Consumer medicine information

Terry White Chemists Atorvastatin Tablets

Atorvastatin

BRAND INFORMATION

Brand name

Terry White Chemists Atorvastatin Tablets

Active ingredient

Atorvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Terry White Chemists Atorvastatin Tablets.

What is in this leaflet

This leaflet answers some common questions about Terry White Chemists Atorvastatin.

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

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits he/she expects it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with the medicine.

You may need to read it again.

What this medicine is used for

The name of your medicine is Terry White Chemists Atorvastatin. It contains the active ingredient atorvastatin.

Atorvastatin lowers high cholesterol levels.

It is also used in people who have high blood pressure and coronary heart disease (CHD) or who are at risk of CHD (for example, if they have diabetes, a history of stroke, or small blood vessel disease). In these people, this medicine is used to reduce the risk of having a heart attack or stroke.

What is Cholesterol?

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

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

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

There are different types of cholesterol. LDL is the 'bad' cholesterol that can block your blood vessels. HDL 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.

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 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, Terry White Chemists Atorvastatin is used to treat high cholesterol and high triglycerides together.

How it works

Terry White Chemists Atorvastatin belongs to a group of medicines called HMG-CoA reductase inhibitors. It works by reducing the amount of cholesterol made by the liver. This medicine reduces the 'bad' cholesterol and raises the 'good' cholesterol. It also helps to protect you from a heart attack or stroke.

When you are taking Terry White Chemists Atorvastatin, you also need to follow a low fat diet and other measures, such as exercise and weight control.

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

Your doctor may have prescribed this medicine for another reason.

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

There is no evidence that this medicine is addictive.

Before you take this medicine

When you must not take it

Do not take Terry White Chemists Atorvastatin if:

  • You are pregnant or intend to become pregnant.
    Women of child-bearing age who are taking the medicine should use a proven method of birth control to avoid pregnancy.
    The medicine may affect your unborn developing baby if you take it during pregnancy.
  • You are breast-feeding or intend to breast-feed.
    The medicine may pass into breast milk and affect your baby.
  • You have active liver disease or have experienced persistent elevations of serum transaminases (liver blood test results).
  • You are taking the antibiotic fusidic acid, which is used to treat infections.
  • You are hypersensitive to, or have had an allergic reaction to, atorvastatin or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The packaging is torn or shows signs of tampering.
  • The expiry date (EXP) on the pack has passed.

If you take this medicine after the expiry date has passed, it may not work or it may make you unwell.

If you are not sure whether to start taking Terry White Chemists Atorvastatin, talk to your doctor.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • liver problems
  • kidney problems
  • muscle pain, tenderness or weakness from other medicines used to treat cholesterol or triglycerides
  • a type of stroke called a haemorrhagic stroke or 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.
  1. You drink alcohol regularly.
  2. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant.
  3. You are currently breastfeeding or you plan to breast-feed. Do not take this medicine whilst breast-feeding.
  4. You are planning to have surgery or an anaesthetic.
  5. You are currently receiving or are planning to receive dental treatment.
  6. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Terry White Chemists Atorvastatin. These include:

  • digoxin, a medicine used to treat some heart problems
  • the antibiotics erythromycin, clarithromycin and rifampicin and fusidic acid
  • phenytoin, a medicine used to treat epilepsy
  • oral contraceptives
  • other medicines to treat high cholesterol or triglycerides
  • antacids, medicines used to treat reflux or ulcers
  • cyclosporin, a medicine used to suppress the immune system
  • some medicines used to treat some fungal infections, such as itraconazole or ketoconazole
  • medicines for the treatment of HIV infection, such as efavirenz, fosamprenavir, ritonavir, tipranavir, lopinavir, saquinavir and darunavir
  • medicines for the treatment of Hepatitis C, such as boceprevir and telaprevir
  • diltiazem, a medicine used to treat angina
  • 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.

These medicines may be affected by Terry White Chemists Atorvastatin, or may affect how well it works. Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking Terry White Chemists Atorvastatin.

How to take this medicine

Follow all directions given to you by your doctor carefully. These directions may differ from the information contained in this leaflet.

Take Terry White Chemists Atorvastatin only when prescribed by your doctor.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

The usual dose of Terry White Chemists Atorvastatin is between 10-80 mg taken once a day.

How to take it

Swallow the tablet(s) whole with a glass of water. Do not chew or crush the tablets.

When to take it

Terry White Chemists Atorvastatin can be taken at any time of the day. However, your dose of Terry White Chemists Atorvastatin should be taken at about the same time each day.

Taking your tablet(s) at the same time each day will have the best effect. It will also help you remember when to take the tablet(s).

Terry White Chemists Atorvastatin can be taken with or without food.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Terry White Chemists Atorvastatin helps to lower your levels of cholesterol, but it does not cure your condition. Therefore, you must continue to take it as directed by your doctor.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your tablet(s) as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

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

This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant.
    If you become pregnant while you are taking this medicine, stop taking it and contact your doctor immediately.
  • you are breastfeeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Have your cholesterol and triglyceride levels checked when your doctor says, to make sure that is working.

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

Your cholesterol and triglyceride levels also need to be checked regularly while you are taking this medicine.

Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Avoid drinking large quantities of alcohol.

Drinking large quantities of alcohol may increase your chance of Terry White Chemists Atorvastatin causing liver problems.

Avoid drinking large quantities of grapefruit juice.

Grapefruit juice contains one or more components that alter the metabolism of some medicines, including Terry White Chemists Atorvastatin.

Drinking very large quantities (over 1.2 litres) of grapefruit juice each day increases your chance of Terry White Chemists Atorvastatin causing side effects.

Be careful driving or operating machinery until you know how Terry White Chemists Atorvastatin affects you.

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

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

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking \ Terry White Chemists Atorvastatin.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following:

  • muscle and joint pain, muscle weakness
  • constipation, diarrhoea
  • stomach or belly pain, nausea (feeling sick)
  • heartburn, indigestion or wind
  • urine infection
  • headache
  • stuffy or runny nose
  • nose bleeds
  • rash

These are the more common side effects, and are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • 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.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • chest pain
  • unexpected muscle pain, tenderness or weakness not caused by exercise
  • 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.

These may be serious side effects requiring urgent medical attention. Serious side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

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

Allergic reactions

If you think you are having an allergic reaction to atorvastatin, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your tablets in their original packaging until it is time to take them.

If you take the tablets out of the original packaging they may not keep well.

Keep it in a cool dry place, where the temperature stays below 25°C. Protect from light. Do not store it or any other medicine in the bathroom or near a sink. Do not leave your tablets in the car or on windowsills.

Heat and dampness can destroy some medicines.

Keep your tablets where young children cannot reach them.

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

Disposal

If your doctor tells you to stop taking Terry White Chemists Atorvastatin, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What Terry White Chemists Atorvastatin looks like

New Formulation

Terry White Chemists Atorvastatin 10 mg tablets are white to off-white, elliptical, film-coated tablets debossed "AS10" on one side and plain on the other side.

Terry White Chemists Atorvastatin 20 mg tablets are white to off-white, elliptical, film-coated tablets debossed "AS20" on one side and plain on the other side.

Terry White Chemists Atorvastatin 40 mg tablets are white to off-white, elliptical, film-coated tablets debossed "AS40" on one side and plain on the other side.

Terry White Chemists Atorvastatin 80 mg tablets are white to off-white, elliptical, film-coated tablets debossed "AS80" on one side and plain on the other side.

They are available in blister packs of 30 tablets.

Old Formulation

Terry White Chemists Atorvastatin 10 mg tablets are white, oval, biconvex, film-coated tablets. Engraved "APO" on one side, "A10" on the other side.

Terry White Chemists Atorvastatin 20 mg tablets are white, oval, biconvex, film-coated tablets. Engraved "APO" on one side, "ATV20" on the other side.

Terry White Chemists Atorvastatin 40 mg tablets are white, oval, biconvex, film-coated tablets. Engraved "APO" on one side, "ATV40" on the other side.

Terry White Chemists Atorvastatin 80 mg tablets are white, oval, biconvex, film-coated tablets. Engraved "APO" on one side, "ATV80" on the other side.

They are available in blister packs of 30 tablets.

Also available in bottles of 30 tablets.

Ingredients

New Formulation

Active Ingredient:

The active ingredient of Terry White Chemists Atorvastatin is atorvastatin (as calcium trihydrate).

It also contains the following inactive ingredients:

  • Calcium Carbonate
  • Croscarmellose sodium
  • Lactose monohydrate
  • microcrystalline cellulose
  • magnesium stearate
  • Polysorbate 80 Opadry YS-1-7040 White (ARTG 2695)
  • Hyprolose
  • Anti foam AF emulsion Q7-2587 (ARTG 1515) Candelilla Wax (Only for 10, 20 and 40 mg)

This medicine is gluten-free, sucrose-free, tartrazine-free and other azo dyes-free.

Old Formulation

Active Ingredient:

The active ingredient of Terry White Chemists Atorvastatin is atorvastatin (as atorvastatin calcium propylene glycol solvate).

It also contains the following inactive ingredients:

  • calcium acetate
  • croscarmellose sodium
  • sodium carbonate anhydrous
  • microcrystalline cellulose
  • magnesium stearate
  • colloidal anhydrous silica
  • hypromellose
  • hydroxypropylcellulose
  • macrogol 8000
  • titanium dioxide
  • purified water.

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and other azo dyes-free.

Australian Registration Numbers

New Formulation

Terry White Chemists Atorvastatin 10 mg tablets (blister pack): AUST R 286644.

Terry White Chemists Atorvastatin 20 mg tablets (blister pack): AUST R 286645.

Terry White Chemists Atorvastatin 40 mg tablets (blister pack): AUST R 286646.

Terry White Chemists Atorvastatin 80 mg tablets (blister pack): AUST R 286647.

Old Formulation

Terry White Chemists Atorvastatin 10 mg tablets (blister pack): AUST R 153733.

Terry White Chemists Atorvastatin 20 mg tablets (blister pack): AUST R 153735.

Terry White Chemists Atorvastatin 40 mg tablets (blister pack): AUST R 153724.

Terry White Chemists Atorvastatin 80 mg tablets (blister pack): AUST R 153739.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

This leaflet was prepared in: October 2017.

BRAND INFORMATION

Brand name

Terry White Chemists Atorvastatin Tablets

Active ingredient

Atorvastatin

Schedule

S4

 

Name of the medicine

Atorvastatin calcium trihydrate.

Excipients.

Lactose monohydrate, microcrystalline cellulose, calcium carbonate, croscarmellose sodium, hyprolose, polysorbate 80, magnesium stearate, Opadry YS-1-7040 White (ARTG No. 2695) and Antifoam AF Emulsion Q7-2587 (ARTG No. 1515). 10, 20 and 40 mg tablets contain Candelilla Wax.

Description

Chemical Name: Calcium (3R,5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3- phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate trihydrate. Molecular Formula: C66H68CaF2N4O10, 3H2O. Molecular Weight: 1209. CAS Registry Number: 344423-98-9.
Atorvastatin calcium trihydrate is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4.0 and below. Atorvastatin calcium trihydrate is slightly soluble in distilled water and pH 7.4 phosphate buffer, very slightly soluble in acetonitrile, practically insoluble in ethanol and sparingly soluble in methanol.
Each tablet contains atorvastatin calcium trihydrate as the active ingredient. In addition each tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, calcium carbonate, croscarmellose sodium, hyprolose, polysorbate 80, magnesium stearate, Opadry YS-1-7040 White (ARTG No. 2695) and Antifoam AF Emulsion Q7-2587 (ARTG No. 1515). 10, 20 and 40 mg tablets contain Candelilla Wax.

Pharmacology

Pharmacological actions.

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), LDL-C and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease. Similarly, decreased levels of 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 FH, nonfamilial forms of hypercholesterolaemia, and mixed dyslipidaemia. Atorvastatin also reduces 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.
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 Dosage and Administration).

Pharmacokinetics.

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 Dosage and 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 Precautions).

Metabolism.

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

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 Dosage and 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 Dosage and Administration, Precautions and Contraindications).

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, 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, TG 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 and nonfatal myocardial infarction was assessed in 10,305 hypertensive patients, 40-79 years of age, without a history of symptomatic coronary heart disease and with TC levels ≤ 6.5 mmol/L. Additionally patients were at moderate risk of coronary heart disease, having at least 3 of the predefined cardiovascular risk factors [male gender (81%), age ≥ 55 years (84%), smoking (33%), noninsulin dependent diabetes mellitus (25%), history of CHD in a first degree relative (26%), plasma TC 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 antihypertensive therapy (goal BP < 140/90 mmHg for nondiabetic patients, < 130/80 mmHg for diabetic patients) and either atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137) and followed for a median duration of 3.3 years. At baseline, in the atorvastatin group, 38 patients (0.7%) had total-C levels less than 3.5 mmol/L; 2,340 patients (45.3%) had total-C 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 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) (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, cardiovascular mortality or heart failure in the atorvastatin treated group compared to placebo.

Noninsulin dependent diabetes mellitus (NIDDM).

A 26 week randomised, double blind, comparator study in NIDDM subjects showed that atorvastatin is effective in dyslipidaemic patients with NIDDM. A 10 mg dose of atorvastatin produced a 34% reduction in LDL 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 which 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 randomized, 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 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, randomized, 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 (see Table 4).

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 Clinical Trials) to reduce the risk of nonfatal myocardial infarction and nonfatal stroke.
These effects do not replace the need to independently control known causes of cardiovascular mortality and morbidity such as hypertension, diabetes and smoking.

Contraindications

Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see Precautions).
Pregnancy and lactation (see Precautions). Women of childbearing potential, unless on an effective contraceptive and highly unlikely to conceive.
Concomitant use with fusidic acid (see Precautions and Interactions with Other Medicines).

Precautions

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).

Use in pregnancy.

(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 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 postimplantation 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/ postnatal 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 nonmaternotoxic dose of 100 mg/kg/day; the plasma AUC for HMG-CoA reductase inhibitory activity at the no effect dose level of 20 mg/kg/day was similar to that in humans dosed at 80 mg/day.
HMG-CoA reductase inhibitors are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series of 178 and 143 cases where pregnant women took 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.

Use in lactation.

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 Contraindications and Precautions).

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.

Use in the elderly.

Treatment experience in adults age ≥ 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.

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.
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 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.

Effects on laboratory tests.

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

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.
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 Contraindications).

Skeletal muscle.

Uncomplicated myalgia has been reported in atorvastatin treated patients (see Adverse 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 during treatment with other drugs in this class is increased with concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, niacin, azole antifungals, colchicine, hepatitis C protease inhibitors (e.g telaprevir or boceprevir) or the combination of tipranavir/ ritonavir (see Interactions with Other Medicines). Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals, 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. Therefore, lower starting and maintenance doses of atorvastatin should also be considered when taken concomitantly with the aforementioned drugs (see Interactions with Other Medicines). 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 Precautions).
Atorvastatin must not be coadministered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. 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.
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).

Haemorrhagic stroke.

A post hoc analysis of a clinical study (SPARCL) in patients without known coronary heart disease who had a recent stroke or 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, 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.

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 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. Presenting features can include dyspnea, nonproductive 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.

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). 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.

Interactions

Atorvastatin is metabolised by cytochrome P450 3A4.
Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects 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), hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole. 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. cyclosporin, 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 cyclosporin, fibric acid derivatives, erythromycin, azole antifungals or niacin (see Precautions).
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 on atorvastatin plasma concentrations.

Fusidic acid.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid 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 interactions studies with statins 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 Contraindications).

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.

Drugs that affect 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 OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporin) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and cyclosporin 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin (see Dosage and Administration).

Erythromycin/ clarithromycin.

In healthy individuals, coadministration of atorvastatin (10 mg QD) and erythromycin (500 mg QID), or clarithromycin (500 mg BID), known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Precautions).

Protease inhibitors.

Coadministration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin.

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).

Drugs that are affected by atorvastatin.

The following drugs have been shown to have their pharmacokinetics or pharmacodynamics affected by atorvastatin.

Digoxin.

When multiple doses of digoxin (0.25 mg QD) 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.

Drugs 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 QD) 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.

Effect on laboratory tests.

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

Adverse Effects

Atorvastatin is generally well tolerated. Adverse events have usually been mild and transient.

Clinical adverse experiences.

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 effects associated with atorvastatin therapy, in patients participating in placebo controlled clinical studies were the following.

Gastrointestinal disorders.

Dyspepsia, nausea, flatulence, diarrhoea.

Infections and infestations.

Nasopharyngitis.

Investigations.

Liver function test abnormal (hepatic enzyme increased, ALT increased, AST increased, blood bilirubin increased, liver function test abnormal and transaminases increased), blood creatine phosphokinase increased.

Metabolism and nutrition disorders.

Hyperglycaemia.

Musculoskeletal system and connective tissue disorders.

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

Respiratory, thoracic and mediastinal disorders.

Pharyngolaryngeal pain, epistaxis.
The following additional adverse effects 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.

Headache.

Uncommon (≥ 0.1% and < 1%).

Gastrointestinal disorders.

Vomiting, abdominal discomfort, abdominal pain.

Metabolism and nutrition.

Anorexia.

General disorders.

Asthenia, malaise.

Infections and infestations.

Infection, influenza.

Nervous system disorders.

Paraesthesia.

Musculoskeletal system and connective tissue disorder.

Back pain, neck pain.

Psychiatric disorders.

Insomnia, nightmare.

Respiratory.

Asthma.

Skin and subcutaneous tissue disorders.

Pruritus, rash, urticaria.

Reproductive system and breast disorders.

Erectile dysfunction.

Ear and labyrinth disorders.

Deafness.

Eye disorders.

Vision blurred.

Rare (≥ 0.01% and < 0.1%).

Gastrointestinal disorders.

Pancreatitis, eructation.

General disorders.

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.

Metabolic and nutritional disorders.

Hypoglycemia.

Musculoskeletal system.

Myositis, myopathy, muscle fatigue.

Nervous system.

Peripheral neuropathy.

Skin and subcutaneous tissue disorders.

Angioedema, alopecia.

Ear and labyrinth disorders.

Tinnitus.
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 Precautions).
In ASCOT (see Clinical Trials) 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.

Postmarketing experience.

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

General disorders.

Chest pain, fatigue, peripheral oedema.

Hepatobiliary disorders.

Hepatic failure.

Musculoskeletal system.

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 Contraindications, Precautions and Interactions with Other Medicines).

Nervous system.

Hypoesthesia, dizziness, amnesia, dysgeusia.

Skin and appendages.

Bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).

Metabolic and nutritional disorders.

Weight gain.

Blood and lymphatic system.

Thrombocytopenia.

Injury, poisoning and procedural complications.

Tendon rupture.

Reproductive system and breast disorders.

Gynaecomastia.
The following adverse events have been reported with some statins: exceptional cases of interstitial lung disease, especially with long term therapy (see Precautions).

Dosage and Administration

Atorvastatin can be administered within the dosage range of 10-80 mg/day as a single daily dose. Atorvastatin can be taken at any time of the day, with or without food. 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 reanalysed 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.

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.

Dosage in patients with renal insufficiency.

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 Pharmacology).

Dosage in patients with hepatic insufficiency.

Hepatic insufficiency.

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 Pharmacology, Contraindications and Precautions).

Use in combination with other medicinal compounds.

In cases where coadministration of atorvastatin with cyclosporin, telaprevir, or the combination tipranavir/ ritonavir is necessary, the dose of atorvastatin should not exceed 10 mg. Caution should be used when coprescribing atorvastatin with medicinal compounds that result in an increase in systemic concentrations of atorvastatin and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see Precautions, Skeletal muscle and Interactions with Other Medicines).

Overdosage

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 alkalinization is not routinely recommended. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.
Contact the Poisons Information Centre on 131 126 (Australia) for advice on the management of overdosage.

Presentation

Terry White Chemists Atorvastatin tablets are intended for oral administration.
Each tablet contains atorvastatin calcium trihydrate equivalent to 10 mg, 20 mg, 40 mg and 80 mg atorvastatin.

10 mg tablets.

White to off-white, elliptical, film-coated tablets debossed “AS10” on one side and plain on the other side.
Blister pack (PA/Al/PVC/Al and OPA/Al/PE + Desiccant/HDPE) of 30 tablets: AUST R 286644.

20 mg tablets.

White to off-white, elliptical, film-coated tablets debossed “AS20” on one side and plain on the other side.
Blister pack (PA/Al/PVC/Al and OPA/Al/PE + Desiccant/HDPE) of 30 tablets: AUST R 286645.

40 mg tablets.

White to off-white, elliptical, film-coated tablets debossed “AS40” on one side and plain on the other side.
Blister pack (PA/Al/PVC/Al and OPA/Al/PE + Desiccant/HDPE) of 30 tablets: AUST R 286646.

80 mg tablet.

White to off-white, elliptical, film-coated tablets debossed “AS80” on one side and plain on the other side.
Blister pack (PA/Al/PVC/Al and OPA/Al/PE + Desiccant/HDPE) of 30 tablets: AUST R 286647.
Not all strengths may be available.

Storage

Store below 25°C.
Protect from light.

Poison Schedule

S4.