.

Cadivast 5/40 tablets.

A white to off-white, film-coated, capsule shaped, biconvex tablet debossed with "AA 6" on one side of the tablet and "M" on the other side.

Cadivast 5/80 tablets.

A white to off-white, film-coated, oval, biconvex tablet debossed with "AA 7" on one side of the tablet and "M" on the other side.

Cadivast 10/10 tablets.

A blue, film-coated, barrel shaped, biconvex tablet debossed with "AA 8" on one side of the tablet and "M" on the other side.

Cadivast 10/20 tablets.

A blue, film-coated, oval, biconvex tablet debossed with "AA 9" on one side of the tablet and "M" on the other side.

Cadivast 10/40 tablets.

A blue, film-coated, round, biconvex tablet debossed with "AA 10" on one side of the tablet and "M" on the other side.

Cadivast 10/80 tablets.

A blue, film-coated, capsule shaped, biconvex tablet debossed with "AA 11" on one side of the tablet and "M" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Amlodipine besilate and atorvastatin calcium trihydrate tablet is indicated for patients in whom treatment with amlodipine and atorvastatin is appropriate at the doses presented.

The indications for amlodipine are:

1. Hypertension.

Amlodipine is indicated for the first line treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately controlled on a single antihypertensive agent may benefit from the addition of amlodipine, which has been used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent or an angiotensin converting enzyme inhibitor.

2. Angina.

Amlodipine is indicated for the first line treatment of chronic stable angina. Amlodipine may be used alone, as monotherapy or in combination with other antianginal drugs.

The indications for atorvastatin are:

1. Atorvastatin is indicated as an adjunct to diet for the treatment of patients with hypercholesterolaemia.
2. Prior to initiating therapy with atorvastatin, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, and alcoholism) should be identified and treated.
3. Atorvastatin is indicated in hypertensive patients with multiple risk factors for coronary heart disease (CHD) which may include diabetes, history of stroke or other cerebrovascular disease, peripheral vascular disease or existing asymptomatic CHD (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Atorvastatin component, Prevention of cardiovascular disease) to reduce the risk of non-fatal myocardial infarction and non-fatal stroke.
These effects do not replace the need to independently control known causes of cardiovascular mortality and morbidity such as hypertension, diabetes and smoking.

4.2 Dose and Method of Administration

Amlodipine besilate and atorvastatin calcium trihydrate tablet is a combination product targeting two distinct cardiovascular risk factors, hypertension and dyslipidaemia.
The starting dose and maintenance doses of amlodipine besilate and atorvastatin calcium trihydrate tablet should be individualised according to goals consistent with current treatment guidelines and patient response.
Amlodipine besilate and atorvastatin calcium trihydrate tablet is available in eight strengths ranging from amlodipine besilate/atorvastatin calcium trihydrate 5 mg/10 mg to amlodipine besilate/atorvastatin calcium trihydrate 10 mg/80 mg to allow the physician maximum flexibility in titrating patients to treatment targets.
Amlodipine besilate and atorvastatin calcium trihydrate tablet is to be taken once daily and may be taken at any time of the day with or without food.
After initiation of amlodipine besilate and atorvastatin calcium trihydrate tablet, lipid levels should be analysed and blood pressure measured after approximately 4 to 6 weeks, and dosage adjusted accordingly. Titration for blood pressure response may proceed more rapidly if clinically warranted.
In patients requiring additional blood pressure lowering and/or angina treatment, amlodipine besilate and atorvastatin calcium trihydrate tablet may be added to existing therapies.

Special patient populations.

Small, fragile or elderly.

Amlodipine besilate and atorvastatin calcium trihydrate tablet can be used in this patient population provided titration to 5 mg of amlodipine has been achieved (see Section 4.4 Special Warnings and Precautions for Use).

Children.

There are no studies to date to determine the safety or efficacy of amlodipine besilate and atorvastatin calcium trihydrate tablet in children.

Use in renal impairment.

No dosage adjustment is necessary in patients taking amlodipine besilate and atorvastatin calcium trihydrate tablet (see Section 4.4 Special Warnings and Precautions for Use).

Use in hepatic impairment.

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease (Child-Pugh B). The half-life of amlodipine is prolonged in patients with impaired liver function and dosage recommendations have not been established. Therefore, amlodipine besilate and atorvastatin calcium trihydrate tablet should be administered with caution in patients with impaired liver function or history of liver disease, and in patients who consume substantial quantities of alcohol (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the Atorvastatin component of Amlodipine besilate and Atorvastatin calcium trihydrate tablet, Liver dysfunction).

Concomitant medications.

The amlodipine component of amlodipine besilate and atorvastatin calcium trihydrate tablet has been safely administered with thiazides, ACE inhibitors, beta-blockers, long acting nitrates, and/or sublingual glyceryl trinitrate. No dose adjustment of amlodipine is required.
The atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet was used concomitantly with antihypertensive agents in clinical studies without evidence of clinically significant adverse interactions. Interaction studies with all specific agents have not been conducted.
The atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet may be used in combination with a bile acid binding resin for additive effect. The combination of HMG-CoA reductase inhibitors and fibrates should generally be avoided (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle). For other interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
In cases where co-administration of atorvastatin with ciclosporin, telaprevir or the combination of tipranavir/ritonavir is necessary, the dose of atorvastatin should not exceed 10 mg.
Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin.
When atorvastatin and letermovir are administered concomitantly, do not exceed 20 mg atorvastatin daily (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of other medicines on atorvastatin, Transporter inhibitors). Appropriate clinical assessment is recommended to ensure that the lowest dose of atorvastatin necessary is used.
Caution should be used when co-prescribing atorvastatin with medicinal compounds that result in an increase in systemic concentrations of atorvastatin, such as elbasvir/grazoprevir and simeprevir, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.3 Contraindications

Amlodipine besilate and atorvastatin calcium trihydrate tablet is contraindicated in patients with a known hypersensitivity to any component of this medication.
Amlodipine besilate and atorvastatin calcium trihydrate tablet contains atorvastatin calcium trihydrate and is, therefore, contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the Atorvastatin component of Amlodipine besilate and Atorvastatin calcium trihydrate tablet, Liver dysfunction).
Amlodipine besilate and atorvastatin calcium trihydrate tablet is contraindicated during pregnancy, while breastfeeding and in women of child-bearing potential, unless on an effective contraceptive and highly unlikely to conceive (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
Concomitant use with fusidic acid hemihydrate is also contraindicated due to the atorvastatin component (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Amlodipine besilate and atorvastatin calcium trihydrate tablet is contraindicated in patients being treated with the Hepatitis C antivirals, glecaprevir/pibrentasvir.

4.4 Special Warnings and Precautions for Use

Amlodipine besilate and atorvastatin calcium trihydrate tablet is a combination of atorvastatin, a HMG-CoA reductase inhibitor (statin) and amlodipine, a calcium channel blocker (CCB). Adverse events may result from either component of this medicine.
As amlodipine besilate and atorvastatin calcium trihydrate tablet contains amlodipine and atorvastatin the precautions applying to both these medicines are applicable and are detailed below.

Precautions relating to the amlodipine component of amlodipine besilate and atorvastatin calcium trihydrate tablet.

Increased angina.

Rarely patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Outflow obstruction (aortic stenosis).

Amlodipine should be used with caution in the presence of a fixed left ventricular outflow obstruction (aortic stenosis).

Use in patients with congestive heart failure.

In general, calcium channel blockers should be used with caution in patients with heart failure (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Hypotension.

The use of amlodipine in patients where there is a risk of hypotension (e.g. in normotensive, small, elderly or fragile patients) is not recommended unless titration to 5 mg amlodipine has been achieved (see Section 4.2 Dose and Method of Administration).

Beta-blocker withdrawal.

Amlodipine is not a beta-blocker and therefore provides no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Use in hepatic impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Peripheral oedema.

Mild to moderate peripheral oedema was the most common adverse event in amlodipine clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). The incidence of peripheral oedema was dose dependent and ranged in frequency from 3.0% to 10.8% in the 5 mg to 10 mg dose range. Care should be taken to differentiate this peripheral oedema from the effects of increasing left ventricular dysfunction.

Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet.

Liver dysfunction.

Amlodipine besilate and atorvastatin calcium trihydrate tablet should be administered with caution in patients with impaired liver function. Following therapy with other lipid lowering agents of the same class as atorvastatin, moderate (> 3 x upper limit of normal [ULN]) elevations of serum transaminases have been reported.
Persistent increases in serum transaminases > 3 x ULN occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6% and 2.3% for 10 mg, 20 mg, 40 mg and 80 mg respectively. Increases were generally not associated with jaundice or other clinical signs or symptoms. When the dosage of atorvastatin was reduced, or drug treatment interrupted or discontinued, transaminase levels returned to pre-treatment levels. Most patients continued treatment on a reduced dose of atorvastatin without sequelae.
Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in alanine transaminase (ALT) or aspartate transaminase (AST) of > 3 x ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin (see Section 4.3 Contraindications).

Skeletal muscle.

Uncomplicated myalgia has been reported in atorvastatin treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine kinase (CK) values > 10 x ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness and/or marked elevation of CK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Atorvastatin therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy and rhabdomyolysis is increased with concurrent administration of drugs that increase the systemic concentration of atorvastatin (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs (i.e. ciclosporin), colchicine, azole antifungals, human immunodeficiency virus (HIV)/ hepatitis C virus (HCV) protease inhibitors (e.g. telaprevir, boceprevir), HCV non-structural protein 5A (NS5A)/5B (NS5B) inhibitors, letermovir or the combination of tipranavir/ritonavir, or lipid-lowering doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. When atorvastatin and letermovir are administered concomitantly, do not exceed 20 mg atorvastatin daily (see Section 4.2 Dose and Method of Administration, Concomitant medications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of other medicines on atorvastatin, Transporter inhibitors). Appropriate clinical assessment is recommended to ensure that the lowest dose of atorvastatin necessary is used. Lower starting and maintenance doses of atorvastatin component should also be considered when taken concomitantly with the other aforementioned drugs (see Section 4.2 Dose and Method of Administration, Concomitant medications).
There have been reports of rhabdomyolysis (including some fatalities) in patients receiving concomitant fusidic acid hemihydrate and statins (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In patients where the use of systemic fusidic acid hemihydrate is considered essential, statin treatment should be discontinued throughout the duration of the fusidic acid hemihydrate treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid hemihydrate.
Periodic creatine kinase (CK) determinations may be considered in such situations, although there is no assurance that such monitoring will prevent the occurrence of severe myopathy (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).
As with other drugs in this class, rhabdomyolysis with acute renal failure has been reported. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine and electrolyte disorders; and uncontrolled seizures).

Immune mediated necrotizing myopathy.

There have been rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatinine kinase, which persists despite discontinuation of statin treatment.

Myasthenia gravis/ocular myasthenia.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see Section 4.8 Adverse Effects (Undesirable Effects)). Atorvastatin should be discontinued in cases where these conditions occur. Recurrences when the same or a different statin was (re-) administered have been reported.

Haemorrhagic stroke.

A post hoc analysis of a clinical study (SPARCL) in patients without known coronary heart disease who had a recent stroke or transient ischaemic attack (TIA), showed a higher incidence of haemorrhagic stroke in patients on atorvastatin 80 mg (55/2365, 2.3%) compared to placebo (33/2366, 1.4%), (p = 0.02). Throughout the study, all cause mortality was numerically higher in the atorvastatin arm than the placebo arm. At study end all cause mortality was 9.1% on atorvastatin vs. 8.9% on placebo.
The increased risk of haemorrhagic stroke was observed in patients who entered the study with prior haemorrhagic stroke (15.6% for atorvastatin vs. 4.2% for placebo, hazard ratio [HR] 4.06; 95% CI 0.84-19.57) or prior lacunar infarct (2.8% for atorvastatin vs. 0.6% for placebo, HR 4.99; 95% CI 1.71-14.61). All cause mortality was also increased in these patients with prior haemorrhagic stroke (15.6% for atorvastatin vs. 10.4% for placebo) or prior lacunar infarct (10.9% for atorvastatin vs. 9.1% for placebo). The potential risk of haemorrhagic stroke should be carefully considered before initiating treatment with atorvastatin in patients with recent (1 to 6 months) stroke or TIA.
In 68% of patients who entered the study with neither a haemorrhagic stroke nor lacunar infarct, the risk of haemorrhagic stroke on atorvastatin vs. placebo was 2% vs. 1.8% (large vessel), 1.7% vs. 1.6% (TIA), 1.6% vs. 1.7% (unknown cause).

Endocrine function.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically may blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration nor impair adrenal reserve. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary gonadal axis in pre-menopausal women are unknown. Caution should be exercised if a HMG-CoA reductase inhibitor is administered concomitantly with other drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone and cimetidine.
Increases in glycated haemoglobin (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.

Effect on ubiquinone levels (COQ10).

Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term, statin-induced deficiency of ubiquinone has not been established.

Effect on lipoprotein(a).

Like other HMG-CoA reductase inhibitors, atorvastatin has variable effects on lipoprotein(a) (Lp(a)). It is unclear whether the beneficial effects of lowering LDL-C and total cholesterol in some patients may be blunted by raised Lp(a) levels.

Interstitial lung disease.

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in the elderly.

Amlodipine.

In elderly patients (≥ 65 years) clearance of amlodipine is decreased with a resulting increase in AUC. In clinical trials, the incidence of adverse reactions in elderly patients was approximately 6% higher than that of younger population (< 65 years). Adverse events include oedema, muscle cramps and dizziness. Amlodipine should be used with caution in the elderly.

Atorvastatin.

The safety and efficacy of atorvastatin in patients ≥ 70 years of age were similar to those of patients < 70 years of age.

Paediatric use.

There have been no studies conducted on the safety and efficacy of amlodipine besilate and atorvastatin calcium trihydrate tablet in paediatric populations.

Effects on laboratory tests.

The atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet can cause elevations in ALT/AST, alkaline phosphatase, GGT, bilirubin and creatine kinase.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There have been two studies (one single and one multiple dose) to examine possible pharmacokinetic interaction between amlodipine and atorvastatin in healthy volunteers.
The single dose study was a randomised, open-label, 3 treatment, 3 period, crossover study in 27 healthy male volunteers (only 24 could be evaluated due to drop out of 3 subjects). Study treatments included atorvastatin 80 mg alone, amlodipine 10 mg alone, or both treatments co-administered, with a 2 week washout period between each dose. In this study, the geometric mean of the atorvastatin AUC was 18% greater when amlodipine was co-administered; however, this was not accompanied by any statistically significant increase in Cmax. An analysis using an estimation approach based on the point estimate and the 90% confidence interval indicated no clinically significant pharmacokinetic interaction.
The multiple-dose study was a randomised, open-label, crossover study in 16 healthy male volunteers. Study treatments included atorvastatin 80 mg alone, amlodipine 10 mg alone, or both treatments co-administered, with a 2-week washout period between each 7 day dosing period. In this study, the geometric mean AUC of atorvastatin was 16% greater when amlodipine was co-administered. Also in this study, an analysis using an estimation approach based on the point estimate and the 95% confidence interval failed to show a clinically significant pharmacokinetic interaction.
Medicines affected by or affecting the individual components are outlined below followed by those where no interaction has been observed with either amlodipine or atorvastatin and other medicines.

Atorvastatin.

Atorvastatin is metabolised by cytochrome P450 3A4.
Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on cytochrome P450 3A4. Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have also been noted with HIV protease inhibitors (fosamprenavir and combinations of lopinavir/ritonavir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir), hepatitis C (HCV) protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir), HCV NS5A/NS5B inhibitors, clarithromycin, itraconazole and letermovir. Based on experience with other HMG-CoA reductase inhibitors, caution should be exercised when atorvastatin is administered with inhibitors of cytochrome P450 3A4 (e.g. ciclosporin, macrolide antibiotics including erythromycin and azole antifungals including itraconazole). The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is increased with concurrent administration of ciclosporin, fibric acid derivatives, erythromycin, azole antifungals or niacin (see Section 4.2 Dose and Method of Administration, Concomitant medications; Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle).
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin, phenytoin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter (OATP1B1)), simultaneous co-administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction on atorvastatin plasma concentrations.

Fusidic acid hemihydrate.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid hemihydrate with statins. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown.
Although interaction studies with atorvastatin and fusidic acid hemihydrate have not been conducted, there have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid hemihydrate is necessary, statin treatment should be discontinued throughout the duration of the fusidic acid hemihydrate treatment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle).

Colchicine.

Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle).
Effects of other medicines on atorvastatin. The following drugs have been shown to have an effect on the pharmacokinetics or pharmacodynamics of atorvastatin.

Antacid.

Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides with atorvastatin decreased atorvastatin plasma concentrations by approximately 35%; however, LDL-C reduction was not altered.

Colestipol.

Plasma concentrations of atorvastatin were lower (approximately 25%) when colestipol and atorvastatin were co-administered. However, LDL-C reduction was greater when atorvastatin and colestipol were co-administered than when either drug was given alone.

Transporter inhibitors.

Atorvastatin is a substrate of the hepatic transporters (see Section 5.2 Pharmacokinetic Properties).
Concomitant administration of atorvastatin 10 mg and ciclosporin 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin. Ciclosporin is an inhibitor of organic anion-transporting polypeptide 1B1 (OATP1B1), OATP1B3, multi-drug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP) as well as CYP3A4, thus it increases exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Section 4.2 Dose and Method of Administration, Concomitant medications).
Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Co-administration of atorvastatin with products containing glecaprevir or pibrentasvir is contraindicated (see Section 4.3 Contraindications).
Concomitant administration of atorvastatin (20 mg single dose) and letermovir (480 mg once daily) for 10 days resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29; ratio of Cmax: 2.17). The ratio of AUC or Cmax is calculated by dividing the AUC or Cmax of co-administered letermovir plus atorvastatin by that of atorvastatin alone, respectively. Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg atorvastatin daily (see Section 4.2 Dose and Method of Administration, Concomitant medications).
The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with ciclosporin. Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin.
Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Use with caution and lowest dose necessary (see Section 4.2 Dose and Method of Administration, Concomitant medications).

Erythromycin/clarithromycin.

In healthy individuals, co-administration of atorvastatin (10 mg once-daily) and erythromycin (500 mg four times a day), or clarithromycin (500 mg twice daily), known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle).

Protease inhibitors.

Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin (see Section 4.4 Special Warnings and Precautions for Use, Precautions relating to the atorvastatin component of amlodipine besilate and atorvastatin calcium trihydrate tablet, Skeletal muscle).

Diltiazem hydrochloride.

Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin.

Itraconazole.

Concomitant administration of atorvastatin (20 to 40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC.

Grapefruit juice.

Contains one or more components that inhibit cytochrome P450 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (> 1.2 L per day).

Ticagrelor.

Co-administration of atorvastatin and ticagrelor increased the atorvastatin acid Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.
Effects of atorvastatin on other medicines. The following medicines have been shown to have their pharmacokinetics or pharmacodynamics affected by atorvastatin.

Digoxin.

When multiple doses of digoxin (0.25 mg once daily) and 10 mg of atorvastatin were co-administered, steady-state plasma digoxin concentrations were unaffected. However, steady-state plasma digoxin concentrations increased by approximately 20% following administration of digoxin with 80 mg of atorvastatin daily. Patients taking digoxin should be monitored appropriately.

Oral contraceptives.

Co-administration of atorvastatin with an oral contraceptive containing norethisterone and ethinylestradiol increased AUC values for norethisterone and ethinylestradiol by approximately 30% and 20%, respectively. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Medicines shown not to interact with atorvastatin.

Cimetidine.

Atorvastatin plasma concentrations and LDL-C reduction were not altered by co-administration of cimetidine.

Warfarin.

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Azithromycin.

Co-administration of atorvastatin 10 mg daily and azithromycin (500 mg once-daily) did not alter the plasma concentrations of atorvastatin.

Other concomitant therapy.

In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with all specific agents have not been conducted.

Amlodipine.

Amlodipine has been safely administered with thiazide diuretics, beta-blockers, ACE inhibitors, long acting nitrates, sublingual glyceryl trinitrate, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycaemic drugs.
Special studies have indicated that the co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in healthy volunteers, that co-administration of cimetidine did not alter the pharmacokinetics of amlodipine; and that co-administration with warfarin did not change the warfarin prothrombin response time.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indometacin).

Grapefruit juice.

Grapefruit juice is known to inhibit the cytochrome P450 system in the gastrointestinal mucosa, thereby affecting the pharmacokinetics of drugs such as calcium channel blockers. Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

CYP3A4 inhibitors.

With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients, the plasma concentration of amlodipine was increased. The clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution when administered with CYP3A4 inhibitors.

Clarithromycin.

Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.

CYP3A4 inducers.

There are no data available regarding the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum (St John's wort)) may decrease the plasma concentration of amlodipine. Amlodipine should be used with caution when administered with CYP3A4 inducers.

Aluminium/magnesium (antacid).

Co-administration of an aluminium/magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil.

A single 100 mg dose of sildenafil in 16 patients with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Ethanol (alcohol).

Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Ciclosporin.

No drug interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients. Various studies in renal transplant patients report that co-administration of amlodipine with ciclosporin affects the trough concentrations of ciclosporin, and consideration should be given for monitoring ciclosporin levels in renal transplant patients on amlodipine.

Tacrolimus.

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic target of rapamycin (mTOR) inhibitors.

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use of mTOR inhibitors and amlodipine may increase exposure of mTOR inhibitors.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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

Amlodipine.

There was no effect on fertility of rats treated with amlodipine at oral doses up to 18 mg/kg/day.

Atorvastatin.

The effects of atorvastatin on spermatogenesis and human fertility have not been investigated in clinical studies. Dietary administration of 100 mg atorvastatin/kg/day to rats caused a decrease in spermatid concentration in the testes, a decrease in sperm motility and an increase in sperm abnormalities. Similar effects, however, were not observed in male rats dosed by gavage to 175 mg/kg/day (plasma AUC for HMG-CoA reductase inhibitory activity 14 times higher than in humans dosed at 80 mg/day) and male fertility was not affected in either study. No adverse events on fertility or reproduction were observed in female rats given doses up to 225 mg/kg/day (plasma AUC for enzyme inhibitory activity 56 times higher than in humans dosed at 80 mg/day). Atorvastatin caused no adverse events on sperm or semen parameters or on reproductive organ histopathology in dogs given doses of 10 mg/kg/day, 40 mg/kg/day, or 120 mg/kg/day for 2 years (Plasma AUC for enzyme inhibitory activity 13 times higher than in humans).
(Category D)
The definition of Pregnancy Category D is drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
Amlodipine besilate and atorvastatin calcium trihydrate tablet is contraindicated in pregnancy due to the atorvastatin component (see Section 4.3 Contraindications).

Atorvastatin.

Atherosclerosis is a chronic process and discontinuation of lipid lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary dyslipidaemia. Cholesterol and other products of cholesterol biosynthesis are essential components for foetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to pregnant women. Amlodipine besilate and atorvastatin calcium trihydrate tablet should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential. If the patient becomes pregnant while taking this drug, therapy should be discontinued and the patient apprised of the potential hazard to the foetus (see Section 4.3 Contraindications).
Atorvastatin crosses the rat placenta and reaches a level in foetal liver equivalent to that in maternal plasma. Animal reproduction studies showed no evidence of teratogenic activity in rats or rabbits at oral doses up to 300 mg/kg/day and 100 mg/kg/day respectively. Increased post-implantation foetal loss, decreased foetal weight and increased skeletal variations were observed in rats dosed at 100 to 300 mg/kg/day and rabbits dosed at 50 to 100 mg/kg/day. In a peri/postnatal study, rats dosed at 225 mg/kg/day showed an increased incidence of stillbirths, decreases in birth weight, an increased incidence of dilated renal pelvis, increased postnatal mortality, suppression of pup growth, retardation of physical development and abnormal behavioural development; some of these effects were also observed at the nonmaternotoxic dose of 100 mg/kg/day; the plasma AUC for HMG-CoA reductase inhibitory activity at the no effect dose level of 20 mg/kg/day was similar to that in humans dosed at 80 mg/day.
HMG-CoA reductase inhibitors are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series of 178 and 143 cases where pregnant women took HMG-CoA reductase inhibitor (statin) during the first trimester of pregnancy, serious foetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and foetal deaths. The exact risk of injury to the foetus occurring after a pregnant woman exposed to HMG-CoA reductase inhibitor has not been determined. The current data do not indicate that the risk of foetal injury in women exposed to HMG-CoA inhibitors is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor she should be informed of the possibility of foetal injury and discuss the implications with her pregnancy specialist.

Amlodipine.

Amlodipine besilate and atorvastatin calcium trihydrate tablet contains amlodipine, a calcium channel blocker. This class of medicines carry the potential to produce foetal hypoxia associated with maternal hypotension. Amlodipine was not teratogenic in rats (18 mg/kg/day) or rabbits (10 mg/kg/day). Oral doses of amlodipine (7 mg/kg/day) given to rats at or near parturition induced a prolongation of gestation time, an increase in the number of stillbirths and a decrease in postnatal survival.
 Experience in humans indicates that amlodipine is transferred into human breast milk. The median amlodipine concentration ratio of milk/plasma in 31 lactating women with pregnancy induced hypertension was 0.85 following amlodipine administration at an initial dose of 5 mg once daily which was adjusted as needed (mean daily dose and body weight adjusted daily dose: 6 mg and 98.7 microgram/kg respectively). The estimated daily dose of amlodipine in the infant via breast milk was 4.17 microgram/kg.
It is not known whether atorvastatin is excreted in human milk. In rats, plasma concentrations of atorvastatin are similar to those in milk. Because of the potential for adverse reactions in nursing infants, women taking amlodipine besilate and atorvastatin calcium trihydrate tablets should not breast-feed (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Amlodipine besilate and atorvastatin calcium trihydrate tablet has been evaluated in 1092 patients in double-blind, placebo-controlled studies who were treated for concomitant hypertension and dyslipidaemia. In clinical trials with amlodipine besilate and atorvastatin calcium trihydrate tablet, no adverse events peculiar to this combination have been observed.
In general, treatment with amlodipine besilate and atorvastatin calcium trihydrate tablet was well tolerated and adverse events were mild to moderate in severity. In controlled clinical trials, discontinuation of therapy due to adverse events or laboratory abnormalities was 5.1% of patients treated with the amlodipine/atorvastatin component vs 4% in the placebo treated patients.
Adverse events reported in more than 1% of patients who took concomitant amlodipine and atorvastatin in the AVALON and RESPOND studies are provided in Table 1.
The safety profile of the combination product is consistent with the adverse events previously reported for amlodipine and/or atorvastatin that are detailed below.

Amlodipine.

In general, treatment with amlodipine was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N = 1,730) in doses up to 10 mg to placebo (N = 1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total TG, total-C, HDL-C, uric acid, blood urea nitrogen or creatinine or liver function tests.
The most common adverse events are headache and oedema. The incidence (%) of side effects that occurred in a dose related manner was as follows (see Table 2).
Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo controlled clinical trials include the following (see Table 3).
The following events occurred in ≤ 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship.

Cardiovascular.

Hypotension, peripheral ischaemia, syncope, tachycardia, postural dizziness, postural hypotension, angioedema.

Central and peripheral nervous system.

Hypoaesthesia, paresthesia, tremor, vertigo, peripheral neuropathy.

Gastrointestinal.

Anorexia, constipation, dyspepsia*, dysphagia, diarrhoea, flatulence, vomiting, altered bowel habits, pancreatitis, gingival hyperplasia.

General.

Allergic reactions, asthenia*, back pain, hot flushes, malaise, pain, rigors, weight gain.

Musculoskeletal system.

Arthralgia, arthrosis, muscle cramps*, myalgia.

Psychiatric.

Sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalisation, mood changes.

Respiratory system.

Dyspnoea*, epistaxis.

Skin and appendages.

Alopecia, pruritus*, rash*, rash erythematous, rash maculopapular, vasculitis.

Special senses.

Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary system.

Micturition frequency, micturition disorder, nocturia.

Autonomic nervous system.

Dry mouth, sweating increased.

Metabolic and nutritional.

Thirst, hyperglycaemia.

Haemopoietic.

Purpura, leucopenia, thrombocytopenia.

Endocrine.

Gynaecomastia.
* These events occurred in less than 1% in placebo-controlled trials, but the incidence of these adverse events was between 1% and 2% in all multiple-dose studies.
The following events occurred in ≤ 0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discolouration, urticaria, skin dryness, dermatitis, erythema multiforme, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, xerophthalmia and weight decrease.
As with other calcium channel blockers, the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.
There have been infrequent, post-marketing reports of hepatitis, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis). Some cases severe enough to require hospitalisation have been reported in association with use of amlodipine. In many instances, causal association is uncertain.
There have been post-marketing reports of extrapyramidal disorder in association with use of amlodipine.
Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well compensated congestive heart failure, peripheral vascular disease, diabetes mellitus and abnormal lipid profiles.

Atorvastatin.

Atorvastatin is generally well tolerated. Adverse events have usually been mild and transient.
Clinical adverse events. In the atorvastatin placebo controlled clinical trial database of 16,066 patients (8,755 atorvastatin; 7,311 placebo), treated for a median period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
The most frequent (≥ 1%) adverse effects associated with atorvastatin therapy reported, in patients participating in placebo-controlled clinical studies include:

Gastrointestinal disorders.

Dyspepsia, nausea, flatulence, diarrhoea.

Infections and infestations.

Nasopharyngitis.

Investigations.

Liver function test abnormal1, blood creatine phosphokinase increased.

Metabolism and nutrition disorders.

Hyperglycaemia.

Musculoskeletal and connective tissue disorders.

Myalgia, arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, joint swelling.

Respiratory, thoracic and mediastinal disorders.

Pharyngolaryngeal pain, epistaxis.
1 Refers to the following preferred terms: hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, liver function test abnormal and transaminases increased.
Additional adverse events. The following have been reported in clinical trials of atorvastatin, however, not all the events listed have been causally associated with atorvastatin therapy.

Common (≥ 1% and < 10%).

Gastrointestinal disorders: constipation.
Infections and infestations: urinary tract infection.
Nervous system disorders: headache.

Uncommon (≥ 0.1% and < 1%).

Ear and labyrinth disorders: deafness.
Eye disorders: vision blurred.
Gastrointestinal disorders: abdominal discomfort, abdominal pain, vomiting.
General disorders and administration site conditions: asthenia, malaise.
Infections and infestations: infection, influenza.
Metabolism and nutrition disorders: anorexia.
Musculoskeletal and connective tissue disorders: back pain, neck pain.
Nervous system disorders: paraesthesia.
Psychiatric disorders: insomnia, nightmare.
Reproductive system and breast disorders: erectile dysfunction.
Respiratory, thoracic and mediastinal disorders: asthma.
Skin and subcutaneous tissue disorders: rash, pruritus, urticaria.

Rare (≥ 0.01% and < 0.1%).

Ear and labyrinth disorders: tinnitus.
Gastrointestinal disorders: pancreatitis, eructation.
General disorders and administration site conditions: pyrexia.
Hepatobiliary disorders: hepatitis, cholestasis.
Immune system disorders: hypersensitivity (including anaphylaxis).
Infections and infestations: sinusitis, pharyngitis.
Injury, poisoning and procedural complications: injury.
Investigations: white blood cells urine positive.
Metabolism and nutrition disorders: hypoglycaemia.
Musculoskeletal and connective tissue disorders: myositis, myopathy, muscle fatigue.
Nervous system disorders: peripheral neuropathy.
Skin and subcutaneous tissue disorders: angioedema, alopecia.
A post-hoc analysis of a clinical study (SPARCL) in patients without known coronary heart disease who had a recent stroke or TIA, showed an increased risk of haemorrhagic stroke in patients with prior haemorrhagic stroke or prior lacunar infarct (see Section 4.4 Special Warnings and Precautions for Use).
In ASCOT (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Prevention of cardiovascular disease) involving 10,305 participants treated with atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137), the safety and tolerability profile of the group treated with atorvastatin was comparable to that of the group treated with placebo during a median of 3.3 years of follow up.

Post-marketing experience.

Rare adverse events that have been reported post-marketing which are not listed above, regardless of causality, include the following.

Blood and lymphatic system disorders.

Thrombocytopenia.

General disorders and administration site conditions.

Chest pain, fatigue, peripheral oedema.

Hepatobiliary disorders.

Hepatic failure.

Injury, poisoning and procedural complications.

Tendon rupture.

Investigations.

Weight increased.

Musculoskeletal and connective tissue disorders.

Lupus-like syndrome, muscle rupture, immune-mediated necrotising myopathy, rhabdomyolysis which may be fatal2 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Nervous system disorders.

Hypoaesthesia, dizziness, amnesia, dysgeusia, myasthenia gravis.

Eye disorders.

Ocular myasthenia.

Reproductive system and breast disorders.

Gynaecomastia.

Skin and subcutaneous tissue disorders.

Bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).
The following adverse events have been reported with some statins: exceptional cases of interstitial lung disease, especially with long-term therapy (see Section 4.4 Special Warnings and Precautions for Use).
2 Examples of signs and symptoms are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure and cardiac arrhythmia.

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.

There is no information on overdoses with amlodipine besilate and atorvastatin calcium trihydrate tablet.
Available data suggest that amlodipine besilate and atorvastatin calcium trihydrate tablet overdose, due to its CCB component, might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. Dysrhythmias may occur following overdose with any calcium antagonist. Hypotension and bradycardia are usually seen within 1 to 5 hours following amlodipine overdose. Hypotension can persist for longer than 24 hours despite treatment. Cardiac rhythm disturbances have been noted to persist for up to 7 days. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment.

If massive amlodipine besilate and atorvastatin calcium trihydrate tablet overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support, including elevation of the extremities, and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors should be considered with attention to circulating volume and urine output. Intravenous calcium may help to reverse the effects of calcium entry blockade. In symptomatic patients, monitor serum creatinine, BUN, creatinine kinase, urine myoglobin for indications of renal impairment secondary to rhabdomyolysis and liver function tests.
If there has been significant ingestion, consider administration of activated charcoal. Administration of activated charcoal to healthy volunteers immediately or up to 2 hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Ipecac emesis is not recommended since haemodynamic instability and CNS depression may rapidly develop. As both amlodipine and atorvastatin are highly protein bound, dialysis is not likely to be of benefit. For atorvastatin induced rhabdomyolysis, administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Diuretics may be necessary to maintain urine output. Urinary alkalinisation is not routinely recommended.
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.

Amlodipine besilate and atorvastatin calcium trihydrate tablet has a dual mechanism of action consisting of the dihydropyridine calcium ion antagonist, amlodipine and the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin.
Studies have been conducted in which placebo, amlodipine alone, atorvastatin alone, and the eight dose combinations of amlodipine and atorvastatin have been administered once daily, in patients with comorbid hyperlipidaemia and hypertension. Analyses of changes in systolic blood pressure demonstrated that there was no overall modification of amlodipine's effect on systolic blood pressure when the drug was taken in combination with atorvastatin compared to amlodipine alone. Analyses of changes in low density lipoprotein cholesterol (LDL-C) demonstrated that there was no overall modification of atorvastatin's effect on LDL-C when the drug was taken in combination with amlodipine compared with atorvastatin alone (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Antihypertensive/anti-anginal action of amlodipine.

Amlodipine is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionised compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterised by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces the total ischaemic burden by the following two actions.
1. Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. Amlodipine has been shown to block constriction in main coronary arteries and coronary arterioles, induced by calcium, potassium, adrenaline, serotonin and thromboxane A2 analogue both in normal and in ischaemic regions.

Haemodynamics.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreased arterial blood pressure and increased heart rate in haemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients.
The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation, thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

The dyslipidaemic action of atorvastatin.

Atorvastatin is an inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the high affinity LDL receptor.
Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL. Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a marked and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles.
A variety of clinical and pathologic studies have demonstrated that elevated cholesterol and lipoprotein levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.
The atorvastatin component reduces total-C, LDL-C, and apo B in both healthy volunteers and in patients with homozygous and heterozygous forms of familial hypercholesterolaemia (FH), non-familial forms of hypercholesterolaemia, and mixed dyslipidaemia. Atorvastatin also reduces very low density lipoprotein cholesterol (VLDL-C) and TG and produces variable increases in HDL-C and apolipoprotein A1 (apo A1). Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B and TG, and increases HDL-C in patients with isolated hypertriglyceridaemia. Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinaemia. In animal models, atorvastatin limits the development of lipid-enriched atherosclerotic lesions and promotes the regression of pre-established atheroma.
Atorvastatin and its metabolites are responsible for pharmacological activity in humans. The liver is its primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dose rather than systemic drug concentration correlates better with LDL-C reduction. Individualisation of drug dose should be based on therapeutic response (see Section 4.2 Dose and Method of Administration).

Clinical trials.

Amlodipine/atorvastatin combination.

Studies in patients with hypertension and dyslipidaemia.

In the RESPOND double blind, placebo controlled study, a total of 1,660 patients with comorbid hypertension and dyslipidaemia received once daily treatment with eight dose combinations of amlodipine and atorvastatin (5 mg/10 mg, 10 mg/10 mg, 5 mg/20 mg, 10 mg/20 mg, 5 mg/40 mg, 10 mg/40 mg, 5 mg/80 mg, 10 mg/80 mg), amlodipine alone (5 mg and 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, 80 mg) or placebo. At 8 weeks, all eight combination treatment groups of amlodipine and atorvastatin demonstrated statistically significant dose-related reductions in systolic blood pressure (SBP) and LDL-C compared to placebo, with no overall modification of effect of either component on SBP and LDL-C (Table 4).
In the AVALON double blind, placebo controlled study, a total of 847 patients with comorbid hypertension and dyslipidaemia received once daily placebo, 5 mg amlodipine, 10 mg of atorvastatin or the combination of 5 mg amlodipine and 10 mg atorvastatin. The primary objective of the study was the percentage of patients on the combination of amlodipine and atorvastatin reaching JNC VI and NCEP III goals compared to atorvastatin, amlodipine and placebo alone. The results following 8 weeks of treatment are summarised in Table 5. Significantly more patients treated with the combination (45.5%) reached both their blood pressure (BP) and LDL-C goals compared to amlodipine or atorvastatin alone. Amlodipine besilate and atorvastatin calcium trihydrate tablet was not studied in patients with decompensated chronic cardiac failure or postmyocardial infarction (within 3 to 6 months).
Amlodipine component.

Studies in patients with congestive heart failure.

Amlodipine has been compared to placebo in four 8 to 12 week studies of male and female patients with New York Heart Association (NYHA) class II-IV heart failure, involving a total of 697 patients. Primary endpoints for these studies were: Symptom Limiting Exercise Time, Pulmonary Capillary Wedge Pressure (PCWP) and Cardiac Index (CI). Secondary endpoints varied from study to study and included Functional Status (NYHA classification), Cardiopulmonary Exam (including symptomatic status), Left Ventricular Ejection Fraction (LVEF), and Gas Exchange Measurement.
Although efficacy in regard to the primary and secondary endpoints was not demonstrated, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. See Table 6.
In a long-term (follow-up at least 6 months, mean 13.8 months) placebo controlled mortality/morbidity study of amlodipine 5 to 10 mg in 1153 patients with NYHA classes III (n = 931) or IV (n = 222) heart failure on stable doses of diuretics, digoxin and angiotensin converting enzyme (ACE) inhibitors, amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all cause mortality and cardiac morbidity (as defined by life threatening arrhythmia, acute myocardial infarction, or hospitalisation for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo: the cardiac morbid events represented about 25% of the endpoints in the study.
In this study, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Electrophysiologic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg of amlodipine and a further 10 mg of amlodipine after a 30 minute interval produced peripheral vasodilation and afterload reduction, but did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse events on electrocardiographic parameters were observed.
In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Effects in hypertension.

In patients with hypertension once daily dosing provides clinically significant reductions in blood pressure in both the supine and standing positions throughout the 24 hour interval post-dose. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration. The blood pressure effect is maintained over the 24 hour dosing interval, with little difference in peak and trough effect. Tolerance has not been demonstrated in patients studied for up to 1 year. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure.

Effects in chronic stable angina.

In patients with angina, once daily administration of amlodipine increases total exercise time to angina onset and total work time to 1 mm ST segment depression and decreases both angina attack frequency and glyceryl trinitrate tablet consumption. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

Other.

In clinical trials amlodipine has shown no harmful effect on lipid levels. Dihydropyridine calcium channel blockers have not been associated with any adverse metabolic effects and are suitable for use in patients with asthma, diabetes and gout.
Atorvastatin component. In a multicentre, placebo controlled, double blind dose response study in patients with hypercholesterolaemia, atorvastatin was given as a single daily dose over 6 weeks. Atorvastatin (10 mg-80 mg) reduced total-C (30%-46%), LDL-C (41%-61%), apo B (34%-50%) and TG (14%-33%) while producing variable increases in HDL-C and apolipoprotein A (Table 7). A therapeutic response was seen within 2 weeks, and maximum response achieved within 4 weeks.
In three further trials, 1,148 patients with either heterozygous familial hypercholesterolaemia, non-familial forms of hypercholesterolaemia, or mixed dyslipidaemia were treated with atorvastatin for one year. The results were consistent with those of the dose response study and were maintained for the duration of therapy.
In patients with primary hypercholesterolaemia and mixed dyslipidaemia (Fredrickson types IIa and IIb), data pooled from 24 controlled trials demonstrated that the adjusted mean percent increases from baseline in HDL-C for atorvastatin (10-80 mg) were 5.0% to 7.8% in a non-dose related manner.
Clinical studies demonstrate that a dose of 10 mg atorvastatin is more effective than simvastatin 10 mg and pravastatin 20 mg in reducing LDL-C, total-C, TG and apo B. In several multicentre, double-blind studies in patients with hypercholesterolaemia, atorvastatin was compared to other HMG-CoA reductase inhibitors. After randomisation, patients were treated with atorvastatin 10 mg per day or the recommended starting dose of the comparative agent. At week 16 a greater proportion of atorvastatin treated patients than those treated with simvastatin (46% vs. 27%) or pravastatin (65% vs. 19%) reached their target LDL-C levels. Increasing the dosage of atorvastatin resulted in more patients reaching target LDL-C goals.

Prevention of cardiovascular disease.

In the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium trihydrate on the composite endpoint of fatal coronary heart disease and non-fatal myocardial infarction (MI) was assessed in 10,305 hypertensive patients, 40 to 79 years of age, without a history of symptomatic coronary heart disease and with total-C levels ≤ 6.5 mmol/L. Additionally, all patients were at moderate risk of coronary heart disease, having at least 3 of the predefined cardiovascular risk factors [male gender (81%), age ≥ 55 years (84%), smoking (33%), noninsulin dependent diabetes mellitus (25%), history of CHD in a first degree relative (26%), plasma total-C to HDL-C ratio ≥ 6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy on echocardiography (14%), past history of cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%)]. Patients with a history of previous myocardial infarction or angina were excluded.
In this randomised, double-blind, placebo-controlled study, patients were treated with antihypertensive therapy (goal BP < 140/90 mmHg for non-diabetic patients, < 130/80 mmHg for diabetic patients) and either atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137) and followed for a median duration of 3.3 years. At baseline, in the atorvastatin group, 38 patients (0.7%) had total-C levels less than 3.5 mmol/L; 2,340 patients (45.3%) had total-C levels greater than or equal to 3.5 mmol/L and less than 5.5 mmol/L; 2,304 patients (44.6%) had total-C levels greater than or equal to 5.5 mmol/L and less than 6.5 mmol/L; and 486 patients (9.4%) had total-C levels greater than or equal to 6.5 mmol/L. At baseline, 457 patients (9.8%) in the atorvastatin group had LDL-C levels less than or equal to 2.5 mmol/L; 1,731 patients (37%) had LDL-C levels greater than 2.5 mmol/L and less than 3.4 mmol/L; and 2,495 patients (53.3%) had LDL-C levels greater than or equal to 3.4 mmol/L. Median (25th and 75th percentile) changes from baseline after 1 year of atorvastatin treatment in total-C, LDL-C, TG and HDL-C were -1.40 mmol/L (-1.80, -0.90), -1.27 mmol/L (-1.66, -0.84), -0.20 mmol/L (-0.60, 0.10) and 0.00 mmol/L (-0.10, 0.10). Blood pressure control throughout the trial was similar in patients assigned to atorvastatin and placebo.
The primary endpoint examined in ASCOT was the rate of fatal coronary heart disease or non-fatal myocardial infarction over 3.3 years. These coronary events occurred in 1.9% of atorvastatin treated patients compared to 3% of placebo treated patients, a relative risk reduction of 36% (p = 0.0005) (Table 8). Although this difference was statistically significant for the whole trial population, this difference was not statistically significant in specified subgroups such as diabetes, patients with left ventricular hypertrophy (LVH), previous vascular disease or metabolic syndrome.
There was no statistically significant reduction in the rate of total mortality, cardiovascular mortality or heart failure in the atorvastatin treated group compared to placebo.

Noninsulin dependent diabetes mellitus (NIDDM).

A 26-week randomised, double-blind, comparator study in NIDDM subjects showed that atorvastatin is effective in dyslipidaemic patients with NIDDM. A 10 mg dose of atorvastatin produced a 34% reduction in LDL-C, a 27% reduction in total-C, a 24% reduction in TG and a 12% rise in HDL-C.

Homozygous familial hypercholesterolaemia.

Atorvastatin has also been shown to reduce LDL-C in patients with homozygous familial hypercholesterolaemia (FH), a population that has not usually responded to other lipid lowering medication. In an uncontrolled compassionate use study, 29 patients aged 6 to 37 years with homozygous FH received maximum daily doses of 20 mg to 80 mg of atorvastatin. The mean LDL reduction in this study was 18%. Twenty five patients with a reduction in LDL-C had a mean response of 20% (range 7%-53%, median 24%). 5 of the 29 patients had absent LDL receptor function, 3 of whom responded to atorvastatin with a mean LDL-C reduction of 22%. Experience in paediatric patients has been limited to patients with homozygous FH.

Hypertriglyceridaemia.

In patients with hypertriglyceridaemia (baseline TG ≥ 2.26 mmol/L and LDL-C < 4.14 mmol/L) atorvastatin (10 to 80 mg) reduced serum TG by 31% to 40%. In patients with severe hypertriglyceridaemia (baseline TG > 5.7 mmol/L), atorvastatin (10 to 80 mg) reduced serum TG by 30% to 56%.
In a randomised, placebo controlled, double blind, multicentre study in patients with hypertriglyceridaemia (TG ≥ 3.95 mmol/L, LDL-C ≤ 4.1 mmol/L), atorvastatin 20 mg/day and 80 mg/day produced significantly greater reductions in TG levels than placebo (Table 9).

Dysbetalipoproteinaemia.

In patients with dysbetalipoproteinaemia, atorvastatin (10 to 80 mg) reduced IDL-C (range 28% to 52%) and IDL-C + VLDL-C (range 34% to 58%).
In an open-label, randomised, crossover study in patients with dysbetalipoproteinaemia, treatment with atorvastatin 80 mg/day resulted in significantly greater mean percent decreases in IDL-C + VLDL-C, IDL-C, total-C, VLDL-C and Apo B than either simvastatin 40 mg/day or gemfibrozil 1200 mg/day and significantly greater mean percent decreases in TG than simvastatin 40 mg/day (Table 10).

5.2 Pharmacokinetic Properties

Amlodipine besilate and atorvastatin calcium trihydrate tablet.

Following oral administration of amlodipine besilate and atorvastatin calcium trihydrate tablet, peak plasma concentrations are observed within 1 to 2 hours for atorvastatin and between 6 and 12 hours for amlodipine. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from amlodipine besilate and atorvastatin calcium trihydrate tablet are not significantly different from the bioavailability of amlodipine and atorvastatin from co-administration of amlodipine and atorvastatin tablets as assessed by Cmax and AUC for the amlodipine component and Cmax and AUC for the atorvastatin component in healthy volunteers.
The bioavailability of amlodipine from amlodipine besilate and atorvastatin calcium trihydrate tablet was not affected by food as assessed by Cmax: 105% (90% CI: 99%-111%) and AUC: 101% (90% CI: 97%-105%). Although food decreases the rate and extent of absorption of atorvastatin from amlodipine besilate and atorvastatin calcium trihydrate tablet by approximately 32% and 11% respectively, as assessed by Cmax: 68% (90% CI: 60%-79%) and AUC: 89% (90% CI: 83%-95%), similar reductions in plasma concentrations in the fed state have been seen with atorvastatin without a reduction in LDL-C effect.
Co-administration of multiple 10 mg doses of amlodipine with 80 mg atorvastatin in healthy subjects resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin compared to when the two drugs were given independently. The individual pharmacokinetic profile of amlodipine and atorvastatin are outlined below.
Amlodipine.

Absorption.

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6 and 12 hours post-dose. This may reflect significant initial uptake by the liver, followed by a phase of redistribution. This interval is shorter (2 to 8 hours) in patients with hepatic insufficiency. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.

Distribution.

The volume of distribution is approximately 20 L/kg. The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Steady-state plasma levels are reached after 7 to 8 days of consecutive dosing in healthy volunteers.

Metabolism and excretion.

Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Atorvastatin.

Absorption.

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. A constant proportion of atorvastatin is absorbed intact. The absolute bioavailability is 14%. The low systemic availability is attributed to pre-systemic clearance in gastrointestinal mucosa and/or hepatic first pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9% respectively as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared to morning. However, LDL-C reduction is the same regardless of the time of day of drug administration (see Section 4.2 Dose and Method of Administration).

Distribution.

The mean volume of distribution of atorvastatin is about 400 L. Atorvastatin is ≥ 98% bound to plasma proteins. A red blood cell/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

Metabolism.

In humans, atorvastatin is extensively metabolised to ortho- and para-hydroxylated derivatives. In vitro inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme (see Section 4.4 Special Warnings and Precautions for Use). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion.

Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters MDR1 and BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Special populations.

No studies have been conducted with amlodipine besilate and atorvastatin calcium trihydrate tablet in special populations. Information is provided below on the individual components of amlodipine besilate and atorvastatin calcium trihydrate tablet.
Elderly (≥ 65 years).

Amlodipine.

In elderly hypertensive patients (mean age 69 years) there was a decrease in clearance of amlodipine from plasma as compared to young volunteers (mean age 36 years) with a resulting increase in the area under the curve (AUC) of about 60%.

Atorvastatin.

Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥ 65 years) than in young adults. Lipid effects are comparable to that seen in younger patient populations given equal doses of atorvastatin.
Gender.

Atorvastatin.

Plasma concentrations of atorvastatin in women differ (approximately 20% higher for Cmax and 10% lower for AUC) from those in men; however, there is no clinically significant difference in lipid effects with atorvastatin between men and women.
Renal impairment.

Amlodipine.

Amlodipine is extensively metabolised to inactive metabolites with 10% excreted as unchanged drug in the urine. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine may be used in such patients at normal doses. Amlodipine is not dialysable.

Atorvastatin.

Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary. While studies have not been conducted in patients with end stage renal disease, haemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Hepatic impairment. See Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.

5.3 Preclinical Safety Data

Genotoxicity.

There are no genotoxicity or carcinogenicity studies with the amlodipine/atorvastatin combination.

Amlodipine.

Amlodipine did not induce gene mutation in bacteria and mouse lymphoma cells; nor did it induce chromosome aberrations in human lymphocytes or Chinese hamster V79 fibroblast cells (in vitro) and in mouse bone marrow cells (in vivo).

Atorvastatin.

Atorvastatin did not demonstrate mutagenic or clastogenic potential in an appropriate battery of assays. It was negative in the Ames test with Salmonella typhimurium and Escherichia coli, and in the in vitro hypoxanthine-guanine phosphoribosyltransferase (HGPRT) forward mutation assay in Chinese hamster lung cells. Atorvastatin did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay and was negative in the in vivo mouse micronucleus test.

Carcinogenicity.

There are no carcinogenicity studies with amlodipine/ atorvastatin combination.

Amlodipine.

The carcinogenic potential of amlodipine has not been fully elucidated. Amlodipine did not induce any tumours when tested in mice or rats at oral doses up to 2.5 mg/kg. This dose gave rise to plasma levels that are similar to or below those achieved clinically.

Atorvastatin.

In a 2-year study in rats given 10 mg/kg/day, 30 mg/kg/day or 100 mg/kg/day, the incidence of hepatocellular adenoma was marginally, although not significantly, increased in females at 100 mg/kg/day. The maximum dose used was 11 times higher than the highest human dose (80 mg/day) based on AUC (0-24) values. In a 2 year study in mice given 100 mg/kg, 200 mg/kg or 400 mg/kg, incidences of hepatocellular adenoma in males and hepatocellular carcinoma in females were increased at 400 mg/kg/day. The maximum dose used was 14 times higher than the highest human dose (80 mg/day) based on AUC (0-24) values. Other HMG-CoA reductase inhibitors have been reported to induce hepatocellular tumours in mice and rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

In addition to the active ingredients amlodipine besilate and atorvastatin calcium trihydrate, each Cadivast tablet contains the following inactive ingredients: colloidal anhydrous silica, sodium carbonate, microcrystalline cellulose, arginine, pregelatinised maize starch, croscarmellose sodium, hyprolose, magnesium stearate, Opadry AMB complete film coating system OY-B-28920 White (ARTG PI No: 4271) [5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg and 5 mg/80 mg], Opadry AMB aqueous moisture barrier coating system 80W10932 Blue (ARTG PI No: 106951) [10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg and 10 mg/80 mg].

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. Protect from light.

6.5 Nature and Contents of Container

Container type: HDPE bottles with PP child resistant closures containing 30 or 90 tablets. HDPE bottles with PP closures containing 500 tablets for dispensing only. Not for individual patient supply.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian Register of Therapeutic Goods (ARTG).

AUST R 199213 - Cadivast 5/10 amlodipine (as besilate) and atorvastatin (as calcium) 5 mg/10 mg tablets bottle.
AUST R 199222 - Cadivast 5/20 amlodipine (as besilate) and atorvastatin (as calcium) 5 mg/20 mg tablets bottle.
AUST R 199214 - Cadivast 5/40 amlodipine (as besilate) and atorvastatin (as calcium) 5 mg/40 mg tablets bottle.
AUST R 199210 - Cadivast 5/80 amlodipine (as besilate) and atorvastatin (as calcium) 5 mg/80 mg tablets bottle.
AUST R 199215 - Cadivast 10/10 amlodipine (as besilate) and atorvastatin (as calcium) 10 mg/10 mg tablets bottle.
AUST R 199223 - Cadivast 10/20 amlodipine (as besilate) and atorvastatin (as calcium) 10 mg/20 mg tablets bottle.
AUST R 199225 - Cadivast 10/40 amlodipine (as besilate) and atorvastatin (as calcium) 10 mg/40 mg tablets bottle.
AUST R 199217 - Cadivast 10/80 amlodipine (as besilate) and atorvastatin (as calcium) 10 mg/80 mg tablets bottle.

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

Amlodipine.


Chemical structure.

Structural formula:
Chemical name: 3-ethyl, 5-methyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzene sulfonate.
Molecular formula: C20H25ClN2O5.C6H6O3S.
Molecular weight: 567.1.

CAS number.

CAS registry no.: 111470-99-6.

Atorvastatin calcium trihydrate.


Chemical structure.

Structural formula:
Chemical name: (3R, 5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate calcium trihydrate.
Molecular formula: C66H68CaF2N4O10.3H2O.
Molecular weight: 1209.39.

CAS number.

CAS registry no.: 344423-98-9.
Amlodipine besilate is white or almost white powder. Atorvastatin calcium trihydrate is white or almost white powder. Amlodipine besilate is slightly soluble in water, freely soluble in methanol, sparingly soluble in anhydrous ethanol and slightly soluble in 2-propanol. Atorvastatin calcium trihydrate slightly soluble in water, slightly soluble in ethanol (96%), and practically insoluble in methylene chloride.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes