Consumer medicine information

Atorvastatin SZ

Atorvastatin

BRAND INFORMATION

Brand name

Atorvastatin SZ

Active ingredient

Atorvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Atorvastatin SZ.

SUMMARY CMI

Atorvastatin SZ

Consumer Medicine Information (CMI) summary

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

1. Why am I using Atorvastatin SZ?

Atorvastatin SZ contains the active ingredient atorvastatin. Atorvastatin SZ is used to lower high cholesterol levels.

Atorvastatin SZ 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 more information, see Section 1. Why am I using Atorvastatin SZ? in the full CMI.

2. What should I know before I use Atorvastatin SZ?

Do not use if you have ever had an allergic reaction to Atorvastatin SZ or any of the ingredients listed at the end of the CMI.

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

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

3. What if I am taking other medicines?

Some medicines may interfere with Atorvastatin SZ and affect how it works.

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

4. How do I use Atorvastatin SZ?

  • The usual dose of Atorvastatin SZ is between 10-80 mg taken once a day.
  • Swallow the tablets whole with a full glass of water. Do not chew or crush the tablets.

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

5. What should I know while using Atorvastatin SZ?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Atorvastatin SZ.
  • Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not give Atorvastatin SZ to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how Atorvastatin SZ affects you.
  • Atorvastatin generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, it may cause dizziness in some people.
Drinking alcohol
  • Avoid drinking large quantities of alcohol.
  • Drinking large quantities of alcohol while taking Atorvastatin SZ may increase your chance of liver problems.
Looking after your medicine
  • Keep Atorvastatin SZ in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets where children cannot reach them.

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

6. Are there any side effects?

Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. Tell your doctor or pharmacist if you notice any of the following and they worry you: muscle and joint pain, muscle weakness, especially in the forearms, thighs, hips, shoulders, neck, and back, difficulty climbing stairs or standing up from a chair, difficulty lifting arms over the head.

This is not a complete list of all possible side effects.

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



FULL CMI

Atorvastatin SZ

Active ingredient(s): atorvastatin calcium trihydrate


Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Atorvastatin SZ?

Atorvastatin SZ contains the active ingredient atorvastatin calcium trihydrate.

Atorvastatin SZ belongs to a group of medicines called HMG-CoA reductase inhibitors. It works by reducing the amount of cholesterol made by the liver. Atorvastatin SZ reduces the ‘bad’ cholesterol and can raise the 'good' cholesterol. Atorvastatin SZ also helps to protect you from a heart attack or stroke.

Atorvastatin SZ is 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. Examples of risk factors for CHD include diabetes, a history of stroke, or small blood vessel disease.

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

Your doctor may have prescribed it for another reason.

Atorvastatin SZ is not addictive.

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

What is cholesterol?

Everyone has cholesterol in their blood. It is a type of blood fat needed by the body for many things, such as building the 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 have 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, cholesterol 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, which 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, Atorvastatin SZ 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.

2. What should I know before I use Atorvastatin SZ?

Warnings

Do not use Atorvastatin SZ if:

  • you are allergic to atorvastatin, or 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 use this medicine.
  • you have active liver disease
  • you are pregnant or intend to become pregnant
  • you are taking the antibiotic fusidic acid which is used to treat infections
  • you are taking the antiviral glecaprevir/pibrentasvir for the treatment of Hepatitis C
  • you have intolerance to some sugars. Contact your doctor before taking Atorvastatin SZ as it contains lactose.

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

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

Check with your doctor if you have any of the following medical conditions:

  • liver problems
  • kidney problems
  • muscle pain, tenderness or weakness from other medicines used to treat high cholesterol or triglycerides
  • a type of stroke called 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 another haemorrhagic stroke
  • breathing problems.

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

Tell your doctor if you drink alcohol regularly.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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 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.

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

Do not breastfeed if you are taking this medicine.

The active ingredient in Atorvastatin SZ may pass into breast milk and affect your baby.

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 be affected by Atorvastatin SZ or may affect how well 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 any of the following:

  • digoxin, a medicine used to treat some heart problems
  • diltiazem, a medicine used to treat angina
  • other medicines used to treat high cholesterol or triglycerides (fats)
  • antacids, medicines used to treat reflux or ulcers
  • the antibiotics erythromycin, clarithromycin, rifampicin and fusidic acid hemihydrate
  • phenytoin, a medicine used to treat epilepsy (seizures)
  • oral contraceptives for birth control
  • ciclosporin, a medicine used to suppress the immune system
  • some medicines used to treat fungal infections, such as Itraconazole or ketoconazole
  • protease inhibitors for the treatment of HIV infection and/or Hepatitis C, such as efavirenz, fosamprenavir, ritonavir, boceprevir, telaprevir, tipranavir/ritonavir, elbasvir/grazoprevir and simeprevir
  • HCV non structural protein 5A (NS5A)/5B (NS5B) inhibitors such as daclatasvir and ledipasvir
  • letermovir
  • 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.

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

4. How do I use Atorvastatin SZ?

How much to take

  • Follow the instructions provided and use Atorvastatin SZ until your doctor tells you to stop.
  • Your doctor will tell you how many tablets you need to take each day. This may depend on your condition and whether or not you are taking other medicines.
  • The usual dose of Atorvastatin SZ is between 10-80 mg taken once a day.

When to take Atorvastatin SZ

  • Atorvastatin SZ can be taken at any time of the day. However, your dose of Atorvastatin SZ should be taken 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.
  • Atorvastatin SZ can be taken with or without food.

How to take Atorvastatin SZ

  • Swallow the tablets whole with a glass of water. Do not crush or chew the tablets.
  • Your doctor will discuss with you the need to be on a diet while you are taking Atorvastatin SZ. Follow your agreed diet plan carefully.

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

How to long to take Atorvastatin SZ

  • Take Atorvastatin SZ every day and continue taking it for as long as your doctor tells you.
  • Atorvastatin SZ helps to lower your cholesterol, but it does not cure your condition. It is important to keep taking your medicine even if you feel well.
  • If you stop taking Atorvastatin SZ, your cholesterol levels may rise again.

If you forget to use Atorvastatin SZ

Atorvastatin SZ should be used regularly at the same time each day.

If you miss your dose at the usual time:

  • if 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 tablet 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, talk to your doctor or pharmacist.

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

If you use too much Atorvastatin SZ

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

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), 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.

5. What should I know while using Atorvastatin SZ?

Things you should do

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor will ask you to have your liver function tested from time to time while you are taking Atorvastatin SZ to make sure the medicine is working and to prevent unwanted side effects.

Your cholesterol and triglyceride levels also 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 Atorvastatin SZ.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Atorvastatin SZ.

Call your doctor straight away if you:

  • become pregnant while you are taking Atorvastatin SZ. If you become pregnant while taking Atorvastatin SZ, stop taking it and contact your doctor immediately.

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

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not give Atorvastatin SZ to anyone else, even if they have the same condition as you.
  • Do not take Atorvastatin SZ to treat any other complaints unless your doctor tells you to.

Things that would be helpful for your condition

Some self-help measures suggested below may assist your condition. Your doctor or pharmacist can give you more information about these measures.

  • weight: While you are taking Atorvastatin SZ, you need to follow a diet plan agreed to with your doctor. This may include measures to lose some weight.
  • exercise: Regular exercise can help lower your cholesterol levels. 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.
  • reduce alcohol: 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.
  • avoid smoking: Smoking increases the risk of you suffering from heart problems. Your doctor may advise you to stop smoking.

Driving or using machines

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

Atorvastatin generally does not cause any problems with the ability to drive a car or operate machinery. However, as with many other medicines, it may cause dizziness in some people.

If you feel dizzy, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Avoid drinking large quantities of alcohol.

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

Tell your doctor if you drink alcohol regularly.

Grapefruit Consumption

Avoid drinking large quantities of grapefruit juice.

Grapefruit juice contains one or more components that alter the metabolism of some medicines, including atorvastatin.

Drinking very large quantities (over 1.2 liters) of grapefruit juice each day while taking atorvastatin increases your chance of getting side effects.

Looking after your medicine

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

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

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

Keep it where young children cannot reach it.

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

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date, or if the packaging is torn or show signs of tampering.

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.

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
Muscle-joint related
  • muscle and joint pain, muscle weakness especially in the forearms, thighs, hips, shoulders, neck and back
  • difficulty climbing stairs or standing up from a chair
  • difficulty lifting arms over the head
  • falling or difficulty getting up from a fall
Gut or Gastrointestinal related
  • constipation, diarrhoea
  • stomach or belly pain, nausea (feeling sick)
  • heartburn, indigestion or wind
General disorders
  • headache
Others
  • 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.
These side effects are the more common side effects of your medicine. They are usually mild and short-lived.

Serious side effects

Serious side effectsWhat to do
Liver related
  • yellowing of skin and eyes and dark coloured urine
Kidney related
  • feeling weak and tired, excessively thirsty and passing more urine
Lungs related
  • problems with breathing, including shortness of breath, persistent cough and fever
Eye related
  • vision problems, eye muscle weakness and drooping eyelids
Call your doctor straight away if you notice any of these serious side effects.
These are serious side effects that may require medical attention. Serious side effects are rare.

Very serious side effects

Very serious side effectsWhat to do
Allergy related
  • symptoms of allergy such as skin rash, itching, swelling of the face, lips, mouth, tongue, throat or neck which may cause difficulty in swallowing or breathing
Heart related
  • chest pain
Muscles related
  • unexpected muscle pain, tenderness or weakness not caused by exercise, particularly if you also feel unwell or have a fever
Others
  • 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
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 hospitalization.

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

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

Reporting side effects

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

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

7. Product details

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

What Atorvastatin SZ contains

Active ingredient
(main ingredient)
atorvastatin calcium trihydrate
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • microcrystalline cellulose
  • calcium carbonate
  • croscarmellose sodium
  • hydroxypropylcellulose
  • polysorbate 80
  • magnesium stearate
  • hypromellose
  • Macrogol 8000
  • titanium dioxide
  • purified talc
  • Antifoam AF Emulsion Q7-2587
  • Euphorbia antisyphilitica leaf wax (only 10 mg, 20 mg and 40 mg)
Potential allergens
  • Sugars as lactose
  • milk or milk products
Atorvastatin SZ tablets do not contain gluten, sucrose or glucose.

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

What Atorvastatin SZ looks like

Atorvastatin SZ 10 mg tablets – white to off-white, elliptical, film-coated tablets debossed with 'AS10' on one side and plain on the other side (Aust R 179845).

Atorvastatin SZ 20 mg tablets – white to off-white, elliptical, film-coated tablets debossed with 'AS20' on one side and plain on the other side (Aust R 179842).

Atorvastatin SZ 40 mg tablets – white to off-white, elliptical, film-coated tablets debossed with 'AS40' on one side and plain on the other side (Aust R 179823).

Atorvastatin SZ 80 mg tablets - white to off-white, elliptical, film-coated tablets debossed with 'AS80' on one side and plain on the other side (Aust R 179833).

Pack size of 30 tablets.

Who distributes Atorvastatin SZ

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was prepared in January 2024.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Atorvastatin SZ

Active ingredient

Atorvastatin

Schedule

S4

 

1 Name of Medicine

Atorvastatin calcium trihydrate.

2 Qualitative and Quantitative Composition

Atorvastatin SZ tablets contain atorvastatin calcium trihydrate equivalent to 10, 20, 40 and 80 mg atorvastatin.

Excipients with known effect.

Sugars as lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Atorvastatin SZ 10 mg tablets are white to off-white; elliptical, film-coated tablets debossed 'AS10' on one side and plain on the other side.
Atorvastatin SZ 20 mg tablets are white to off-white; elliptical, film-coated tablets debossed 'AS20' on one side and plain on the other side.
Atorvastatin SZ 40 mg tablets are white to off-white; elliptical, film-coated tablets debossed 'AS40' on one side and plain on the other side.
Atorvastatin SZ 80 mg tablets are white to off-white; elliptical, film-coated tablets debossed 'AS80' on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Atorvastatin SZ is indicated as an adjunct to diet for the treatment of patients with hypercholesterolaemia.
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.
Atorvastatin SZ 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, Prevention of cardiovascular disease) to reduce the risk of nonfatal 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

Dosage.

Atorvastatin SZ can be administered within the dosage range of 10-80 mg/day as a single daily dose. Therapy should be individualised according to the target lipid levels, the recommended goal of therapy, and the patient's response. After initiation and/or upon titration of Atorvastatin SZ, lipid levels should be re-analysed within 4 weeks and dosage adjusted according to the patient's response.
Primary hypercholesterolaemia and mixed dyslipidaemia. The majority of patients are controlled with 10 mg Atorvastatin SZ once a day. A therapeutic response is evident within two weeks and the maximum response is usually achieved within four weeks. The response is maintained during chronic therapy.
Homozygous familial hypercholesterolaemia.

Adults.

In the compassionate use study of patients with homozygous familial hypercholesterolaemia, most patients responded to 80 mg of atorvastatin with a greater than 15% reduction in LDL-C (18%-42%).

Children.

Treatment experience in a paediatric population (with doses of atorvastatin up to 80 mg/day) is limited.

Method of administration.

Atorvastatin SZ is for oral administration and can be taken at any time of the day, with or without food.

Dosage adjustment.

Renal impairment.

Renal disease has no influence on the plasma concentrations or on the LDL-C reduction of atorvastatin; thus, no adjustment of the dose is required (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Hepatic impairment.

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease (Child-Pugh B). The benefits of therapy should be weighed against the risks when atorvastatin is to be given to patients with hepatic insufficiency (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Liver dysfunction; Section 5.1 Pharmacodynamic Properties).

Combination with other medicinal compounds.

In cases where coadministration of atorvastatin with ciclosporin, telaprevir, or the combination 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.
Caution should be used when coprescribing atorvastatin with medical 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, Skeletal muscle; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.3 Contraindications

Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see Section 4.4 Special Warnings and Precautions for Use, Liver dysfunction).
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation). Women of childbearing potential, unless on an effective contraceptive and highly unlikely to conceive.
Concomitant use with fusidic acid hemihydrate (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Treatment with the hepatitis C antivirals, glecaprevir/pibrentasvir.

4.4 Special Warnings and Precautions for Use

Liver dysfunction.

As with other lipid lowering agents of the same class, moderate (> 3 x upper limit of normal [ULN]) elevations of serum transaminases have been reported following therapy with atorvastatin.
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, 20, 40 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 pretreatment 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 ALT or AST of > 3 x ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.

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, azole antifungals, human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors, HCV non-structural protein 5A (NS5A)/5B (NS5B) inhibitors, letermovir 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. Lower starting and maintenance doses of atorvastatin should also be considered when taken concomitantly with the aforementioned drugs (see Section 4.2 Dose and Method of Administration, Combination with other medicinal compounds).
Atorvastatin must not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving concomitant fusidic acid 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 is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid 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.
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 necrotising 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 case 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 (1-6 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.

3-hydroxy-3-methylglutaryl-coenzyme A (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 an 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 haemoglobin A1c (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.

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.
Atorvastatin SZ contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Use in hepatic impairment.

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).

Use in the elderly.

Treatment experience in adults aged ≥ 70 years with doses of atorvastatin up to 80 mg/day has been evaluated in 221 patients. The safety and efficacy of atorvastatin in this population were similar to those of patients < 70 years of age.

Paediatric use.

Treatment experience in a paediatric population is limited to doses of atorvastatin up to 80 mg/day for 1 year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in these patients.

Effects on laboratory tests.

Atorvastatin can cause elevations in ALT/AST, alkaline phosphatase, GGT, bilirubin and creatine kinase.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Atorvastatin is metabolised by cytochrome P450 3A4 (CYP 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 depends on the variability of effect on cytochrome P450 3A4. Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have been noted with HIV protease inhibitors (fosamprenavir and combinations of lopinavir/ritonavir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir), 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, Combination with other medicinal compounds; Section 4.4 Special Warnings and Precautions for Use, 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 coadministration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in 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. Coadministration of this combination may cause increased plasma concentrations of both agents.
The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown.
Although interaction studies with statins 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, Skeletal muscle).

Colchicine.

Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine (see Section 4.4 Special Warnings and Precautions for Use, 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.

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

Colestipol.

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

Transporter inhibitors.

Atorvastatin and atorvastatin-metabolites are substrates 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 CYP 3A4, thus it increases exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Section 4.2 Dose and Method of Administration, Use in combination with other medicinal compounds).
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 (see Section 4.2 Dose and Method of Administration, Use in combination with other medicinal compounds).
The magnitude of cytochrome P450 3A- 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, Combination with other medicinal compounds).

Erythromycin/clarithromycin.

In healthy individuals, coadministration 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, Skeletal muscle).

Protease inhibitors.

Coadministration 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, Skeletal muscle).

Diltiazem hydrochloride.

Coadministration 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 atorvastatin were coadministered, steady-state plasma digoxin concentrations were unaffected. However, steady-state plasma digoxin concentrations increased by approximately 20% following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately.

Oral contraceptives.

Coadministration with an oral contraceptive containing norethindrone and ethinyl oestradiol increased AUC values for norethindrone and ethinyl oestradiol by approximately 30% and 20%. 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 coadministration of cimetidine.

Warfarin.

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

Amlodipine.

Atorvastatin pharmacokinetics were not altered by the coadministration of atorvastatin 80 mg daily and amlodipine 10 mg daily at steady state. In a drug-drug interaction study in healthy subjects, coadministration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin, which was not clinically meaningful.

Azithromycin.

Coadministration 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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 effects 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 effects on sperm or semen parameters, or on reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for 2 years (plasma AUC for enzyme inhibitory activity 13 times higher than in humans).
(Category D)
Atorvastatin is contraindicated in pregnancy. 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 hypercholesterolaemia. 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.
Atorvastatin 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 loss, decreased foetal weight and increased skeletal variations were observed in rats dosed at 100-300 mg/kg/day and rabbits dosed at 50-100 mg/kg/day. In a peri/post-natal study, rats dosed at 225 mg/kg/day showed an increased incidence of stillbirths, decreases in birthweight, 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 non-maternotoxic 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 a 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 is 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 reductase 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.
It is not known whether this drug 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 atorvastatin should not breastfeed (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

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)

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 events that may be 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 abnormal (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), 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.

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, abdominal pain.

Infections and infestations.

Urinary tract infection.

Musculoskeletal and connective tissue disorders.

Back pain.

Nervous system disorders.

Headache.
Uncommon (≥ 0.1% and < 1%).

Ear and labyrinth disorders.

Deafness, tinnitus.

Eye disorders.

Vision blurred.

Gastrointestinal disorders.

Abdominal discomfort, abdominal pain, vomiting.

General disorders and administration site conditions.

Asthenia, malaise.

Infections and infestations.

Infection, influenza.

Investigations.

White blood cells urine positive.

Metabolism and nutrition disorders.

Anorexia.

Musculoskeletal and connective tissue disorders.

Neck pain, back pain, muscle fatigue.

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%).

Eye and labyrinth disorders.

Visual disturbance, 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.

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 = 5168) or placebo (n = 5137), 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.

Haemic 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.

Metabolic and nutritional disorders.

Weight gain.

Musculoskeletal and connective tissue disorders.

Lupus-like syndrome, muscle rupture, immune mediated necrotizing myopathy, rhabdomyolysis which may be fatal (example of signs and symptoms are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure and cardiac arrhythmia) (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).

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/reportingproblems.

4.9 Overdose

There is no specific treatment for atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically, and supportive measures instituted as required. In symptomatic patients, monitor serum creatinine, BUN, creatinine phosphokinase, and urine myoglobin for indications of renal impairment secondary to rhabdomyolysis. Liver function tests should be performed in symptomatic patients.
If there has been significant ingestion, consider administration of activated charcoal. Activated charcoal is most effective when administered within 1 hour of ingestion. 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. For 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. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Atorvastatin is a synthetic lipid lowering agent. Atorvastatin is an inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-coenzyme A 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.
Atorvastatin reduces total-C, LDL-C, and apo B in both normal volunteers and in patients with homozygous and heterozygous familial hypercholesterolaemia (FH), nonfamilial 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 A-1. 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.

Pharmacodynamics.

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.

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 (10-80 mg) reduced total-C (30%-46%), LDL-C (41%-61%), apolipoprotein B (34%-50%) and triglycerides (14%-33%) while producing variable increases in HDL-C and apolipoprotein A (Table 1). A therapeutic response was seen within 2 weeks, and maximum response achieved within 4 weeks.
In three further trials, 1148 patients with either heterozygous familial hypercholesterolaemia, nonfamilial 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 nondose related manner.
Clinical studies demonstrate that the starting dose of 10 mg atorvastatin is more effective than simvastatin 10 mg and pravastatin 20 mg in reducing LDL-C, total-C, triglycerides 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 on the composite endpoint of fatal coronary heart disease (CHD) and non-fatal myocardial infarction (MI) was assessed in 10,305 hypertensive patients, 40-79 years of age, without a history of symptomatic coronary heart disease and with total C (TC) levels ≤ 6.5 mmol/L. Additionally patients were at moderate risk of coronary heart disease, having at least 3 of the predefined cardiovascular (CV) risk factors [male gender (81%), age ≥ 55 years (84%), smoking (33%), non insulin dependent diabetes mellitus (25%), history of CHD in a first degree relative (26%), plasma TC to HDL cholesterol ratio ≥ 6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy on echocardiography (14%), past history of cerebrovascular event (10%), specific electrocardiogram (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 nondiabetic patients, < 130/80 mmHg for diabetic patients) and either atorvastatin 10 mg daily (n = 5168) or placebo (n = 5137), 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; 2340 patients (45.3%) had total-C levels greater than or equal to 3.5 mmol/L and less than 5.5 mmol/L; 2304 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; 1731 patients (37%) had LDL-C greater than 2.5 mmol/L and less than 3.4 mmol/L; and 2495 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 nonfatal 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 2). 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 (CV) 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-cholesterol, 27% reduction in total cholesterol, a 24% reduction in triglycerides and a 12% rise in HDL cholesterol.

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 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%). Five of the 29 patients had absent LDL-receptor function, three 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 triglycerides by 31% to 40%.
In patients with severe hypertriglyceridaemia (baseline TG > 5.7 mmol/L), atorvastatin (10 to 80 mg) reduced serum triglycerides 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 triglyceride levels than placebo (Table 3).

Dysbetalipoproteinaemia.

In patients with dysbetalipoproteinaemia, atorvastatin (10 to 80 mg) reduced intermediate density lipoprotein (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 triglycerides than simvastatin 40 mg/day (Table 4).

5.2 Pharmacokinetic Properties

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 presystemic 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 with 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 litres. Atorvastatin is ≥ 98% bound to plasma proteins. A RBC/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 4.4 Special Warnings and Precautions for Use).

Metabolism.

In humans, atorvastatin is extensively metabolised to ortho and parahydroxylated derivatives. In vitro inhibition of HMG-CoA reductase by ortho and parahydroxylated 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 coadministration with erythromycin, a known inhibitor of this isozyme (see Section 4.4 Special Warnings and Precautions for Use). In animals, the orthohydroxy 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.

Elderly (≥ 65 years).

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.

Paediatric.

Pharmacokinetic studies have not been conducted in the paediatric population.

Gender.

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.

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 (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Haemodialysis.

While studies have not been conducted in patients with endstage renal disease, haemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.

Hepatic impairment.

Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax and 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B) (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

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.

In a 2 year study in rats given 10, 30 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/kg) based on AUC(0-24) values. In a 2 year study in mice given 100, 200, or 400 mg/kg, incidences of hepatocellular adenoma in males and hepatocellular carcinoma in females were increased at 400 mg/kg. The maximum dose used was 14 times higher than the highest human dose (80 mg/kg) 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

The inactive (excipients) ingredients are lactose monohydrate, microcrystalline cellulose, calcium carbonate, croscarmellose sodium, hyprolose, polysorbate 80, magnesium stearate, Opadry White YS-1-7040 (PI 2695), and Antifoam AF Emulsion Q7-2587 (PI 1515). In addition, the 10, 20 and 40 mg tablets contain Euphorbia antisyphilitica leaf wax.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 in the original container.
Protect from light.

6.5 Nature and Contents of Container

Atorvastatin SZ tablets all strengths are supplied in blister packs containing 6* or 30 tablets.
*Not currently marketed in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Atorvastatin calcium trihydrate is a white to off white crystalline powder. It is insoluble in aqueous solutions of pH 4 and below, insoluble in water, very slightly soluble in pH 7.4 phosphate buffer, insoluble in acetonitrile, slightly soluble in alcohol and freely soluble in methanol. pKa of atorvastatin calcium is approximately 4.4.

Chemical structure.

Atorvastatin SZ contains the active ingredient atorvastatin calcium trihydrate. The structural formula is shown below:
Molecular formula: (C33H34FN2O5)2Ca.3H2O.
Molecular weight: 1209.42.
Chemical name: Calcium (3R,5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)- 1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate trihydrate.

CAS number.

344423-98-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes