Atorvastatin Teva 80 mg Film-coated Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Atorvastatin
Available from:
Teva Pharma B.V.
ATC code:
C10AA; C10AA05
INN (International Name):
Atorvastatin
Dosage:
80 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
HMG CoA reductase inhibitors; atorvastatin
Authorization status:
Marketed
Authorization number:
PA0749/110/004
Authorization date:
2010-10-08

Package leaflet: Information for the user

Atorvastatin Teva 10 mg film-coated tablets

Atorvastatin Teva 20 mg film-coated tablets

Atorvastatin Teva 40 mg film-coated tablets

Atorvastatin Teva 80 mg film-coated tablets

Atorvastatin

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Atorvastatin Teva is and what it is used for

What you need to know before you take Atorvastatin Teva

How to take Atorvastatin Teva

Possible side effects

How to store Atorvastatin Teva

Contents of the pack and other information

1.

What Atorvastatin Teva is and what it is used for

Atorvastatin belongs to a group of medicines known as statins, which are lipid (fat) regulating

medicines.

Atorvastatin is used to lower lipids known as cholesterol and triglycerides in the blood when a low fat

diet and lifestyle changes on their own have failed. If you are at an increased risk of heart disease,

Atorvastatin can also be used to reduce such risk even if your cholesterol levels are normal. You

should maintain a standard cholesterol lowering diet during treatment.

2.

What you need to know before you take Atorvastatin Teva

Do not take Atorvastatin Teva

If you are allergic to atorvastatin or to any similar medicines used to lower blood lipids or to

any of the other ingredients of this medicine (listed in section 6)

If you have or have ever had a disease that affects the liver

If you have had any unexplained abnormal blood tests for liver function

If you are a woman able to have children and not using reliable contraception

If you are pregnant or trying to become pregnant

If you are breast-feeding

If you use the combination of glecaprevir/pibrentasvir in the treatment of hepatitis C.

Warnings and precautions

Talk to your doctor or pharmacist before taking Atorvastatin Teva.

If you are taking or have taken in the last 7 days a medicine called fusidic acid, (a medicine for

bacterial infection) orally or by injection. The combination of fusidic acid and Atorvastatin can

lead to serious muscle problems (rhabdomyolysis).

If you have had a previous stroke with bleeding into the brain, or have small pockets of fluid in

the brain from previous strokes

If you have kidney problems

If you have an under-active thyroid gland (hypothyroidism)

If you have had repeated or unexplained muscle aches or pains, a personal history or family

history of muscle problems

If you have had previous muscular problems during treatment with other lipid-lowering

medicines (e.g. other ‘-statin’ or ‘-fibrate’ medicines)

If you regularly drink a large amount of alcohol

If you have a history of liver disease

If you are older than 70 years.

While you are on this medicine your doctor will monitor you closely if you have diabetes or are at risk

of developing diabetes. You are likely to be at risk of developing diabetes if you have high levels of

sugars and fats in your blood, are overweight and have high blood pressure.

Talk to your doctor or pharmacist before taking Atorvastatin

If you have severe respiratory failure.

If any of these apply to you, your doctor will need to carry out a blood test before and possibly during

your Atorvastatin treatment to predict your risk of muscle-related side effects. The risk of muscle-

related side effects e.g rhabdomyolysis is known to increase if certain medicines are taken at the same

time as atorvastatin (see section 2 “Other medicines and Atorvastatin”).

Also tell your doctor or pharmacist if you have a muscle weakness that is constant. Additional tests

and medicines may be needed to diagnose and treat this.

Other medicines and Atorvastatin Teva

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

There are some medicines that may change the effect of Atorvastatin, or their effect may be changed

by Atorvastatin. This type of interaction could make one or both of the medicines less effective.

Alternatively it could increase the risk or severity of side effects, including the important muscle-

wasting condition known as rhabdomyolysis described in section 4:

If you need to take oral fusidic acid to treat a bacterial infection you will need to temporarily

stop using this medicine. Your doctor will tell you when it is safe to restart Atorvastatin. Taking

Atorvastatin with fusidic acid may rarely lead to muscle weakness, tenderness or pain

(rhabdomyolysis). See more information regarding rhabdomyolysis in section 4.

Medicines used to alter the way your immune system works, e.g. ciclosporin

Other antibiotics (medicines for bacterial infections) or antifungal medicines, e.g. erythromycin,

clarithromycin, telithromycin, ketoconazole, itraconazole, voriconazole, fluconazole,

posaconazole, rifampicin

Other medicines to regulate lipid levels, e.g. gemfibrozil, other fibrates, colestipol

Some calcium channel blockers used for angina or high blood pressure, e.g. amlodipine,

diltiazem; medicines to regulate your heart rhythm e.g. digoxin, verapamil, amiodarone

Medicines used in the treatment of HIV e.g. efavirenz, ritonavir, lopinavir, atazanavir,

indinavir, darunavir, the combination of tipranavir/ritonavir etc.

Some medicines used in the treatment of hepatitis C e.g telaprevir, boceprevir and combination

of elbasvir/grazoprevir

Other medicines known to interact with atorvastatin include ezetimibe (which lowers

cholesterol), warfarin (which reduces blood clotting), oral contraceptives, stiripentol (an anti-

convulsant for epilepsy), cimetidine (used for heartburn and peptic ulcers), phenazone (a

painkiller), colchicine (used to treat gout) and antacids (indigestion products containing

aluminium or magnesium)

Medicines obtained without a prescription: St. John’s wort.

Atorvastatin Teva with food ,drink and alcohol

See section 3 for instructions on how to take Atorvastatin. Please note the following:

Grapefruit juice

Do not take more than one or two small glasses of grapefruit juice per day because large quantities of

grapefruit juice can change the effects of Atorvastatin.

Alcohol

Avoid drinking too much alcohol while taking this medicine. See section 2 “Warnings and

precautions” for details.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

Do not take Atorvastatin if you are pregnant, or if you are trying to become pregnant.

Do not take Atorvastatin if you are able to become pregnant unless you use reliable contraceptive

measures.

Do not take Atorvastatin if you are breast-feeding.

The safety of Atorvastatin during pregnancy and breast-feeding has not yet been proven. Ask your

doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Normally this medicine does not affect your ability to drive or operate machines. However, do not

drive if this medicine affects your ability to drive. Do not use any tools or machines if your ability to

use them is affected by this medicine.

This medicine contains sodium.

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say

essentially ‘sodium-free’.

3.

How to take Atorvastatin Teva

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

Before starting treatment, your doctor will place you on a low-cholesterol diet, which you should

maintain also during therapy with Atorvastatin

The recommended starting dose of of Atorvastatin is 10 mg once a day

in adults and children aged

10 years or older

. This may be increased if necessary by your doctor until you are taking the amount

you need. Your doctor will adapt the dosage at intervals of 4 weeks or more. The maximum dose of

Atorvastatin is 80 mg once daily.

Atorvastatin tablets should be swallowed whole with a drink of water, and can be taken at any time of

day, with or without food. However, try to take your tablet at the same time every day.

The duration of treatment with Atorvastatin is determined by your doctor.

Please ask your doctor if you think that the effect of Atorvastatin is too strong or too weak.

If you take more Atorvastatin Teva than you should

If you accidentaly take too many Atorvastatin tablets (more than your usual daily dose), contact your

doctor or nearest hospital for advice.

If you forget to take Atorvastatin Teva

If you forget to take a dose, just take your next scheduled dose at the correct time. Do not take a

double dose to make up for a forgotten dose.

If you stop taking Atorvastatin Teva

If you have any further questions on the use of this medicine or wish to stop your treatment, ask your

doctor or pharmacist.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience any of the following serious side effects or symptoms, stop taking your tablets

and tell your doctor immediately or go to the nearest hospital accident and emergency

department.

Rare: may affect up to 1 in 1,000 people

Serious allergic reaction which causes swelling of the face, tongue and throat that can cause

great difficulty in breathing.

Serious illness with severe peeling and swelling of the skin, blistering of the skin, mouth, eyes

genitals and fever. Skin rash with pink-red blotches especially on palms of hands or soles of feet

which may blister.

Muscle weakness, tenderness, pain, rupture or red-brown discolouration of urine and

particularly, if at the same time, you feel unwell or have a high temperature it may be caused by

an abnormal muscle breakdown (rhabdomyolysis). The abnormal muscle breakdown does not

always go away, even after you have stopped taking atorvastatin, and it can be life-threatening

and lead to kidney problems.

Very rare: may affect up to 1 in 10,000 people

lupus-like disease syndrome (including rash, joint disorders and effects on blood cells)

If you experience problems with unexpected or unusual bleeding or bruising, this may be

suggestive of a liver complaint. You should consult your doctor as soon as possible.

Other possible side effects with Atorvastatin Teva

Common: may affect up to 1 in 10 people:

inflammation of the nasal passages, pain in the throat, nose bleed

allergic reactions

increases in blood sugar levels (if you have diabetes continue careful monitoring of your blood

sugar levels), increase in blood creatine kinase

headache

nausea, constipation, wind, indigestion, diarrhoea

joint pain, muscle pain and back pain

blood test results that show your liver function can become abnormal

Uncommon: may affect up to 1 in 100 people

anorexia (loss of appetite), weight gain, decreases in blood sugar levels (if you have diabetes

you should continue careful monitoring of your blood sugar levels)

having nightmares, insomnia

dizziness, numbness or tingling in the fingers and toes, reductions of sensation to pain or touch,

change in sense of taste, loss of memory

blurred vision

ringing in the ears and/or head

vomiting, belching, abdominal pain upper and lower, pancreatitis (inflammation of the pancreas

leading to stomach pain)

hepatitis (liver inflammation)

rash, skin rash and itching, hives, hair loss

neck pain, muscle fatigue

fatigue, feeling unwell, weakness, chest pain, swelling especially in the ankles (oedema), raised

temperature

urine tests that are positive for white blood cells

Rare: may affect up to 1 in 1,000 people

visual disturbance

unexpected bleeding or bruising

cholestasis (yellowing of the skin and whites of the eyes)

tendon injury

Very rare: may affect up to 1 in 10,000 people

an allergic reaction - symptoms may include sudden wheezing and chest pain or tightness,

swelling of the eyelids, face, lips, mouth, tongue or throat, difficulty breathing, collapse

hearing loss

gynecomastia (breast enlargement in men).

Not known (frequency cannot be estimated from the available data) include:

muscle weakness that is constant

Possible side effects reported with some statins (medicines of the same type):

Sexual difficulties

Depression

Breathing problems including persistent cough and/or shortness of breath or fever

Diabetes. This is more likely if you have high levels of sugars and fats in your blood, are

overweight and have high blood pressure. Your doctor will monitor you while you are taking

this medicine.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet.

You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL -

Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:

medsafety@hpra.ie. By reporting side effects you can help provide more information on the safety of

this medicine..

5.

How to store Atorvastatin Teva

Keep out of the sight and reach of children.

Store below 30

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date

refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longeruse. These measures will help protect the environment.

6.

Contents of the pack and other information

What Atorvastatin Teva contains

The active substance is atorvastatin

Each 10 mg tablet contains 10 mg of atorvastatin as atorvastatin calcium

Each 20 mg tablet contains 20 mg of atorvastatin as atorvastatin calcium

Each 40 mg tablet contains 40 mg of atorvastatin as atorvastatin calcium

Each 80 mg tablet contains 80 mg of atorvastatin as atorvastatin calcium

The other ingredients in the tablet core are microcrystalline cellulose, sodium carbonate,

maltose, croscarmellose sodium and magnesium stearate.

The other ingredients in the film-coating are hypromellose (E464), hydroxypropylcellulose,

triethyl citrate (E1505), polysorbate 80 and titanium dioxide (E171).

What Atorvastatin Teva looks like and contents of the pack

10 mg: Atorvastatin Teva

film-coated tablets are white to off-white, elliptic, biconvex and

smooth film-coated tablets. The dimensions of each tablet are approximately 9.7 mm x 5.2 mm.

20 mg: Atorvastatin Teva

film-coated tablets are white to off-white, elliptic, biconvex and

smooth film-coated tablets. The dimensions of each tablet are approximately 12.5 mm x 6.6

40 mg: Atorvastatin Teva

film-coated tablets are white to off-white, elliptic, biconvex and

smooth film-coated tablets. The dimensions of each tablet are approximately 15.6 mm x 8.3

80 mg: Atorvastatin Teva

film-coated tablets are white to off-white, elliptic, biconvex and

smooth film-coated tablets. The dimensions of each tablet are approximately 18.8 mm x 10.3

Atorvastatin Teva

is available in aluminium-aluminium blisters containing 7, 10, 14, 15, 20,

28, 30, 50, 50x1, 56, 60, 84, 90, 98, 100 or 200 tablets and in high density polyethylene bottle

containing 50 or 100 tablets and as multipack containing 100 tablets (2 bottles of 50 tablets).

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Teva Pharma B.V.

Swensweg 5

2031GA Haarlem

The Netherlands

Manufacturers

Teva Pharma S.L.U.

C/C, n. 4, Poligono Industrial Malpica, 50016 Zaragoza,

Spain

TEVA UK Ltd

Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG,

United Kingdom

Teva Operations Poland Sp. z.o.o.

ul. Mogilska 80, 31-546, Krakow

Poland

Merckle GmbH

Ludwig-Merckle-Straße 3

89143 Blaubeuren

Germany

Pharmachemie B.V.

Swensweg 5,

2031 GA Haarlem

The Netherlands

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria

Atorvastatin ratiopharm 10 mg Filmtabletten

Atorvastatin ratiopharm 20 mg Filmtabletten

Atorvastatin ratiopharm 40 mg Filmtabletten

Atorvastatin ratiopharm 80 mg Filmtabletten

Belgium

Atorvastatine Teva 10 mg filmomhulde tabletten

Atorvastatine Teva 20 mg filmomhulde tabletten

Atorvastatine Teva 40 mg filmomhulde tabletten

Atorvastatine Teva 80 mg filmomhulde tabletten

Bulgaria

Avanor 10 mg Film-coated tablets

Avanor 20 mg Film-coated tablets

Avanor 40 mg Film-coated tablets

Avanor 80 mg Film-coated tablets

Czech Republic

Atorvastatin ratiopharm GmbH 10 mg potahované tablety

Atorvastatin ratiopharm GmbH 20 mg potahované tablety

Atorvastatin ratiopharm GmbH 40 mg potahované tablety

Denmark

Atorvastatin Teva

Estonia

Atorvastatin Teva

Finland

Atorvastatin ratiopharm 10 mg kalvopäällysteiset tabletit

Atorvastatin ratiopharm 20 mg kalvopäällysteiset tabletit

Atorvastatin ratiopharm 40 mg kalvopäällysteiset tabletit

Atorvastatin ratiopharm 80 mg kalvopäällysteiset tabletit

France

ATORVASTATINE TEVA Santé 10 mg, comprimé pelliculé

ATORVASTATINE TEVA Santé 20 mg, comprimé pelliculé

ATORVASTATINE TEVA Santé 40 mg, comprimé pelliculé

ATORVASTATINE TEVA Santé 80 mg, comprimé pelliculé

Greece

TEVASTATIN 10 mg Επικαλυμμένα με λεπτό υμένιο δισκία

TEVASTATIN 20 mg Επικαλυμμένα με λεπτό υμένιο δισκία

TEVASTATIN 40 mg Επικαλυμμένα με λεπτό υμένιο δισκία

TEVASTATIN 80 mg Επικαλυμμένα με λεπτό υμένιο δισκία

Ireland

Atorvastatin Teva 10mg film-coated tablets

Atorvastatin Teva 20mg film-coated tablets

Atorvastatin Teva 40mg film-coated tablets

Atorvastatin Teva 80mg film-coated tablets

Italy

Atorvastatina Teva Italia 10 mg compresse rivestite con film

Atorvastatina Teva Italia 20 mg compresse rivestite con film

Atorvastatina Teva Italia 40 mg compresse rivestite con film

Atorvastatina Teva Italia 80 mg compresse rivestite con film

Lithuania

Atorvastatin Teva 10 mg plėvele dengtos tabletės

Atorvastatin Teva 20 mg plėvele dengtos tabletės

Atorvastatin Teva 40 mg plėvele dengtos tabletės

Atorvastatin Teva 80 mg plėvele dengtos tabletės

The Netherlands

Atorvastatine 10 mg Teva, filmomhulde tabletten

Atorvastatine 20 mg Teva, filmomhulde tabletten

Atorvastatine 40 mg Teva, filmomhulde tabletten

Atorvastatine 80 mg Teva, filmomhulde tabletten

Norway

Atorvastatin Teva 10 mg filmdrasjerte tabletter

Atorvastatin Teva 20 mg filmdrasjerte tabletter

Atorvastatin Teva 40 mg filmdrasjerte tabletter

Atorvastatin Teva 80 mg filmdrasjerte tabletter

Poland

10 mg, 20 mg & 40 mg: Atorvastatinum 123ratio

80 mg: Atorvox

Portugal

Atorvastatina Teva

Sweden

Atorvastatin Teva 10 mg filmdragerade tabletter

Atorvastatin Teva 20 mg filmdragerade tabletter

Atorvastatin Teva 40 mg filmdragerade tabletter

Atorvastatin Teva 80 mg filmdragerade tabletter

Slovenia

Bisatum 10 mg filmsko obložene tablete

Bisatum 20 mg filmsko obložene tablete

Bisatum 40 mg filmsko obložene tablete

Bisatum 80 mg filmsko obložene tablete

Slovak Republic

Atorvastatin Teva Pharma 10 mg

Atorvastatin Teva Pharma 20 mg

Atorvastatin Teva Pharma 40 mg

Atorvastatin Teva Pharma 80 mg

United Kingdom

Atorvastatin 10 mg film-coated tablets

Atorvastatin 20 mg film-coated tablets

Atorvastatin 40 mg film-coated tablets

Atorvastatin 80 mg film-coated tablets

This leaflet was last revised in

August 2019

Health Products Regulatory Authority

13 November 2019

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Atorvastatin Teva 80 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet contains 80 mg atorvastatin (as atorvastatin calcium).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Atorvastatin Teva 80 mg Film-coated Tablets are white to off-white, elliptic, biconvex and smooth film-coated tablets. The

dimensions of each tablet are approximately 18.8 mm x 10.3 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Hypercholesterolaemia

Atorvastatin is indicated as an adjunct to diet for reduction of elevated total cholesterol (total‑C), LDL‑cholesterol (LDL‑C),

apolipoprotein B and triglycerides in adults, adolescents and children aged 10 years or older with primary

hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia

(corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other non pharmacological

measures is inadequate.

Atorvastatin is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterolaemia as an

adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Prevention of cardiovascular disease

Atorvastatin is indicated in prevention of cardiovascular events in adult patients estimated to have a high risk for a first

cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.

4.2 Posology and method of administration

Posology

The patient should be placed on a standard cholesterol-lowering diet before receiving Atorvastatin and should continue on this

diet during treatment with Atorvastatin.

The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response.

The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The

maximum dose is 80 mg once a day.

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia

The majority of patients are controlled with Atorvastatin 10 mg once a day. A therapeutic response is evident within 2 weeks,

and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.

Heterozygous familial hypercholesterolaemia

Patients should be started with Atorvastatin 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg

daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined

with 40 mg atorvastatin once daily.

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Homozygous familial hypercholesterolaemia

Only limited data are available (see section 5.1).

The dose of atorvastatin in patients with homozygous familial hypercholesterolaemia is 10 to 80 mg daily (see section 5.1).

Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such

treatments are unavailable.

Prevention of cardiovascular disease

In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL-) cholesterol

levels according to current guidelines.

Co-administration with other medicines

In patients taking hepatitis C antiviral agents elbasvir/grazoprevir concomitantly with atorvastatin, the dose of atorvastatin

should not exceed 20 mg/day (see sections 4.4 and 4.5).

Renal impairment

No adjustment of dose is required (see section 4.4).

Hepatic impairment

Atorvastatin should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2). Atorvastatin is

contraindicated in patients with active liver disease (see section 4.3).

Elderly

Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population.

Paediatric population

Hypercholesterolaemia:

Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients

should be re‑evaluated on a regular basis to assess progress.

For patients with Heterozygous Familial Hypercholesterolemia aged 10 years and above, the recommended starting dose of

atorvastatin is 10 mg per day (see section 5.1).

The dose may be increased to 80 mg daily, according to the response and tolerability. Doses should be individualised

according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more. The dose

titration to 80 mg daily is supported by study data in adults and by limited clinical data from studies in children with

Heterozygous Familial Hypercholesterolemia (see sections 4.8 and 5.1).with titration up to 20 mg per day. Titration should be

conducted according to the individual response and tolerability in paediatric patients. Safety information for paediatric patients

treated with doses above 20 mg, corresponding to about 0.5 mg/kg, is limited.

There are limited safety and efficacy data available in children with Heterozygous Familial Hypercholesterolemia between 6 to

10 years of age derived from open-label studies. Atorvastatin is not indicated in the treatment of patients below the age of 10

years. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be

made.There is limited experience in children between 6-10 years of age (see section 5.1). Atorvastatin is not indicated in the

treatment of patients below the age of 10 years.

Other pharmaceutical forms/strengths may be more appropriate for this population.

Method of administration

Atorvastatin is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at any time of day

with or without food.

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4.3 Contraindications

Atorvastatin is contraindicated in patients:

with hypersensitivity to the active substance or to any of the excipients listed in section 6.1

with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper

limit of normal

during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate

contraceptive measures (see section 4.6).

treated with the hepatitis C antivirals glecaprevir/pibrentasvir.

4.4 Special warnings and precautions for use

Liver effects

Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who

develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who

develop increased transaminase levels should be monitored until the abnormality(ies) resolve. Should an increase in

transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of

Atorvastatin is recommended (see section 4.8).

Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a

history of liver disease.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In a post‑hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or

transient ischemic attack (TIA) there was a higher incidence of haemorrhagic stroke in patients initiated on atorvastatin

80 mg compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or

lacunar infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and

benefits of atorvastatin 80 mg is uncertain, and the potential risk of haemorrhagic stroke should be carefully

considered before initiating treatment (see section 5.1).

Skeletal muscle effects

Atorvastatin, like other HMG‑CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause

myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life-threatening condition

characterised by markedly elevated creatine kinase (CK) levels (>10 times ULN), myoglobinaemia and myoglobinuria

which may lead to renal failure.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment

with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum

creatine kinase, which persist despite discontinuation of statin treatment.

Before the treatment

Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be

measured before starting statin treatment in the following situations:

Renal impairment

Hypothyroidism

Personal or familial history of hereditary muscular disorders

Previous history of muscular toxicity with a statin or fibrate

Previous history of liver disease and/or where substantial quantities of alcohol are consumed

In elderly (age >70 years), the necessity of such measurement should be considered, according to the presence of

other pre‑disposing factors for rhabdomyolysis.

Situations where an increase in plasma levels may occur, such as interactions (see section 4.5) and special

populations including genetic subpopulations (see section 5.2)

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is

recommended.If CK levels are significantly elevated (>5 times ULN) at baseline, treatment should not be started.

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Creatine kinase measurement

Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause

of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (>5 times ULN),

levels should be remeasured within 5 to 7 days later to confirm the results.

Whilst on treatment

Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise

or fever.

If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should be

measured. If these levels are found to be significantly elevated (>5 times ULN), treatment should be stopped.

If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to ≤5 x ULN,

treatment discontinuation should be considered.

If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an

alternative statin may be considered at the lowest dose and with close monitoring.

Atorvastatin must be discontinued if clinically significant elevation of CK levels (>10 x ULN) occur, or if

rhabdomyolysis is diagnosed or suspected

Concomitant treatment with other medicinal products

Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may

increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporine,

telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease

inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). The risk of myopathy may also be increased with

the concomitant use of gemfibrozil and other fibric acid derivates, erythromycin, niacin and ezetimibe. If possible, alternative

(non-interacting) therapies should be considered instead of these medicinal products.

In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of

concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma

concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent

CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these

patients is recommended (see section 4.5).

Atorvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid

treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued

throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in

patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical

advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the

need for co-administration of Atorvastatin and fusidic acid should only be considered on a case by case basis and under close

medical supervision.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see

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section 4.8). 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.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may

produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the

reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk

(fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m

, raised triglycerides, hypertension) should be monitored both clinically and

biochemically according to national guidelines.

Paediatric population

No clinically significant effect on growth and sexual maturation was observed in a 3-year study based on the assessment of

overall maturation and development, assessment of Tanner Stage, and measurement of height and weight (see section 4.8).

Excipient

Atorvastatin film-coated tablets contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per film-coated

tablet, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

Effect of co-administered medicinal products on atorvastatin

Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic

anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of

OATP1B1. Atorvastatin is also identified as a substrate of the multi-drug resistance protein 1 (MDR1) and breast cancer

resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see section 5.2).

Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased

plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant

administration of atorvastatin with other medicinal products that have a potential to induce myopathy, such as fibric acid

derivates and ezetimibe (see section 4.4).

CYP3A4 inhibitors

Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see Table 1 and

specific information below). Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin,

delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole some antivirals used in the treatment of HCV

(e.g. elbasvir/grazoprevir) and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should

be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower

starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is

recommended (see Table 1).

Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of

atorvastatin (see Table 1).. An increased risk of myopathy has been observed with the use of erythromycin in combination with

statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both

amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in

increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate

clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate

clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.

CYP3A4 inducers

Concomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. efavirenz, rifampin, St. John's Wort) can

lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin

(cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of

atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been

associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampin on atorvastatin

concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be

carefully monitored for efficacy.

Transport inhibitors

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Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin (see Table 1). The effect of

inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant

administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1).

Gemfibrozil / fibric acid derivatives

The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these

events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. If concomitant administration

cannot be avoided, the lowest dose of atorvastatin to achieve the therapeutic objective should be used and the patients should

be appropriately monitored (see section 4.4).

Ezetimibe

The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may

therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is

recommended.

Colestipol

Plasma concentrations of atorvastatin and its active metabolites were lower (ratio of atorvastatin concentration: 0.74) when

colestipol was co-administered with Atorvastatin. However, lipid effects were greater when Atorvastatin and colestipol were

co-administered than when either medicinal product was given alone.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid

with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown.

There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, atorvastatin treatment should be discontinued throughout the duration of

the fusidic acid treatment.( see section 4.4)

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.

Effect of atorvastatin on co-administered medicinal products

Digoxin

When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin concentrations increased

slightly. Patients taking digoxin should be monitored appropriately.

Oral contraceptives

Co-administration of Atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone

and ethinyl oestradiol.

Warfarin

In a clinical study in patients receiving chronic warfarin therapy, co-administration of atorvastatin 80 mg daily with warfarin

caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of dosing which returned to normal

within 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have

been reported, prothrombin time should be determined before starting atorvastatin in patients taking coumarin anticoagulants

and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable

prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for

patients on coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure should be

repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not

taking anticoagulants.

Paediatric population

Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is

not known. The above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the

paediatric population.

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Table 1: Effect of co-administered medicinal products on the pharmacokinetics of atorvastatin

Co-administered medicinal

product

and dosing regimen

Atorvastatin

Dose (mg)

Ratio of

&

Clinical Recommendation

Glecaprevir 400 mg OD/ Pibrentasvir 120 mg OD, 7

days

10 mg OD for 7 days

Co-administration with products

containing glecaprevir or

pibrentasvir is contraindicated (see

section 4.3).

Tipranavir 500 mg BID/

Ritonavir 200 mg BID, 8 days

(days 14 to 21)

40 mg on day 1,

10 mg on day 20

In cases where co-administration

with atorvastatin is necessary, do

not exceed 10 mg atorvastatin daily.

Clinical monitoring of these

patients is recommended

Telaprevir 750 mg q8h, 10 days

20 mg, SD

Ciclosporin 5.2 mg/kg/day,

stable dose

10 mg OD for 28

days

Elbasvir 50 mg OD/

Grazoprevir 200 mg OD, 13 days

10 mg SD

1.95

The dose of atorvastatin should not

exceed a daily dose of 20 mg

during co-administration with

products containing elbasvir or

grazoprevir.

Lopinavir 400 mg BID/ Ritonavir 100 mg BID, 14

days

20 mg OD for 4 days

In cases where co- administration

with atorvastatin is necessary, lower

maintenance doses of atorvastatin

are recommended. At atorvastatin

doses exceeding 20 mg, clinical

monitoring of these patients is

recommended.

Clarithromycin 500 mg BID, 9

days

80 mg OD for 8

days

Saquinavir 400 mg BID/

Ritonavir (300 mg BID from days 5-7, increased to

400 mg BID on day 8), days 4-18, 30 min after

atorvastatin dosing

40 mg OD for 4

days

In cases where co-administration

with atorvastatin is necessary, lower

maintenance doses of atorvastatin

are recommended. At atorvastatin

doses exceeding 40 mg, clinical

monitoring of these patients is

recommended.

Darunavir 300 mg BID/ Ritonavir 100 mg BID, 9 days

10 mg OD for 4 days

Itraconazole 200 mg OD, 4 days

40 mg SD

Fosamprenavir 700 mg BID/ Ritonavir 100 mg BID, 14

days

10 mg OD for 4 days

Fosamprenavir 1400 mg BID,

14 days

10 mg OD for 4

days

Nelfinavir 1250 mg BID, 14

days

10 mg OD for 28

days

1.74

No specific recommendation

Grapefruit Juice, 240 mL OD *

40 mg, SD

1.37

Concomitant intake of large

quantities of grapefruit juice and

atorvastatin is not recommended.

Diltiazem 240 mg OD, 28 days

40 mg, SD

1.51

After initiation or following dose

adjustments of diltiazem,

appropriate clinical monitoring of

these patients is recommended.

Erythromycin 500 mg QID, 7

days

10 mg, SD

1.33

Lower maximum dose and clinical

monitoring of these patients is

recommended.

Amlodipine 10 mg, single dose

80 mg, SD

1.18

No specific recommendation.

Cimetidine 300 mg QID, 2

10 mg OD for 2 weeks

1.00

No specific recommendation.

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weeks

Colestipol 10 g BID, 24 weeks

40 mg OD for 8 weeks

0.74**

No specific recommendation

Antacid suspension of magnesium and aluminium

hydroxides, 30 mL QID, 17 days

10 mg OD for 15 days

0.66

No specific recommendation.

Efavirenz 600 mg OD, 14 days

10 mg for 3 days

0.59

No specific recommendation.

Rifampin 600 mg OD, 7 days

(co-administered)

40 mg SD

1.12

If co-administration cannot be

avoided, simultaneous co-

administration of atorvastatin with

rifampin is recommended, with

clinical monitoring.

Rifampin 600 mg OD, 5 days

(doses separated)

40 mg SD

0.20

Gemfibrozil 600 mg BID, 7

days

40 mg SD

1.35

Lower starting dose and clinical

monitoring of these patients is

recommended.

Fenofibrate 160 mg OD, 7 days

40 mg SD

1.03

Lower starting dose and clinical

monitoring of these patients is

recommended.

Boceprevir 800 mg TID, 7 days

40 mg SD

Lower starting dose and clinical

monitoring of these patients is

recommended. The dose of

atorvastatin should not exceed a

daily dose of 20 mg during co-

administration with boceprevir.

&

Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

See sections 4.4 and 4.5 for clinical significance.

Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of medicinal products

metabolized by CYP3A4. Intake of one 240 ml glass of grapefruit juice also resulted in a decreased AUC of 20.4% for the active

orthohydroxy metabolite. Large quantities of grapefruit juice (over 1.2 l daily for 5 days) increased AUC of atorvastatin 2.5 fold

and AUC of active (atorvastatin and metabolites) HMG-CoA reductase inhibitors 1.3 fold.

** Ratio based on a single sample taken 8-16 h post dose.

OD = once daily; SD = single dose; BID = twice daily; TID = three times daily; QID = four times daily

Table 2: Effect of atorvastatin on the pharmacokinetics of co-administered medicinal products

Atorvastatin and

dosing regimen

Co-administered medicinal product

Medicinal product/Dose (mg)

Ratio of AUC

&

Clinical Recommendation

80 mg OD for

10 days

Digoxin 0.25 mg OD, 20 days

1.15

Patients taking digoxin

should be monitored

appropriately.

40 mg OD for

22 days

Oral contraceptive OD, 2 months

- norethindrone 1 mg

-ethinyl estradiol 35 μg

1.28

1.19

No specific

recommendation.

80 mg OD for

15 days

* Phenazone, 600 mg SD

1.03

No specific

recommendation

10 mg, SD

Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days

1.08

No specific

recommendation

10 mg, OD for 4 days

Fosamprenavir 1400 mg BID, 14 days

0.73

No specific

recommendation

10 mg OD for 4 days

Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days

0.99

No specific

recommendation

&

Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

* Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of

phenazone.

OD = once daily; SD = single dose; BID = twice daily

4.6 Fertility, pregnancy and lactation

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Women of childbearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).

Pregnancy

Atorvastatin is contraindicated during pregnancy (see section 4.3). Safety in pregnancy woman has not been established (see

section 4.3). No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital

anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown

toxicity to reproduction (see section 5.3).

Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis.

Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy

should have little impact on the long-term risk associated with primary hypercholesterolaemia.

For these reasons, Atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are

pregnant. Treatment with Atorvastatin should be suspended for the duration of pregnancy or until it has been determined that

the woman is not pregnant (see section 4.3.)

Breast-feeding

It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of

atorvastatin and its active metabolites are similar to those in milk (see section 5.3). Because of the potential for serious adverse

reactions, women taking Atorvastatin should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated

during breast-feeding (see section 4.3).

Fertility

In animal studies atorvastatin had no effect on male or female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Atorvastatin has negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Lipitor vs. 7311 placebo) patients treated for a

mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the

patients on placebo.

Based on data from clinical studies and extensive post-marketing experience, the following list presents the adverse reaction

profile for Atorvastatin.

Estimated frequencies of reactions are ranked according to the following convention: common (≥1/100 to <1/10); uncommon

(≥1/1,000 to 1/100); rare (≥1/10,000 to <1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available

data).

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Rare: thrombocytopenia.

Immune system disorders

Common: allergic reactions

Very rare: anaphylaxis

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Metabolism and nutrition disorders

Common: hyperglycaemia

Uncommon: hypoglycaemia, weight gain, anorexia

Psychiatric disorders

Uncommon: nightmare, insomnia

Nervous system disorders

Common: headache

Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia

Rare: peripheral neuropathy

Eye disorders

Uncommon: vision blurred

Rare: visual disturbance

Ear and labyrinth disorders

Uncommon: tinnitus

Very rare: hearing loss

Respiratory, thoracic and mediastinal disorders

Common: pharyngolaryngeal pain, epistaxis

Gastrointestinal disorders

Common: constipation, flatulence, dyspepsia, nausea, diarrhoea

Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis

Hepatobiliary disorders

Uncommon: hepatitis

Rare: cholestasis

Very rare: hepatic failure

Skin and subcutaneous tissue disorders

Uncommon: urticaria, skin rash, pruritus, alopecia

Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic

epidermal necrolysis

Musculoskeletal and connective tissue disorders

Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain

Uncommon: neck pain, muscle fatigue

Rare: myopathy, myositis, rhabdomyolysis, musclerupture, tendinopathy, sometimes complicated by rupture

Not known: immune-mediated necrotizing myopathy (see section 4.4)

Reproductive system and breast disorders

Very rare: gynaecomastia

General disorders and administration site conditions

Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Investigations

Common: liver function test abnormal, blood creatine kinase increased

Uncommon: white blood cells urine positive

As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving

Atorvastatin. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (>3

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times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on Atorvastatin. These elevations were

dose-related and were reversible in all patients.

Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on

Atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range

occurred in 0.4% Atorvastatin-treated patients (see section 4.4).

Paediatric population

Paediatric patients aged from 10 to 17 years of age treated with atorvastatin had an adverse experience profile generally

similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of

causality assessment, were infections. No clinically significant effect on growth and sexual maturation was observed in a 3-year

study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of

height and weight. The safety and tolerability profile in paediatric patients was similar to the known safety profile of

atorvastatin in adult patients.

The clinical safety database includes safety data for 520 paediatric patients who received atorvastatin, among which 7 patients

were < 6 years old, 121 patients were in the age range of 6 to 9, and 392 patients were in the age range of 10 to 17. Based on

the data available, the frequency, type and severity of adverse reactions in children is similar to adults.

The following adverse events have been reported with some statins:

Sexual dysfunction

Depression

Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6

mmol/L, BMI>30kg/m

, raised triglycerides, history of hypertension).

Paediatric Population

The clinical safety database includes safety data for 249 paediatric patients who received atorvastatin, among which 7 patients

were < 6 years old, 14 patients were in the age range of 6 to 9, and 228 patients were in the age range of 10 to 17.

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Common: Abdominal pain

Investigations

Common: Alanine aminotransferase increased, blood creatine phosphokinase increased

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Based on the data available, frequency, type and severity of adverse reactions in children are expected to be the same as in

adults. There is currently limited experience with respect to long‑term safety in the paediatric population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail:medsafety@hpra.ie.

4.9 Overdose

Specific treatment is not available for Atorvastatin overdose. Should an overdose occur, the patient should be treated

symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels

should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly

enhance atorvastatin clearance.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA reductase inhibitors

ATC code: C10A A05

Mechanism of action

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the

conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (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 receptor with high affinity to LDL (LDL receptor).

Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and

subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for

enhanced uptake and catabolism of LDL.

Pharmacodynamic effects

Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained

increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is

effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually

responded to lipid-lowering agents.

Clinical efficacy and safety

Atorvastatin has been shown to reduce concentrations of 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 A1 in a dose-response study.

These results are consistent in patients with heterozygous familial hypercholesterolaemia, non-familial forms of

hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.

Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce the risk for cardiovascular events and

cardiovascular mortality.

Homozygous familial hypercholesterolaemia

In a multicenter 8 week open-label compassionate-use study with an optional extension phase of variable length, 335 patients

were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia patients. From these 89 patients, the

mean percent reduction in LDL-C was approximately 20%. Atorvastatin was administered at doses up to 80 mg/day.

Atherosclerosis

In the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study (REVERSAL), the effect of intensive lipid lowering with

atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by

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intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomised, double- blind,

multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group

(n=253), there was no progression of atherosclerosis.

The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the

atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin the effects of

atorvastatin were statistically significant (p=0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e. g. need

for revascularisation, non fatal myocardial infarction, coronary death) was not investigated in this study.

In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/l ±

0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/l ± 0.7 (110 mg/dl ± 26) from

baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 26) (p<0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin:

-18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin:

-22.0%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction

in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p<0.0001).

Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.

The safety and tolerability profiles of the two treatment groups were comparable.

The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. Therefore, the

clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is

unknown.

Acute coronary syndrome

In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n=1,538; placebo n=1,548) with an

acute coronary syndrome (non Q-wave MI or unstable angina). Treatment was initiated during the acute phase after hospital

admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg/day increased the time to occurrence of the

combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with

evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16% (p=0.048). This was mainly due

to a 26% reduction in re-hospitalisation for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other

secondary endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).

The safety profile of atorvastatin in the MIRACL study was consistent with what is described in section 4.8.

Prevention of cardiovascular disease

The effect of atorvastatin on fatal and non‑fatal coronary heart disease was assessed in a randomised, double-blind,

placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were

hypertensive, 40‑79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels

≤6.5 mmol/L (251 mg/dL). All patients had at least 3 of the predefined cardiovascular risk factors: male gender, age ≥55 years,

smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C >6, peripheral vascular disease, left ventricular

hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were

estimated to have a high risk for a first cardiovascular event.

Patients were treated with antihypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin

10 mg daily (n=5,168) or placebo (n=5,137).

The absolute and relative risk reduction effect of atorvastatin was as follows:

Event

Relative

risk

reduction

(%)

No. of events

(atorvastatin

vs placebo)

Absolute

risk

reduction

1

(%)

P value

Fatal CHD plus non-fatal MI

100 vs. 154

1.1%

0.0005

Total cardiovascular events and revascularisation procedures

389 vs. 483

1.9%

0.0008

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Total coronary events

178 vs 247

1.4%

0.0006

Based on difference in crude events rates occurring over a median follow-up of 3.3 years.

CHD = coronary heart disease; MI = myocardial infarction.

Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p=0.17 and 74 vs. 82 events,

p=0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of atorvastatin was seen in males

but could not be established in females possibly due to the low event rate in the female subgroup. Overall and cardiovascular

mortality were numerically higher in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There

was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI)

was significantly reduced by atorvastatin in patients treated with amlodipine (HR 0.47 (0.32‑0.69), p=0.00008), but not in those

treated with atenolol (HR 0.83 (0.59‑1.17), p=0.287).

The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a randomised, double-blind,

multicentre, placebo-controlled trial, the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with type 2 diabetes,

40‑75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤4.14 mmol/L (160 mg/dL) and TG

≤6.78 mmol/L (600 mg/dL). All patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy,

microalbuminuria or macroalbuminuria.

Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-up of 3.9 years.

The absolute and relative risk reduction effect of atorvastatin was as follows:

Event

Relative

risk

reduction

(%)

No. of events

(atorvastatin

vs placebo)

Absolute

risk

reduction

1

(%)

P value

Major cardiovascular events (fatal and non‑fatal AMI, silent MI, acute CHD

death, unstable angina, CABG, PTCA, revascularisation, stroke)

83 vs. 127

3.2%

0.0010

MI (fatal and non‑fatal AMI, silent MI)

38 vs. 64

1.9%

0.0070

Strokes (fatal and non‑fatal)

21 vs 39

1.3%

0.0163

Based on difference in crude events rates occurring over a median follow-up of 3.9 years.

AMI = acute myocardial infarction; CABG = coronary artery bypass graft; CHD = coronary heart disease; MI = myocardial

infarction; PTCA = percutaneous transluminal coronary angioplasty.

There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable

trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group,

p=0.0592).

Recurrent stroke

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of atorvastatin 80 mg daily or

placebo on stroke was evaluated in 4,731 patients who had a stroke or transient ischaemic attack (TIA) within the preceding 6

months and no history of coronary heart disease (CHD). Patients were 60% male, 21-92 years of age (average age 63 years) and

had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with

atorvastatin and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.

Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00;

p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All-cause mortality was

9.1% (216/2,365) for atorvastatin versus 8.9% (211/2,366) for placebo.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischaemic stroke (218/2,365, 9.2% vs. 274/2,366, 11.6%,

p=0.01) and increased the incidence of haemorrhagic stroke (55/2,365, 2.3% vs. 33/2,366, 1.4%, p=0.02) compared to placebo.

The risk of haemorrhagic stroke was increased in patients who entered the study with prior haemorrhagic stroke

(7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84‑19.57) and the risk of ischaemic stroke was

similar between groups (3/45 for atorvastatin versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).

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The risk of haemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708

for atorvastatin versus 4/701 for placebo; HR 4.99; 95% CI, 1.71‑14.61), but the risk of ischaemic stroke was also

decreased in these patients (79/708 for atorvastatin versus 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is

possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive atorvastatin

80 mg/day.

All-cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in the subgroup of patients with prior haemorrhagic

stroke. All-cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the subgroup of patients

with prior lacunar infarct.

Paediatric Population

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6‑17 years old

An 8‑week, open‑label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of atorvastatin was

conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline

LDL‑C ≥ 4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children,

6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage ≥ 2.

The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in

Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target LDL‑C of < 3.35 mmol/L at

Week 4 and if atorvastatin was well tolerated.

Mean values for LDL‑C, TC, VLDL‑C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was

doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean

percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial

dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL‑C and TC was

approximately 40% and 30%, respectively, over the range of exposures.

In a second open label, single arm study, 271 male and female HeFH children 6-15 years of age were enrolled and treated with

atorvastatin for up to three years. Inclusion in the study required confirmed HeFH and a baseline LDL-C level ≥ 4 mmol/L

(approximately 152 mg/dL). The study included 139 children at Tanner 1 developmental stage (generally ranging from 6-10

years of age). The dosage of atorvastatin (once daily) was initiated at 5 mg (chewable tablet) in children less than 10 years of

age. Children age 10 and above were initiated at 10 mg atorvastatin (once daily). All children could titrate to higher doses to

achieve a target of < 3.35 mmol/L LDL-C. The mean weighted dose for children aged 6 to 9 years was 19.6 mg and the mean

weighted dose for children aged 10 years and above was 23.9 mg.

The mean (+/- SD) baseline LDL-C value was 6.12 (1.26) mmol/L which was approximately 233 (48) mg/dL. See table 3 below

for final results.

The data were consistent with no drug effect on any of the parameters of growth and development (i.e., height, weight, BMI,

Tanner stage, Investigator assessment of Overall Maturation and Development) in paediatric and adolescent subjects with

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HeFH receiving atorvastatin treatment over the 3 year study. There was no Investigator- assessed drug effect noted in height,

weight, BMI by age or by gender by visit.

TABLE 3 Lipid-lowering Effects of Atorvastatin in

Adolescent Boys and Girls with Heterozygous

Familial Hypercholesterolemia (mmol/L)

Timepoint

TC (S.D.)

LDL-C (S.D.)

HDL-C (S.D.)

TG (S.D.)

Apo B (S.D.)#

Baseline

7.86(1.30)

6.12(1.26)

1.314(0.2663)

0.93(0.47)

1.42(0.28)**

Month 30

4.95(0.77)*

3.25(0.67)

1.327(0.2796)

0.79(0.38)*

0.90(0.17)*

Month 36/ET

5.12(0.86)

3.45(0.81)

1.308(0.2739)

0.78(0.41)

0.93(0.20)***

TC= total cholesterol; LDL-C = low density

lipoprotein cholesterol-C; HDL-C = high density

lipoprotein cholesterol-C;

TG = triglycerides; Apo B = apolipoprotein B;

"Month 36/ET" included final visit data for

subjects who ended participation prior to the

scheduled 36 month timepoint as well as full 36

month data for subjects competing the 36

month participation; "*"= Month 30 N for this

parameter was 207; "**"= Baseline N for this

parameter was 270; "***" =Month 36/ET N for

this parameter was 243; "#"=g/L for Apo B.

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10‑17 years old

In a double‑blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10‑17 years

of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were

randomised to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks.. The

dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL‑C level was >

3.36 mmol/l. Atorvastatin significantly decreased plasma levels of total‑C, LDL‑C, triglycerides, and apolipoprotein B during

the 26 week double-blind phase. The mean achieved LDL‑C value was 3.38 mmol/l (range: 1.81‑6.26 mmol/l) in the

atorvastatin group compared to 5.91 mmol/l (range: 3.93‑9.96 mmol/l) in the placebo group during the 26‑week

double‑blind phase.

An additional paediatric study of atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10‑18 years

demonstrated that atorvastatin (N=25) caused a significant reduction in LDL‑C at week 26 (p<0.05) compared with colestipol

(N=31).

A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia)

included 46 paediatric patients treated with atorvastatin titrated according to response (some subjects received 80 mg

atorvastatin per day). The study lasted 3 years: LDL‑cholesterol was lowered by 36%.

The long‑term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been

established.

The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in children aged 0

to less than 6 years in the treatment of heterozygous hypercholesterolaemia and in children aged 0 to less than 18 years in the

treatment of homozygous familial hypercholesterolaemia, combined (mixed) hypercholesterolaemia, primary

hypercholesterolaemia and in the prevention of cardiovascular events (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (C

) occur within 1 to 2 hours.

Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are

95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of atorvastatin is approximately 12% and

the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is

attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism

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Distribution

Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins.

Biotransformation

Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation

products. Apart from other pathways these products are further metabolised via glucuronidation. In vitro, inhibition of

HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of

circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.

Elimination

Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, atorvastatin does not

appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is

approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the

contribution of active metabolites.

Atorvastatin is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3

(OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of

the efflux transporters multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the

intestinal absorption and biliary clearance of atorvastatin.

Other special populations

Elderly: Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than

in young adults while the lipid effects were comparable to those seen in younger patient populations.

Paediatric population: In an open‑label, 8‑week study, Tanner Stage 1 (N=15) and Tanner Stage ≥ 2 (N=24)

paediatric patients (ages 6‑17 years) with heterozygous familial hypercholesterolemia and baseline LDL‑C

≥ 4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film‑coated atorvastatin tablets once

daily, respectively. Body weight was the only significant covariate in atorvastatin population PK model. Apparent

oral clearance of atorvastatin in paediatric subjects appeared similar to adults when scaled allometrically by body

weight. Consistent decreases in LDL‑C and TC were observed over the range of atorvastatin and

o‑hydroxyatorvastatin exposures.

Gender: Concentrations of atorvastatin and its active metabolites in women differ from those in men (women:

approximately 20% higher for C

and approximately 10% lower for AUC). These differences were of no clinical

significance, resulting in no clinically significant differences in lipid effects among men and women.

Renal impairment: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and

its active metabolites.

Hepatic impairment: Plasma concentrations of atorvastatin and its active metabolites are markedly increased

(approximately 16‑fold in C

and approximately 11‑fold in AUC) in patients with chronic alcoholic liver disease

(Childs-Pugh B).

SLOC1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including atorvastatin, involves the

OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Atorvastatin,

which may lead to an increased risk of rhabdomyolysis (see section 4.4). Polymorphism in the gene encoding

OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher Atorvastatin exposure (AUC) than in individuals

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without this genotype variant (c.521TT). A genetically impaired hepatic uptake of Atorvastatin is also possible in

these patients. Possible consequences for the efficacy are unknown.

5.3 Preclinical safety data

Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay.

Atorvastatin was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC0-24h reached in

humans at the highest recommended dose) showed hepatocellular adenomas in males and hepatocellular carcinomas in

females.

There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of

embryos or fetuses. In rats, rabbits and dogs atorvastatin had no effect on fertility and was not teratogenic, however, at

maternally toxic doses fetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and

post-natal survival reduced during exposure of the dams to high doses of atorvastatin. In rats, there is evidence of placental

transfer. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether atorvastatin or its

metabolites are excreted in human milk.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose

Sodium carbonate anhydrous

Maltose

Croscarmellose sodium

Magnesium stearate

Film-coating

Hypromellose (E464)

Hydroxypropylcellulose

Triethyl citrate (E1505)

Polysorbate 80

Titanium dioxide (E171).

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 30

6.5 Nature and contents of container

Aluminium-aluminium blisters.

Atorvastatin Teva is available in pack sizes of 7, 10, 14, 15, 20, 28, 30, 50, 50x1, 56, 60, 84, 90, 98, 100 or 200 tablets.

High density polyethylene bottle with a polypropylene cap provided with a compartment for desiccant.

Atorvastatin Teva is available in pack sizes of 50, 100 tablets and as multipack containing 100 tablets (2 bottles of 50 tablets)

Not all pack sizes may be marketed.

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6.6 Special precautions for disposal

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Swansweg 5

2031GA Haarlem

Netherlands

8 MARKETING AUTHORISATION NUMBER

PA0749/110/004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 8th October 2010

Date of last renewal: 3rd August 2015

10 DATE OF REVISION OF THE TEXT

November 2019

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