Consumer medicine information

Blooms the Chemist Atorvastatin

Atorvastatin

BRAND INFORMATION

Brand name

Blooms the Chemist Atorvastatin

Active ingredient

Atorvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Blooms the Chemist Atorvastatin.

SUMMARY CMI

BLOOMS THE CHEMIST ATORVASTATIN

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 BLOOMS THE CHEMIST ATORVASTATIN?

BLOOMS THE CHEMIST ATORVASTATIN contains the active ingredient atorvastatin. BLOOMS THE CHEMIST ATORVASTATIN is used to lower high cholesterol levels.

BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN? in the full CMI.

2. What should I know before I use BLOOMS THE CHEMIST ATORVASTATIN?

Do not use if you have ever had an allergic reaction to BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN?

  • The usual dose of BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN? in the full CMI.

5. What should I know while using BLOOMS THE CHEMIST ATORVASTATIN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using BLOOMS THE CHEMIST ATORVASTATIN.
  • 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 BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN affects you.
  • BLOOMS THE CHEMIST ATORVASTATIN generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, BLOOMS THE CHEMIST ATORVASTATIN may cause dizziness in some people.
Drinking alcohol
  • Avoid drinking large quantities of alcohol
  • Drinking large quantities of alcohol while taking BLOOMS THE CHEMIST ATORVASTATIN may increase your chance of liver problems.
Looking after your medicine
  • Keep BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN? 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

BLOOMS THE CHEMIST ATORVASTATIN

Active ingredient(s): atorvastatin (as calcium trihydrate)


Consumer Medicine Information (CMI)

This leaflet provides important information about using BLOOMS THE CHEMIST ATORVASTATIN. 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 BLOOMS THE CHEMIST ATORVASTATIN.

Where to find information in this leaflet:

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

1. Why am I using BLOOMS THE CHEMIST ATORVASTATIN?

BLOOMS THE CHEMIST ATORVASTATIN contains the active ingredient atorvastatin.

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

BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN has been prescribed for you.

Your doctor may have prescribed it for another reason.

BLOOMS THE CHEMIST ATORVASTATIN 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, holesterol 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, BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST

Warnings

Do not use BLOOMS THE CHEMIST ATORVASTATIN 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.
  • have active liver disease
  • are pregnant or intend to become pregnant
  • are taking the antibiotic fusidic acid hemihydrate which is used to treat infections
  • are taking the antiviral glecaprevir/pibrentasvir for the treatment of Hepatitis C.

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
  • vision problems, eye muscle weakness and drooping eyelid
  • 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
  • breathing problems.

Your doctor will ask you to have your liver function tested before you start to take BLOOMS THE CHEMIST ATORVASTATIN.

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 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.

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 BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN 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 to treat high cholesterol or triglycerides (fats)
  • antacids, medicines used to treat reflux or ulcers the antibiotics erythromycin, clarithromycin, rifampicin or 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 some 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.

Your doctor and pharmacist have more information on medicines to be careful with or to avoid while taking BLOOMS THE CHEMIST ATORVASTATIN.

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

4. How do I use BLOOMS THE CHEMIST ATORVASTATIN?

How much to take

  • Follow the instructions provided and use BLOOMS THE CHEMIST ATORVASTATIN 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 any other medicines.
  • The usual dose of BLOOMS THE CHEMIST ATORVASTATIN is between 10-80 mg taken once a day.

When to take BLOOMS THE CHEMIST ATORVASTATIN

  • BLOOMS THE CHEMIST ATORVASTATIN can be taken at any time of the day. However, your dose of BLOOMS THE CHEMIST ATORVASTATIN 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 to remember when to take it.
  • BLOOMS THE CHEMIST ATORVASTATIN can be taken with or without food.

How to take BLOOMS THE CHEMIST ATORVASTATIN

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

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

How long to take BLOOMS THE CHEMIST ATORVASTATIN

  • Take BLOOMS THE CHEMIST ATORVASTATIN every day and continue taking it for as long as your doctor tells you.
  • BLOOMS THE CHEMIST ATORVASTATIN helps to lower your levels of 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 BLOOMS THE CHEMIST ATORVASTATIN, your cholesterol levels may rise again.

If you forget to use BLOOMS THE CHEMIST ATORVASTATIN

BLOOMS THE CHEMIST ATORVASTATIN 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 that 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 tablets, ask your pharmacist for some hints.

If you use too much BLOOMS THE CHEMIST ATORVASTATIN

If you think that you have used too much BLOOMS THE CHEMIST ATORVASTATIN, 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 BLOOMS THE CHEMIST ATORVASTATIN

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 BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BLOOMS THE CHEMIST ATORVASTATIN.

Call your doctor straight away if you:

  • become pregnant while you are taking BLOOMS THE CHEMIST ATORVASTATIN.
    If you become pregnant while taking BLOOMS THE CHEMIST ATORVASTATIN, stop taking it and contact your doctor immediately.

Remind any doctor, dentist or pharmacist you visit that you are using BLOOMS THE CHEMIST ATORVASTATIN.

Things you should not do

  • Do not stop using this medicine suddenly
  • Do not give BLOOMS THE CHEMIST ATORVASTATIN to anyone else, even if they have the same condition as you
  • Do not take BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN, 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 driving or operating machinery until you know how BLOOMS THE CHEMIST ATORVASTATIN affects you.

BLOOMS THE CHEMIST ATORVASTATIN generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, BLOOMS THE CHEMIST ATORVASTATIN 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 BLOOMS THE CHEMIST ATORVASTATIN may increase your chance of getting liver problems.

Tell your doctor if you drink alcohol regularly.

Drinking Grapefruit juice

Avoid drinking large quantities of grapefruit juice.

Grapefruit juice contains one or more components that alter the metabolism of some medicines, including BLOOMS THE CHEMIST ATORVASTATIN.

Drinking very large quantities (over 1.2 liters) of grapefruit juice each day while taking BLOOMS THE CHEMIST 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 BLOOMS THE CHEMIST ATORVASTATIN in a cool dry place where the temperature stays below 25°C.

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

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

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

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half meters 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.

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 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 and difficulty getting up from a fall
  • constipation, diarrhoea
  • stomach or belly pain, nausea (feeling sick)
  • heartburn, indigestion or wind
  • urine infection
  • headache
  • 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
These are serious side effects that may require medical attention. Serious side effects are rare.
  • yellowing of the skin and eyes and dark coloured urine
  • feeling weak and tired, excessively thirsty and passing more urine
  • problems with breathing, including shortness of breath, persistent cough and fever
  • vision problems, eye muscle weakness and drooping eyelid.
Call your doctor straight away if you notice any of these serious side effects.
The below list includes very serious side effects.
You may need urgent medical attention or hospitalisation.
  • 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
  • chest pain
  • unexpected muscle pain, tenderness or weakness not caused by exercise, particularly if you also feel unwell or have a fever
  • 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.

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 BLOOMS THE CHEMIST ATORVASTATIN contains

Active ingredient
(main ingredient)
Atorvastatin (as calcium trihydrate)
Other ingredients
(inactive ingredients)
  • calcium carbonate
  • lactose monohydrate
  • microcrystalline cellusose
  • croscarmellose sodium
  • polysorbate 80
  • hyprolose
  • magnesium stearate
  • opadry white YS-1-7040
  • candilla wax (only for 10mg, 20mg and 40 mg tablets)
  • antifoam emulsion Q7-2587

This medicine does not contain gluten.

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

What BLOOMS THE CHEMIST ATORVASTATIN looks like

BLOOMS THE CHEMIST ATORVASTATIN tablets are available in four strengths:

  • BLOOMS THE CHEMIST ATORVASTATIN 10 mg - white to off-white, elliptical, film-coated tablets debossed "AS10" on one side and plain on the other side. AUST R 286640
  • BLOOMS THE CHEMIST ATORVASTATIN 20 mg - white to off-white, elliptical, film-coated tablets debossed "AS20" on one side and plain on the other side. AUST R 286641.
  • BLOOMS THE CHEMIST ATORVASTATIN 40 mg - white to off-white, elliptical, film-coated tablets debossed "AS40" on one side and plain on the other side. AUST R 286642.
  • BLOOMS THE CHEMIST ATORVASTATIN 80 mg - white to off-white, elliptical, film-coated tablets debossed "AS80" on one side and plain on the other side. AUST R 286643.

BLOOMS THE CHEMIST ATORVASTATIN comes in blister packs of 30 tablets

Who distributes BLOOMS THE CHEMIST ATORVASTATIN

BLOOMS THE CHEMIST ATORVASTATIN is supplied in Australia by:

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel st,
Cremorne, VIC 3121
Tel: 1800 195 055

This leaflet was prepared in January 2024.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Blooms the Chemist Atorvastatin

Active ingredient

Atorvastatin

Schedule

S4

 

1 Name of Medicine

Atorvastatin as calcium trihydrate.

2 Qualitative and Quantitative Composition

Each tablet contains atorvastatin calcium trihydrate equivalent to 10 mg, 20 mg, 40 mg and 80 mg atorvastatin.

Excipients with known effect.

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

3 Pharmaceutical Form

10 mg tablets.

White to off-white, elliptical, film-coated tablets debossed 'AS10' on one side and plain on the other side.

20 mg tablets.

White to off-white, elliptical, film-coated tablets debossed 'AS20' on one side and plain on the other side.

40 mg tablets.

White to off-white, elliptical, film-coated tablets debossed 'AS40' on one side and plain on the other side.

80 mg tablets.

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 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 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 non-fatal myocardial infarction and non-fatal stroke.
These effects do not replace the need to independently control known causes of cardiovascular (CV) mortality and morbidity such as hypertension, diabetes and smoking.

4.2 Dose and Method of Administration

Dosage.

Atorvastatin 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, 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 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.

Method of administration.

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

Dosage adjustment.

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.

Use in 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 5.2 Pharmacokinetic Properties; 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 benefits of therapy should be weighed against the risks when atorvastatin is to be given to patients with hepatic insufficiency (see Section 5.2 Pharmacokinetic Properties; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Liver dysfunction).

Use in combination with other medicinal compounds.

In cases where co-administration 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.
When atorvastatin and letermovir are administered concomitantly, do not exceed 20 mg atorvastatin daily (see Section 4.4 Special Warnings and Precautions for Use, 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, 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 (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

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. When atorvastatin and letermovir are administered concomitantly, do not exceed 20 mg atorvastatin daily (see Section 4.2 Dose and Method of Administration, Use in combination with other medicinal compounds; 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 should also be considered when taken concomitantly with the other aforementioned drugs (see Section 4.2 Dose and Method of Administration, Use in 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 reintroduced 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 premenopausal 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.

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.

Lactose intolerance.

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

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 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 ALT or AST of > 3 x ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.

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 CYP 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 CYP 3A4. Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have also been noted with other 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 CYP 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 4.4 Special Warnings and Precautions for Use, Skeletal muscle; Section 4.2 Dose and Method of Administration, Use in combination with other medicinal compounds).
Concomitant administration of atorvastatin with inducers of CYP 3A4 (e.g. efavirenz, rifampicin, phenytoin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin (CYP 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 in atorvastatin plasma concentrations.

Fusidic acid.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Co-administration 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 atorvastatin and fusidic acid have not been conducted, there have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary, statin treatment should be discontinued throughout the duration of the fusidic acid 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 co-administered 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.

Co-administration 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 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 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 coadministered 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, Use in combination with other medicinal compounds).
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, Use in combination with other medicinal compounds).

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 CYP 3A4, was associated with higher plasma concentrations of atorvastatin (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle).

Protease inhibitors.

Co-administration of atorvastatin and protease inhibitors, known inhibitors of CYP 3A4, was associated with increased plasma concentrations of atorvastatin (see Section 4.4 Special Warnings and Precautions for Use, 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 mg to 40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC.

Grapefruit juice.

Contains one or more components that inhibit CYP 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 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 atorvastatin daily. Patients taking digoxin should be monitored appropriately.

Oral contraceptives.

Co-administration 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 co-administration 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 co-administration of atorvastatin 80 mg daily and amlodipine 10 mg daily at steady-state. In a drug-drug interaction study in healthy subjects, co-administration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin, which was not clinically meaningful.

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 oestrogen 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 mg, 40 mg, or 120 mg/kg 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.
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 post-natal 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 breast-feed (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 (8755 atorvastatin; 7311 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.

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 necrotizing myopathy, rhabdomyolysis which may be fatal (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) (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.

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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (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.
Atorvastatin reduces total-C, LDL-C, and apo B in both normal volunteers and in patients with homozygous and heterozygous 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 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 (see 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, 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 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 calcium on the composite endpoint of fatal coronary heart disease (CHD) and non-fatal myocardial infarction was assessed in 10,305 hypertensive patients, 40-79 years of age, without a history of symptomatic coronary heart disease and with total-C levels ≤ 6.5 mmol/L. Additionally patients were at moderate risk of coronary heart disease, having at least 3 of the predefined 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 total-C to HDL cholesterol 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 anti-hypertensive 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; 2340 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 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) (see 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, CV mortality or heart failure in the atorvastatin treated group compared to placebo.

Non-insulin 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 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%). 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 mg to 80 mg) reduced serum triglycerides by 31% to 40%.
In patients with severe hypertriglyceridaemia (baseline TG > 5.7 mmol/L), atorvastatin (10 mg 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 (see Table 3).

Dysbetalipoproteinaemia.

In patients with dysbetalipoproteinaemia, atorvastatin (10 mg 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, cross-over 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 (see 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 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 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 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 CYP 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.

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.

Children and adolescents.

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 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.

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 mg, 30 mg 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 mg, 200 mg 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

Lactose monohydrate, microcrystalline cellulose, calcium carbonate, croscarmellose sodium, hyprolose, polysorbate 80, magnesium stearate, Opadry white YS-1-7040 (PI 2695), Antifoam AF emulsion Q7-2587 (PI 1515), 10 mg, 20 mg and 40 mg tablets contain candelilla wax.

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 in the original container. Protect from light.

6.5 Nature and Contents of Container

Blooms the Chemist Atorvastatin tablets.

10 mg tablets.

Blister pack (PA/Al/PVC/Al) of 30 tablets: AUST R 286640.

20 mg tablets.

Blister pack (PA/Al/PVC/Al) of 30 tablets: AUST R 286641.

40 mg tablets.

Blister pack (PA/Al/PVC/Al) of 30 tablets: AUST R 286642.

80 mg tablets.

Blister pack (PA/Al/PVC/Al) of 30 tablets: AUST R 286643.
Note: Not all strengths may be available.

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 name: Calcium (3R, 5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)- 3-phenyl-4-(phenylcarbamoyl)- 1H-pyrrol-1-yl]-3, 5-dihydroxyheptanoate trihydrate.

Chemical structure.


Molecular formula: C66H68CaF2N4O10.3H2O.
Molecular weight: 1209.42.

CAS number.

344423-98-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes