Atorvastatin 20 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Atorvastatin-calcium
Available from:
Actavis Group PTC ehf
ATC code:
C10AA; C10AA05
INN (International Name):
Atorvastatin-calcium
Dosage:
20 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:
PA1380/017/002
Authorization date:
2009-09-18

Atorvastatin 10 mg, 20 mg, 40 mg & 80 mg

Film-coated Tablets

Atorvastatin

Package leaflet: Information for the user

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

1

What Atorvastatin is and what

it is used for

2

What you need to know

before you take Atorvastatin

3

How to take Atorvastatin

4

Possible side effects

5

How to store Atorvastatin

6

Contents of the pack and

other information

1

What Atorvastatin 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

life style 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

Do not take Atorvastatin:

if you are allergic to Atorvastatin

or any of the other ingredients of

medicine (listed in section 6)

if you have or have ever had a disease

which 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

if you have severe respiratory failure

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.

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

when certain medicines are taken at

the same time (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.

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.

Other medicines and

Atorvastatin

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:

Medicines used to alter the way your

immune system works, e.g. ciclosporin

Certain antibiotics or antifungal

medicines, e.g. erythromycin,

clarithromycin, telithromycin,

ketoconazole, itraconazole,

voriconazole, fluconazole,

posaconazole, rifampin

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.

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. 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 the 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 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

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.

Atorvastatin 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

Before starting treatment, your doctor

will place you on a low-cholesterol diet,

which you should maintain also during

therapy with Atorvastatin.

The usual starting dose 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

dose at intervals of 4 weeks or more.

The maximum dose of Atorvastatin is

80 mg once a day.

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.

Always take this medicine exactly as

your doctor has told you. Check with

your doctor or pharmacist if you are

not sure.

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.

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Details

Atorvastatin 10 mg, 20 mg, 40 mg & 80 mg Film-coated Tablets PIL - IE

Black

BBBA4687

T. Hull

29.04.2019

30.04.2019

T. Hull

190 x 380

8.5pt

Teva Malta Zejtun

29.04.2019

29.04.2019

2

Version 2

01.11.2017

If you take more Atorvastatin

than you should

If you accidentally 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

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

If you have any further questions on

the use of this medicine or wish to

stop your treatment, 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 to 1000 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:

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 1000

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

gynaecomastia (breast enlargement

in men).

Not known (cannot be estimated from

the available data):

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, pharmacist or nurse. 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

Keep this medicine out of the sight and

reach of children.

[only 10 mg, 20 mg and 40 mg]

This medicine does not require any

special storage conditions.

And Shelf life after first opening of

tablet container is 100 days.

[only 80 mg]

This medicinal product does not

require any special temperature storage

conditions.

Store in the original package in order to

protect from moisture.

Do not use this medicine after the

expiry date which is stated on the pack

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 longer use.

These measures will help protect the

environment.

6

Contents of the pack and

other information

What Atorvastatin contains

The active substance is atorvastatin as

atorvastatin calcium trihydrate. Each

10 mg, 20 mg, 40 mg or 80 mg

film-coated tablet contains 10 mg,

20 mg, 40 mg or 80 mg respectively,

of atorvastatin.

The other ingredients are:

[only 10 mg, 20 mg and 40 mg]

Tablet core: mannitol, cellulose

microcrystalline, crospovidone,

sodium carbonate, povidone,

methionine, magnesium stearate.

Tablet coating: hypromellose 6cP,

titanium dioxide (E171), macrogol

6000. Talc.

[only 80 mg]

Tablet core: cellulose microcrystalline,

crospovidone Type A, sodium

carbonate, povidone, glycerol

dibehenate, magnesium stearate.

Tablet coating: hypromellose 6cP,

titanium dioxide (E171), macrogol

6000.

What Atorvastatin looks like and

contents of the pack

Film-coated tablets.

10 mg: White, oval, biconvex, 4.9 x 9.1

mm film-coated tablets marked with

“10” on one side and “A” on the other.

20 mg: White, oval, biconvex, 6.2 x 11.5

mm film-coated tablets marked with

“20” on one side and “A” on the other.

40 mg: White, oval, biconvex, 7.8 x 14.5

mm film-coated tablets marked with

“40” on one side and “A” on the other.

80 mg: White, oval, biconvex, 10 x 19

mm film-coated tablets marked with

“80” on one side and “A” on the other.

Pack sizes:

Blisters:

Atorvastatin 10 mg film-coated tablets:

10, 20, 28, 30, 50, 90, 98, 100 tablets.

Atorvastatin 20 mg film-coated tablets:

10, 20, 28, 30, 50, 90, 98, 100 tablets.

Atorvastatin 40 mg film-coated tablets:

10, 20, 28, 30, 50, 90, 98, 100 tablets.

Atorvastatin 80 mg film-coated tablets:

20, 28, 30, 50, 98, 100 tablets.

Tablet container:

Atorvastatin 10 mg film-coated tablets:

30, 100, 200, 250, 500 tablets.

Atorvastatin 20 mg film-coated tablets:

30, 100, 250, 500 tablets.

Atorvastatin 40 mg film-coated tablets:

30, 100, 250, 500 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

and Manufacturer

Marketing Authorisation Holder

Actavis Group PTC ehf., Reykjavikurvegi

76-78, 220 Hafnarfjordur, Iceland

Manufacturers

[only 10 mg, 20 mg, 40 mg and 80 mg]

Actavis hf., Reykjavikurvegur 76-78, 220

Hafnarfjordur, Iceland

Actavis Ltd, BLB016 Bulebel Industrial

Estate, Zejtun ZTN 3000, MALTA

[only 10 mg, 20 mg and 40 mg]

Actavis UK Ltd., Whiddon Valley,

Barnstaple, North Devon, EX32 8NS,

United Kingdom

This medicinal product is authorised

in the Member States of the EEA

under the following names:

Ireland

Atorvastatin 10 mg, 20 mg,

40 mg and 80 mg

Film-Coated Tablets

Atorvastatin 10 mg, 20 mg,

40 mg & 80 mg Tablets

This leaflet was last revised in

April 2019.

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Dimensions:

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Details

Atorvastatin 10 mg, 20 mg, 40 mg & 80 mg Film-coated Tablets PIL - IE

Black

BBBA4687

T. Hull

29.04.2019

30.04.2019

T. Hull

190 x 380

8.5pt

Teva Malta Zejtun

29.04.2019

29.04.2019

2

Version 2

01.11.2017

HealthProductsRegulatoryAuthority

26September2019

CRN0091QN

Page1of18

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Atorvastatin20mgfilm-coatedtablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Eachfilm-coatedtabletcontains20 mgofatorvastatinasatorvastatincalciumtrihydrate.

For thefulllistofexcipients,seesection6.1.

3 PHARMACEUTICAL FORM

Film-coatedtablet.

White,oval,biconvex6.2x11.5mm film-coatedtabletsmarkedwith“20”ononesideand“A”ontheother.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Hypercholesterolaemia

Atorvastatinisindicatedasanadjuncttodietforreductionofelevatedtotalcholesterol(total-C),LDL-cholesterol(LDL-C),

apolipoproteinB,andtriglyceridesinadults,adolescentsandchildrenaged10yearsorolderwithprimary

hypercholesterolaemiaincludingfamilialhypercholesterolaemia(heterozygousvariant)orcombined(mixed)hyperlipidaemia

(correspondingtoTypesIIaandIIboftheFredricksonclassification)whenresponsetodietandothernonpharmacological

measuresisinadequate.

Atorvastatinisalsoindicatedtoreducetotal-CandLDL-Cinadultswithhomozygousfamilialhypercholesterolaemiaasan

adjuncttootherlipid-loweringtreatments(e.g.LDLapheresis)orifsuchtreatmentsareunavailable.

Prevention of cardiovascular disease

Preventionofcardiovasculareventsinadultpatientsestimatedtohaveahighriskforafirstcardiovascularevent(seesection

5.1),asanadjuncttocorrectionofotherriskfactors.

4.2 Posology and method of administration

Posology

Thepatientshouldbeplacedonastandardcholesterol-loweringdietbeforereceivingAtorvastatinandshouldcontinueonthis

dietduringtreatmentwithAtorvastatin.

ThedoseshouldbeindividualisedaccordingtobaselineLDL-Clevels,thegoaloftherapy,andpatientresponse.

Theusualstartingdoseis10mgonceaday.Adjustmentofdoseshouldbemadeatintervalsof4weeksormore.The

maximumdoseis80mgonceaday.

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia

Themajorityofpatientsarecontrolledwith Atorvastatin10mgonceaday.Atherapeuticresponseisevidentwithin2weeks,

andthemaximumtherapeuticresponseisusuallyachievedwithin4weeks.Theresponseismaintainedduringchronictherapy.

Heterozygous familial hypercholesterolaemia

PatientsshouldbestartedwithAtorvastatin10mgdaily.Dosesshouldbeindividualisedandadjustedevery4weeksto40mg

daily.Thereafter,eitherthedosemaybeincreasedtoamaximumof80mgdailyorabileacidsequestrantmaybecombined

with40mgatorvastatinoncedaily.

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Homozygous familial hypercholesterolaemia

Onlylimiteddataareavailable(seesection5.1).

Thedoseofatorvastatininpatientswithhomozygousfamilialhypercholesterolaemiais10to80mgdaily(seesection5.1).

Atorvastatinshouldbeusedasanadjuncttootherlipid-loweringtreatments(e.g.LDLapheresis)inthesepatientsorifsuch

treatmentsareunavailable.

Prevention of cardiovascular disease

Intheprimarypreventiontrialsthedosewas10mg/day.Higherdosesmaybenecessaryinordertoattain(LDL-)cholesterol

levelsaccordingtocurrentguidelines.

Co-administration with other medicines

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

shouldnotexceed20mg/day(seesections4.4and4.5).

Renal impairment

Noadjustmentofdoseisrequired(seesection4.4).

Hepatic impairment

Atorvastatinshouldbeusedwithcautioninpatientswithhepaticimpairment(seesections4.4and5.2).Atorvastatinis

contraindicatedinpatientswithactiveliverdisease(seesection4.3).

Elderly

Efficacyandsafetyinpatientsolderthan70usingrecommendeddosesaresimilartothoseseeninthegeneralpopulation.

Paediatric population

Hypercholesterolaemia:

Paediatricuseshouldonlybecarriedoutbyphysiciansexperiencedinthetreatmentofpaediatrichyperlipidaemiaandpatients

shouldbere-evaluatedonaregularbasistoassessprogress.

ForpatientswithHeterozygousFamilialHypercholesterolaemiaaged10yearsandabove,therecommendedstartingdoseof

atorvastatinis10mgperday(seesection5.1).Thedosemaybeincreasedto80mgdaily,accordingtotheresponseand

tolerability.Dosesshouldbeindividualisedaccordingtotherecommendedgoaloftherapy.Adjustmentsshouldbemadeat

intervalsof4weeksormore.Thedosetitrationto80mgdailyissupportedbystudydatainadultsandbylimitedclinicaldata

fromstudiesinchildrenwithHeterozygousFamilialHypercholesterolaemia(seesections4.8and5.1).

TherearelimitedsafetyandefficacydataavailableinchildrenwithHeterozygousFamilialHypercholesterolaemiabetween6to

10yearsofagederivedfromopen-labelstudies.Atorvastatinisnotindicatedinthetreatmentofpatientsbelowtheageof10

years.Currentlyavailabledataaredescribedinsections4.8,5.1and5.2butnorecommendationonaposologycanbemade.

Otherpharmaceuticalforms/strengthsmaybemoreappropriateforthispopulation.

Method of administration

Atorvastatinisfororaladministration.Eachdailydoseofatorvastatinisgivenallatonceandmaybegivenatanytimeofday

withorwithoutfood.

4.3 Contraindications

Atorvastatiniscontraindicatedinpatients:

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withhypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1

withactiveliverdiseaseorunexplainedpersistentelevationsofserumtransaminasesexceeding3timestheupper

limitofnormal

duringpregnancy,whilebreast-feedingandinwomenofchild-bearingpotentialnotusingappropriate

contraceptivemeasures(seesection4.6)

treatedwiththehepatitisCantiviralsglecaprevir/pibrentasvir.

4.4 Special warnings and precautions for use

Liver effects

Liverfunctiontestsshouldbeperformedbeforetheinitiationoftreatmentandperiodicallythereafter.Patientswhodevelop

anysignsorsymptomssuggestiveofliverinjuryshouldhaveliverfunctiontestsperformed.Patientswhodevelopincreased

transaminaselevelsshouldbemonitoreduntiltheabnormality(ies)resolve.Shouldanincreaseintransaminasesofgreaterthan

3timestheupperlimitofnormal(ULN)persist,reductionofdoseorwithdrawalofAtorvastatinisrecommended(seesection

4.8).

Atorvastatinshouldbeusedwithcautioninpatientswhoconsumesubstantialquantitiesofalcoholand/orhaveahistoryof

liverdisease.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

Inapost-hocanalysisofstrokesubtypesinpatientswithoutcoronaryheartdisease(CHD)whohadarecentstrokeortransient

ischaemicattack(TIA)therewasahigherincidenceofhaemorrhagicstrokeinpatientsinitiatedonatorvastatin80mg

comparedtoplacebo.Theincreasedriskwasparticularlynotedinpatientswithpriorhaemorrhagicstrokeorlacunarinfarctat

studyentry.Forpatientswithpriorhaemorrhagicstrokeorlacunarinfarct,thebalanceofrisksandbenefitsofatorvastatin80

mgisuncertain,andthepotentialriskofhaemorrhagicstrokeshouldbecarefullyconsideredbeforeinitiatingtreatment(see

section5.1).

Skeletal muscle effects

Atorvastatin,likeotherHMG-CoAreductaseinhibitors,mayinrareoccasionsaffecttheskeletalmuscleandcausemyalgia,

myositis,andmyopathythatmayprogresstorhabdomyolysis,apotentiallylife-threateningconditioncharacterisedby

markedlyelevatedcreatinekinase(CK)levels(>10timesULN),myoglobinaemiaandmyoglobinuriawhichmayleadtorenal

failure.

Therehavebeenveryrarereportsofanimmune-mediatednecrotisingmyopathy(IMNM)duringoraftertreatmentwithsome

statins.IMNMisclinicallycharacterisedbypersistentproximalmuscleweaknessandelevatedserumcreatinekinase,which

persistdespitediscontinuationofstatintreatment.

Before the treatment

Atorvastatinshouldbeprescribedwithcautioninpatientswithpre-disposingfactorsforrhabdomyolysis.ACKlevelshouldbe

measuredbeforestartingstatintreatmentinthefollowingsituations:

- Renalimpairment

- Hypothyroidism

- Personalorfamilialhistoryofhereditarymusculardisorders

- Previoushistoryofmusculartoxicitywithastatinorfibrate

- Previoushistoryofliverdiseaseand/orwheresubstantialquantitiesofalcoholareconsumed

- Inelderly(age>70years),thenecessityofsuchmeasurementshouldbeconsidered,accordingtothepresenceofother

predisposingfactorsforrhabdomyolysis

- Situationswhereanincreaseinplasmalevelsmayoccur,suchasinteractions(seesection4.5)andspecialpopulations

includinggeneticsubpopulations(seesection5.2)

Insuchsituations,theriskoftreatmentshouldbeconsideredinrelationtopossiblebenefit,andclinicalmonitoringis

recommended.

IfCKlevelsaresignificantlyelevated(>5timesULN)atbaseline,treatmentshouldnotbestarted.

Creatine kinase measurement

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Creatinekinase(CK)shouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofanyplausiblealternativecause

ofCKincreaseasthismakesvalueinterpretationdifficult.IfCKlevelsaresignificantlyelevatedatbaseline(>5timesULN),

levelsshouldberemeasuredwithin5to7dayslatertoconfirmtheresults.

Whilst on treatment

- Patientsmustbeaskedtopromptlyreportmusclepain,cramps,orweaknessespeciallyifaccompaniedbymalaiseorfever.

- Ifsuchsymptomsoccurwhilstapatientisreceivingtreatmentwithatorvastatin,theirCKlevelsshouldbemeasured.Ifthese

levelsarefoundtobesignificantlyelevated(>5timesULN),treatmentshouldbestopped.

- Ifmuscularsymptomsaresevereandcausedailydiscomfort,eveniftheCKlevelsareelevatedto<5xULN,treatment

discontinuationshouldbeconsidered.

- IfsymptomsresolveandCKlevelsreturntonormal,thenre-introductionofatorvastatinorintroductionofanalternative

statinmaybeconsideredatthelowestdoseandwithclosemonitoring.

- AtorvastatinmustbediscontinuedifclinicallysignificantelevationofCKlevels(>10xULN)occur,orifrhabdomyolysisis

diagnosedorsuspected.

Concomitant treatment with other medicinal products

Riskofrhabdomyolysisisincreasedwhenatorvastatinisadministeredconcomitantlywithcertainmedicinalproductsthatmay

increasetheplasmaconcentrationofatorvastatinsuchaspotentinhibitorsofCYP3A4ortransportproteins(e.g.ciclosporin,

telithromycin,clarithromycin,delavirdine,stiripentol,ketoconazole,voriconazole,itraconazole,posaconazoleandHIVprotease

inhibitorsincludingritonavir,lopinavir,atazanavir,indinavir,darunavir,tipranavir/ritonavir,etc).Theriskofmyopathymayalso

beincreasedwiththeconcomitantuseofgemfibrozilandotherfibricacidderivates,antiviralsforthetreatmentofhepatitisC

(HCV)(boceprevir,telaprevir,elbasvir/grazoprevir),erythromycin,niacinorezetimibe.Ifpossible,alternative(non-interacting)

therapiesshouldbeconsideredinsteadofthesemedicinalproducts.

Incaseswhereco-administrationofthesemedicinalproductswithatorvastatinisnecessary,thebenefitandtheriskof

concurrenttreatmentshouldbecarefullyconsidered.Whenpatientsarereceivingmedicinalproductsthatincreasetheplasma

concentrationofatorvastatin,alowermaximumdoseofatorvastatinisrecommended.Inaddition,inthecaseofpotent

CYP3A4inhibitors,alowerstartingdoseofatorvastatinshouldbeconsideredandappropriateclinicalmonitoringofthese

patientsisrecommended(seesection4.5).

Atorvastatinmustnotbeco-administeredwithsystemicformulationsoffusidicacidorwithin7daysofstoppingfusidicacid

treatment.Inpatientswheretheuseofsystemicfusidicacidisconsideredessential,statintreatmentshouldbediscontinued

throughoutthedurationoffusidicacidtreatment.Therehavebeenreportsofrhabdomyolysis(includingsomefatalities)in

patientsreceivingfusidicacidandstatinsincombination(seesection4.5).Thepatientshouldbeadvisedtoseekmedical

adviceimmediatelyiftheyexperienceanysymptomsofmuscleweakness,painortenderness.

Statintherapymaybere-introducedsevendaysafterthelastdoseoffusidicacid.

Inexceptionalcircumstances,whereprolongedsystemicfusidicacidisneeded,e.g.,forthetreatmentofsevereinfections,the

needforco-administrationofatorvastatinandfusidicacidshouldonlybeconsideredonacasebycasebasisandunderclose

medicalsupervision.

Paediatric population

Noclinicallysignificanteffectongrowthandsexualmaturationwasobservedina3-yearstudybasedontheassessmentof

overallmaturationanddevelopment,assessmentofTannerStage,andmeasurementofheightandweight(seesection4.8).

Interstitial lung disease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy(see

section4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth(fatigue,

weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshouldbediscontinued.

Diabetes Mellitus

Someevidencesuggeststhatstatinsasaclassraisebloodglucoseandinsomepatients,athighriskoffuturediabetes,may

producealevelofhyperglycaemiawhereformaldiabetescareisappropriate.Thisrisk,however,isoutweighedbythe

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reductioninvascularriskwithstatinsandthereforeshouldnotbeareasonforstoppingstatintreatment.Patientsatrisk

(fastingglucose5.6to6.9mmol/L,BMI>30kg/m

,raisedtriglycerides,hypertension)shouldbemonitoredbothclinicallyand

biochemicallyaccordingtonationalguidelines.

Excipient

Thismedicinecontainslessthan1mmolsodium(23mg)perfilm-coatedtablet,thatistosayessentially'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

Effect of co-administered medicinal products on atorvastatin

AtorvastatinismetabolisedbycytochromeP4503A4(CYP3A4)andisasubstrateofthehepatictransporters,organic

anion-transportingpolypeptide1B1(OATP1B1)and1B3(OATP1B3)transporter.Metabolitesofatorvastatinaresubstratesof

OATP1B1.Atorvastatinisalsoidentifiedasasubstrateofthemulti-drugresistanceprotein1(MDR1)andbreastcancer

resistanceprotein(BCRP),whichmaylimittheintestinalabsorptionandbiliaryclearanceofatorvastatin(seesection5.2).

ConcomitantadministrationofmedicinalproductsthatareinhibitorsofCYP3A4ortransportproteinsmayleadtoincreased

plasmaconcentrationsofatorvastatinandanincreasedriskofmyopathy.Theriskmightalsobeincreasedatconcomitant

administrationofatorvastatinwithothermedicinalproductsthathaveapotentialtoinducemyopathy,suchasfibricacid

derivatesandezetimibe(seesection4.4).

CYP3A4 inhibitors

PotentCYP3A4inhibitorshavebeenshowntoleadtomarkedlyincreasedconcentrationsofatorvastatin(seeTable1and

specificinformationbelow).Co-administrationofpotentCYP3A4inhibitors(e.g.ciclosporin,telithromycin,clarithromycin,

delavirdine,stiripentol,ketoconazole,voriconazole,itraconazole,posaconazole,someantiviralsusedinthetreatmentofHCV

(e.g.elbasvir/grazoprevir)andHIVproteaseinhibitorsincludingritonavir,lopinavir,atazanavir,indinavir,darunavir,etc.)should

beavoidedifpossible.Incaseswhereco-administrationofthesemedicinalproductswithatorvastatincannotbeavoidedlower

startingandmaximumdosesofatorvastatinshouldbeconsideredandappropriateclinicalmonitoringofthepatientis

recommended(seeTable1).

ModerateCYP3A4inhibitors(e.g.erythromycin,diltiazem,verapamilandfluconazole)mayincreaseplasmaconcentrationsof

atorvastatin(seeTable1).Anincreasedriskofmyopathyhasbeenobservedwiththeuseoferythromycinincombinationwith

statins.Interactionstudiesevaluatingtheeffectsofamiodaroneorverapamilonatorvastatinhavenotbeenconducted.Both

amiodaroneandverapamilareknowntoinhibitCYP3A4activityandco-administrationwithatorvastatinmayresultin

increasedexposuretoatorvastatin.Therefore,alowermaximumdoseofatorvastatinshouldbeconsideredandappropriate

clinicalmonitoringofthepatientisrecommendedwhenconcomitantlyusedwithmoderateCYP3A4inhibitors.Appropriate

clinicalmonitoringisrecommendedafterinitiationorfollowingdoseadjustmentsoftheinhibitor.

CYP3A4 inducers

ConcomitantadministrationofatorvastatinwithinducersofcytochromeP4503A(e.g.efavirenz,rifampin,St.John'sWort)can

leadtovariablereductionsinplasmaconcentrationsofatorvastatin.Duetothedualinteractionmechanismofrifampin,

(cytochromeP4503AinductionandinhibitionofhepatocyteuptaketransporterOATP1B1),simultaneousco-administrationof

atorvastatinwithrifampinisrecommended,asdelayedadministrationofatorvastatinafteradministrationofrifampinhasbeen

associatedwithasignificantreductioninatorvastatinplasmaconcentrations.Theeffectofrifampinonatorvastatin

concentrationsinhepatocytesis,however,unknownandifconcomitantadministrationcannotbeavoided,patientsshouldbe

carefullymonitoredforefficacy.

Transport inhibitors

Inhibitorsoftransportproteins(e.g.ciclosporin)canincreasethesystemicexposureofatorvastatin(seeTable1).Theeffectof

inhibitionofhepaticuptaketransportersonatorvastatinconcentrationsinhepatocytesisunknown.Ifconcomitant

administrationcannotbeavoided,adosereductionandclinicalmonitoringforefficacyisrecommended(seeTable1).

Gemfibrozil / fibric acid derivatives

Theuseoffibratesaloneisoccasionallyassociatedwithmusclerelatedevents,includingrhabdomyolysis.Theriskofthese

eventsmaybeincreasedwiththeconcomitantuseoffibricacidderivativesandatorvastatin.Ifconcomitantadministration

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cannotbeavoided,thelowestdoseofatorvastatintoachievethetherapeuticobjectiveshouldbeusedandthepatientsshould

beappropriatelymonitored(seesection4.4).

Ezetimibe

Theuseofezetimibealoneisassociatedwithmusclerelatedevents,includingrhabdomyolysis.Theriskoftheseeventsmay

thereforebeincreasedwithconcomitantuseofezetimibeandatorvastatin.Appropriateclinicalmonitoringofthesepatientsis

recommended.

Colestipol

Plasmaconcentrationsofatorvastatinanditsactivemetaboliteswerelower(ratioofatorvastatinconcentration:0.74)when

colestipolwasco-administeredwithatorvastatin.However,lipideffectsweregreaterwhenatorvastatinandcolestipolwere

co-administeredthanwheneithermedicinalproductwasgivenalone.

Fusidic acid

Theriskofmyopathyincludingrhabdomyolysismaybeincreasedbytheconcomitantadministrationofsystemicfusidicacid

withstatins.Themechanismofthisinteraction(whetheritispharmacodynamicorpharmacokinetic,orboth)isyetunknown.

Therehavebeenreportsofrhabdomyolysis(includingsomefatalities)inpatientsreceivingthiscombination.

Iftreatmentwithsystemicfusidicacidisnecessary,atorvastatintreatmentshouldbediscontinuedthroughoutthedurationof

thefusidicacidtreatment(seesection4.4).

Colchicine

Althoughinteractionstudieswithatorvastatinandcolchicinehavenotbeenconducted,casesofmyopathyhavebeenreported

withatorvastatinco-administeredwithcolchicine,andcautionshouldbeexercisedwhenprescribingatorvastatinwith

colchicine.

Effect of atorvastatin on co-administered medicinal products

Digoxin

Whenmultipledosesofdigoxinand10mgatorvastatinwereco-administered,steady-statedigoxinconcentrationsincreased

slightly.Patientstakingdigoxinshouldbemonitoredappropriately.

Oral contraceptives

Co-administrationofatorvastatinwithanoralcontraceptiveproducedincreasesinplasmaconcentrationsofnorethindrone

andethinyloestradiol.

Warfarin

Inaclinicalstudyinpatientsreceivingchronicwarfarintherapy,coadministrationofatorvastatin80mgdailywithwarfarin

causedasmalldecreaseofabout1.7secondsinprothrombintimeduringthefirst4daysofdosingwhichreturnedtonormal

within15daysofatorvastatintreatment.Althoughonlyveryrarecasesofclinicallysignificantanticoagulantinteractionshave

beenreported,prothrombintimeshouldbedeterminedbeforestartingatorvastatininpatientstakingcoumarinanticoagulants

andfrequentlyenoughduringearlytherapytoensurethatnosignificantalterationofprothrombintimeoccurs.Onceastable

prothrombintimehasbeendocumented,prothrombintimescanbemonitoredattheintervalsusuallyrecommendedfor

patientsoncoumarinanticoagulants.Ifthedoseofatorvastatinischangedordiscontinued,thesameprocedureshouldbe

repeated.Atorvastatintherapyhasnotbeenassociatedwithbleedingorwithchangesinprothrombintimeinpatientsnot

takinganticoagulants.

Paediatric population

Drug-druginteractionstudieshaveonlybeenperformedinadults.Theextentofinteractionsinthepaediatricpopulationisnot

known.Theabovementionedinteractionsforadultsandthewarningsinsection4.4shouldbetakenintoaccountforthe

paediatricpopulation.

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Drug Interactions

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

Co-administered

medicinal

product and

dosingregimen

Atorvastatin​

Dose

(mg)

RatioofAUC

&

ClinicalRecommendation

Glecaprevir400

mgOD/

Pibrentasvir120

mgOD,7days

10mg

OD

for7

days

Co-administrationwithproductscontainingglecaprevirorpibrentasviris

contraindicated(seesection4.3).

Tipranavir500

mgBID/

Ritonavir200

mgBID,8days

(days14to21)

40mg

on

day1,

10mg

on

day20

9.4

Incaseswherecoadministrationwithatorvastatinisnecessary,donotexceed10

mgatorvastatindaily.Clinicalmonitoringofthesepatientsisrecommended​​

Telaprevir750

mgq8h,10days

20mg,

Ciclosporin5.2

mg/kg/day,

stabledose

10mg

OD

for28

days

8.7

Elbasvir50mg

OD/Grazoprevir

200mgOD,13

days

10mg

1.95

Thedoseofatorvastatinshouldnotexceedadailydoseof20mgduring

co-administrationwithproductscontainingelbasvirorgrazoprevir.

Lopinavir400

mgBID/

Ritonavir100

mgBID,14days

20mg

OD

for4

days

5.9

Incaseswhereco-administrationwithatorvastatinisnecessary,lowermaintenance

dosesofatorvastatinarerecommended.Atatorvastatindosesexceeding20mg,

clinicalmonitoringofthesepatientsisrecommended.

Clarithromycin

500mgBID,9

days

80mg

OD

for8

days

4.4

Saquinavir400

mgBID/

Ritonavir300

mgBIDfrom

days5-7,

increasedto

400mgBIDon

day8),days

5-18,30min

after

atorvastatin

dosing

40mg

OD

for4

days

3.9

Incaseswhereco-administrationwithatorvastatinisnecessary,lowermaintenance

dosesofatorvastatinarerecommended.Atatorvastatindosesexceeding40mg,

clinicalmonitoringofthesepatientsisrecommended.

​​​

Darunavir300

mgBID/

Ritonavir100

mgBID,9days

10mg

OD

for4

days

3.3

Itraconazole

200mgOD,4

days

40mg

SD

3.3

Fosamprenavir

700mgBID/

10mg

OD

2.5

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Ritonavir100

mgBID,14days

for4

days

Fosamprenavir

1,400mgBID,

14days

10mg

OD

for4

days

2.3

Nelfinavir1,250

mgBID,14days

10mg

OD

for28

days

1.74

Nospecificrecommendation

GrapefruitJuice,

240mLOD*

40mg,

SD

1.37

Concomitantintakeoflargequantitiesofgrapefruitjuiceandatorvastatinisnot

recommended.

Diltiazem240

mgOD,28days

40mg,

SD

1.51

Afterinitiationorfollowingdoseadjustmentsofdiltiazem,appropriateclinical

monitoringofthesepatientsisrecommended.

Erythromycin

500mgQID,7

days

10mg,

SD

1.33

Lowermaximumdoseandclinicalmonitoringofthesepatientsisrecommended.

Amlodipine10

mg,singledose

80mg,

SD

1.18

Nospecificrecommendation.

Cimetidine300

mgQID,2

weeks

10mg

OD

for2

weeks

1.00^

Nospecificrecommendation.

Colestipol10g

BID,24weeks

40mg

OD

for8

weeks

0.74**

Nospecificrecommendation

Antacid

suspensionof

magnesiumand

aluminium

hydroxides,30

mLQID,17days

10mg

OD

for15

days

0.66

Nospecificrecommendation.

Efavirenz600

mgOD,14days

10mg

for3

days

0.59

Nospecificrecommendation.

Rifampin600

mgOD,7days

(co-administere

d)

40mg

SD

1.12

Ifco-administrationcannotbeavoided,simultaneousco-administrationof

atorvastatinwithrifampinisrecommended,withclinicalmonitoring.​

Rifampin600

mgOD,5days

(doses

separated)

40mg

SD

0.20

Gemfibrozil600

mgBID,7days

40mg

SD

1.35

Lowerstartingdoseandclinicalmonitoringofthesepatientsisrecommended.

Fenofibrate160

mgOD,7days

40mg

SD

1.03

Lowerstartingdoseandclinicalmonitoringofthesepatientsisrecommended.

Boceprevir800

mgTID,7days

40mg

Lowerstartingdoseandclinicalmonitoringofthesepatientsisrecommended.

Thedoseofatorvastatinshouldnotexceedadailydoseof20mgduringco-

administrationwithboceprevir.

&

Representsratiooftreatments(co-administereddrugplusatorvastatinversusatorvastatinalone).

Seesections4.4and4.5forclinicalsignificance.

ContainsoneormorecomponentsthatinhibitCYP3A4andcanincreaseplasmaconcentrationsofmedicinalproducts

metabolisedbyCYP3A4.Intakeofone240mLglassofgrapefruitjuicealsoresultedinadecreasedAUCof20.4%fortheactive

orthohydroxymetabolite.Largequantitiesofgrapefruitjuice(over1.2ldailyfor5days)increasedAUCofatorvastatin2.5fold

andAUCofactive(atorvastatinandmetabolites).HMG-CoAreductaseinhibitors1.3fold.

Ratiobasedonasinglesampletaken8-16hpostdose.

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OD=oncedaily;SD=singledose;BID=twicedaily;TID=threetimesdaily;QID=fourtimesdaily

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

Atorvastatinanddosingregimen​

Co-administeredmedicinalproduct​

Medicinalproduct/Dose(mg)

RatioofAUC

&

Clinical

Recommendation

80mgODfor10days

Digoxin0.25mgOD,20days

1.15

Patientstaking

digoxinshouldbe

monitored

appropriately.

40mgODfor22days

OralcontraceptiveOD,2months

-norethindrone1mg

-ethinylestradiol35 micrograms

1.28

1.19

Nospecific

recommendation.

80mgODfor15days

*Phenazone,600mgSD

↑1.03

Nospecific

recommendation

10mg,SD

Tipranavir500mgBID/ritonavir200mgBID,7days

1.08

Nospecific

recommendation

10mg,ODfor4days

Fosamprenavir1,400mgBID,14days

0.73

Nospecific

recommendation

10mgODfor4days

Fosamprenavir700mgBID/ritonavir

100mgBID,14days

0.99

Nospecific

recommendation

&

Representsratiooftreatments(co-administereddrugplusatorvastatinversusatorvastatinalone).

* Co-administrationofmultipledosesofatorvastatinandphenazoneshowedlittleornodetectableeffectintheclearanceof

phenazone.

OD=oncedaily;SD=singledose;BID=twicedaily

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Womenofchild-bearingpotentialshoulduseappropriatecontraceptivemeasuresduringtreatment(seesection4.3).

Pregnancy

Atorvastatiniscontraindicatedduringpregnancy(seesection4.3).Safetyinpregnantwomenhasnotbeenestablished.No

controlledclinicaltrialswithatorvastatinhavebeenconductedinpregnantwomen.Rarereportsofcongenitalanomalies

followingintrauterineexposuretoHMG-CoAreductaseinhibitorshavebeenreceived.Studiesinanimalshaveshowntoxicity

toreproduction(seesection5.3).

Maternaltreatmentwithatorvastatinmayreducethefoetallevelsofmevalonatewhichisaprecursorofcholesterol

biosynthesis.Atherosclerosisisachronicprocess,andordinarilydiscontinuationoflipid-loweringmedicinalproductsduring

pregnancyshouldhavelittleimpactonthelong-termriskassociatedwithprimaryhypercholesterolaemia.

Forthesereasons,Atorvastatinshouldnotbeusedinwomenwhoarepregnant,tryingtobecomepregnantorsuspecttheyare

pregnant.TreatmentwithAtorvastatinshouldbesuspendedforthedurationofpregnancyoruntilithasbeendeterminedthat

thewomanisnotpregnant(seesection4.3).

Breast-feeding

Itisunknownwhetheratorvastatinoritsmetabolitesareexcretedinhumanmilk.Inrats,plasmaconcentrationsofatorvastatin

anditsactivemetabolitesaresimilartothoseinmilk(seesection5.3).Becauseofthepotentialforseriousadversereactions,

womentakingAtorvastatinshouldnotbreast-feedtheirinfants(seesection4.3).Atorvastatiniscontraindicatedduring

breast-feeding(seesection4.3).

Fertility

Inanimalstudiesatorvastatinhadnoeffectonmaleorfemalefertility(seesection5.3).

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4.7 Effects on ability to drive and use machines

Atorvastatinhasnegligibleinfluenceontheabilitytodriveandusemachines.

4.8 Undesirable effects

Intheatorvastatinplacebo-controlledclinicaltrialdatabaseof16,066(8,755atorvastatinvs.7,311placebo)patientstreatedfor

ameanperiodof53weeks,5.2%ofpatientsonatorvastatindiscontinuedduetoadversereactionscomparedto4.0%ofthe

patientsonplacebo.

Basedondatafromclinicalstudiesandextensivepost-marketingexperience,thefollowingtablepresentstheadversereaction

profileforatorvastatin.

Estimatedfrequenciesofreactionsarerankedaccordingtothefollowingconvention:common(>1/100to<1/10);uncommon

(>1/1,000to<1/100);rare(>1/10,000to<1/1,000);veryrare(<1/10,000);notknown(cannotbeestimatedfromthe

availabledata).

Infections and infestations:

Common:nasopharyngitis.

Blood and lymphatic system disorders

Rare:thrombocytopenia.

Immune system disorders

Common:allergicreactions.

Veryrare:anaphylaxis.

Metabolism and nutrition disorders

Common:hyperglycaemia.

Uncommon:hypoglycaemia,weightgain,anorexia

Psychiatric disorders

Uncommon:nightmare,insomnia.

Nervous system disorders

Common:headache.

Uncommon:dizziness,paraesthesia,hypoesthesia,dysgeusia,amnesia.

Rare:peripheralneuropathy.

Eye disorders

Uncommon:visionblurred.

Rare:visualdisturbance.

Ear and labyrinth disorders

Uncommon:tinnitus

Veryrare:hearingloss.

Respiratory, thoracic and mediastinal disorders:

Common:pharyngolaryngealpain,epistaxis.

Gastrointestinal disorders

Common:constipation,flatulence,dyspepsia,nausea,diarrhoea.

Uncommon:vomiting,abdominalpainupperandlower,eructation,pancreatitis.

Hepatobiliary disorders

Uncommon:hepatitis.

Rare:cholestasis.

Veryrare:hepaticfailure.

Unknown:hepatotoxicity.

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Skin and subcutaneous tissue disorders

Uncommon:urticaria,skinrash,pruritus,alopecia.

Rare:angioneuroticoedema,dermatitisbullousincludingerythemamultiforme,Stevens-Johnsonsyndromeandtoxic

epidermalnecrolysis.

Musculoskeletal and connective tissue disorders

Common:myalgia,arthralgia,paininextremity,musclespasms,jointswelling,backpain.

Uncommon:neckpain,musclefatigue.

Rare:myopathy,myositis,rhabdomyolysis,musclerupture,tendinopathy,sometimescomplicatedbyrupture.

Veryrare:lupus-likesyndrome.

Notknown:immune-mediatednecrotisingmyopathy(seesection4.4).

Reproductive system and breast disorders

Veryrare:gynaecomastia.

General disorders and administration site conditions

Uncommon:malaise,asthenia,chestpain,peripheraloedema,fatigue,pyrexia.

Investigations

Common:liverfunctiontestabnormal, bloodcreatinekinaseincreased.

Uncommon:whitebloodcellsurinepositive.

AswithotherHMG-CoAreductaseinhibitorselevatedserumtransaminaseshavebeenreportedinpatientsreceiving

atorvastatin.Thesechangeswereusuallymild,transient,anddidnotrequireinterruptionoftreatment.Clinicallyimportant(>3

timesuppernormallimit)elevationsinserumtransaminasesoccurredin0.8%patientsonatorvastatin.Theseelevationswere

doserelatedandwerereversibleinallpatients.

Elevatedserumcreatinekinase(CK)levelsgreaterthan3timesupperlimitofnormaloccurredin2.5%ofpatientson

atorvastatin,similartootherHMG-CoAreductaseinhibitorsinclinicaltrials.Levelsabove10timesthenormalupperrange

occurredin0.4%atorvastatin-treatedpatients(seesection4.4).

Paediatric population

Paediatricpatientsagedfrom10to17yearsofagetreatedwithatorvastatinhadanadverseexperienceprofilegenerally

similartothatofpatientstreatedwithplacebo,themostcommonadverseexperiencesobservedinbothgroups,regardlessof

causalityassessment,wereinfections.Noclinicallysignificanteffectongrowthandsexualmaturationwasobservedina3-year

studybasedontheassessmentofoverallmaturationanddevelopment,assessmentofTannerStage,andmeasurementof

heightandweight.Thesafetyandtolerabilityprofileinpaediatricpatientswassimilartotheknownsafetyprofileof

atorvastatininadultpatients.

Theclinicalsafetydatabaseincludessafetydatafor520paediatricpatientswhoreceivedatorvastatin,amongwhich7patients

were<6yearsold,121patientswereintheagerangeof6to9,and392patientswereintheagerangeof10to17.Basedon

thedataavailable,thefrequency,typeandseverityofadversereactionsinchildrenissimilartoadults.

Thefollowingadverseeventshavebeenreportedwithsomestatins:

- Sexualdysfunction.

- Depression.

- Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seesection4.4).

- DiabetesMellitus:Frequencywilldependonthepresenceorabsenceofriskfactors(fastingbloodglucose≥5.6mmol/L,

BMI>30kg/m

,raisedtriglycerides,historyofhypertension).

Reporting of suspected adverse reactions

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Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportanysuspected

adversereactionsviaHPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin2;Tel:+35316764971;Fax:+35316762517.

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

4.9 Overdose

Specifictreatmentisnotavailableforatorvastatinoverdose.Shouldanoverdoseoccur,thepatientshouldbetreated

symptomaticallyandsupportivemeasuresinstituted,asrequired.LiverfunctiontestsshouldbeperformedandserumCKlevels

shouldbemonitored.Duetoextensiveatorvastatinbindingtoplasmaproteins,haemodialysisisnotexpectedtosignificantly

enhanceatorvastatinclearance.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeuticgroup:Lipidmodifyingagents,HMG-CoA-reductaseinhibitors,ATCcode:C10AA05

Atorvastatinisaselective,competitiveinhibitorofHMG-CoAreductase,therate-limitingenzymeresponsibleforthe

conversionof3-hydroxy-3-methyl-glutaryl-coenzymeAtomevalonate,aprecursorofsterols,includingcholesterol.

Triglyceridesandcholesterolintheliverareincorporatedintoverylow-densitylipoproteins(VLDL)andreleasedintothe

plasmafordeliverytoperipheraltissues.Low-densitylipoprotein(LDL)isformedfromVLDLandiscatabolizedprimarily

throughthereceptorwithhighaffinitytoLDL(LDLreceptor).

AtorvastatinlowersplasmacholesterolandlipoproteinserumconcentrationsbyinhibitingHMG-CoAreductaseand

subsequentlycholesterolbiosynthesisintheliverandincreasesthenumberofhepaticLDLreceptorsonthecellsurfacefor

enhanceduptakeandcatabolismofLDL.

AtorvastatinreducesLDLproductionandthenumberofLDLparticles.Atorvastatinproducesaprofoundandsustainedincrease

inLDLreceptoractivitycoupledwithabeneficialchangeinthequalityofcirculatingLDLparticles.Atorvastatiniseffectivein

reducingLDL-Cinpatientswithhomozygousfamilialhypercholesterolaemia,apopulationthathasnotusuallyrespondedto

lipid-loweringmedicinalproducts.

Atorvastatinhasbeenshowntoreduceconcentrationsoftotal-C(30%-46%),LDL-C(41%-61%),apolipoproteinB(34%-

50%),andtriglycerides(14%-33%)whileproducingvariableincreasesinHDL-CandapolipoproteinA1inadoseresponse

study.Theseresultsareconsistentinpatientswithheterozygousfamilialhypercholesterolaemia,nonfamilialformsof

hypercholesterolaemia,andmixedhyperlipidaemia,includingpatientswithnoninsulin-dependentdiabetesmellitus.

Reductionsintotal-C,LDL-C,andapolipoproteinBhavebeenproventoreduceriskforcardiovasculareventsand

cardiovascularmortality.

Homozygous familial hypercholesterolaemia

Inamulticenter8weekopen-labelcompassionate-usestudywithanoptionalextensionphaseofvariablelength,335patients

wereenrolled,89ofwhichwereidentifiedashomozygousfamilialhypercholesterolaemiapatients.Fromthese89patients,the

meanpercentreductioninLDL-Cwasapproximately20%.Atorvastatinwasadministeredatdosesupto80mg/day.

Atherosclerosis

IntheReversingAtherosclerosiswithAggressiveLipid-LoweringStudy(REVERSAL),theeffectofintensivelipidloweringwith

atorvastatin80mgandstandarddegreeoflipidloweringwithpravastatin40mgoncoronaryatherosclerosiswasassessedby

intravascularultrasound(IVUS),duringangiography,inpatientswithcoronaryheartdisease.Inthisrandomised,double-blind,

multicenter,controlledclinicaltrial,IVUSwasperformedatbaselineandat18monthsin502patients.Intheatorvastatingroup

(n=253),therewasnoprogressionofatherosclerosis.

Themedianpercentchange,frombaseline,intotalatheromavolume(theprimarystudycriteria)was-0.4%(p=0.98)inthe

atorvastatingroupand+2.7%(p=0.001)inthepravastatingroup(n=249).Whencomparedtopravastatintheeffectsof

atorvastatinwerestatisticallysignificant(p=0.02).Theeffectofintensivelipidloweringoncardiovascularendpoints(e.g.need

forrevascularisation,nonfatalmyocardialinfarction,coronarydeath)wasnotinvestigatedinthisstudy.

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Intheatorvastatingroup,LDL-Cwasreducedtoameanof2.04mmol/L±0.8(78.9mg/dl±30)frombaseline3.89mmol/l±

0.7(150mg/dl±28)andinthepravastatingroup,LDL-Cwasreducedtoameanof2.85mmol/l±0.7(110mg/dl±26)from

baseline3.89mmol/l±0.7(150mg/dl±26)(p<0.0001).AtorvastatinalsosignificantlyreducedmeanTCby34.1%(pravastatin:

-18.4%,p<0.0001),meanTGlevelsby20%(pravastatin:-6.8%,p<0.0009),andmeanapolipoproteinBby39.1%(pravastatin:

-22.0%,p<0.0001).AtorvastatinincreasedmeanHDL-Cby2.9%(pravastatin:+5.6%,p=NS).Therewasa36.4%meanreduction

inCRPintheatorvastatingroupcomparedtoa5.2%reductioninthepravastatingroup(p<0.0001).

Studyresultswereobtainedwiththe80mgdosestrength.Therefore,theycannotbeextrapolatedtothelowerdosestrengths.

Thesafetyandtolerabilityprofilesofthetwotreatmentgroupswerecomparable.

Theeffectofintensivelipidloweringonmajorcardiovascularendpointswasnotinvestigatedinthisstudy.Therefore,the

clinicalsignificanceoftheseimagingresultswithregardtotheprimaryandsecondarypreventionofcardiovasculareventsis

unknown.

Acute coronary syndrome

IntheMIRACLstudy,atorvastatin80mghasbeenevaluatedin3,086patients(atorvastatinn=1,538;placebon=1,548)withan

acutecoronarysyndrome(nonQ-waveMIorunstableangina).Treatmentwasinitiatedduringtheacutephaseafterhospital

admissionandlastedforaperiodof16weeks.Treatmentwithatorvastatin80mg/dayincreasedthetimetooccurrenceofthe

combinedprimaryendpoint,definedasdeathfromanycause,nonfatalMI,resuscitatedcardiacarrest,oranginapectoriswith

evidenceofmyocardialischaemiarequiringhospitalization,indicatingariskreductionby16%(p=0.048).Thiswasmainlydue

toa26%reductioninre-hospitalisationforanginapectoriswithevidenceofmyocardialischaemia(p=0.018).Theother

secondaryendpointsdidnotreachstatisticalsignificanceontheirown(overall:Placebo:22.2%,Atorvastatin:22.4%).

ThesafetyprofileofatorvastatinintheMIRACLstudywasconsistentwithwhatisdescribedinsection4.8.

Prevention of cardiovascular disease

Theeffectofatorvastatinonfatalandnon-fatalcoronaryheartdiseasewasassessedinarandomized,double-blind,

placebo-controlledstudy,theAnglo-ScandinavianCardiacOutcomesTrialLipidLoweringArm(ASCOT-LLA).Patientswere

hypertensive,40-79yearsofage,withnopreviousmyocardialinfarctionortreatmentforangina,andwithTClevels≤6.5

mmol/l(251mg/dl).Allpatientshadatleast3ofthepre-definedcardiovascularriskfactors:malegender,age≥55years,

smoking,diabetes,historyofCHDinafirst-degreerelative,TC:HDL-C>6,peripheralvasculardisease,leftventricular

hypertrophy,priorcerebrovascularevent,specificECGabnormality,proteinuria/albuminuria.Notallincludedpatientswere

estimatedtohaveahighriskforafirstcardiovascularevent.

Patientsweretreatedwithanti-hypertensivetherapy(eitheramlodipineoratenolol-basedregimen)andeitheratorvastatin10

mgdaily(n=5,168)orplacebo(n=5,137).

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Event

Relative

Risk

Reduction

(%)

No.ofEvents

(Atorvastatin

vsPlacebo)

Absolute

Risk

Reduction

1

(%)

p-value

FatalCHDplusnon-fatalMI

36%

100vs.154

1.1%

0.0005

Totalcardiovasculareventsandrevascularizationprocedures

20%

389vs.483

1.9%

0.0008

Totalcoronaryevents

178vs247

1.4%

0.0006

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.3years.

CHD=coronaryheartdisease;MI=myocardialinfarction.

Totalmortalityandcardiovascularmortalitywerenotsignificantlyreduced(185vs.212events,p=0.17and74vs.82events,

p=0.51).Inthesubgroupanalysesbygender(81%males,19%females),abeneficialeffectofatorvastatinwasseeninmales

butcouldnotbeestablishedinfemalespossiblyduetotheloweventrateinthefemalesubgroup.Overallandcardiovascular

mortalitywerenumericallyhigherinthefemalepatients(38vs.30and17vs.12),butthiswasnotstatisticallysignificant.There

wassignificanttreatmentinteractionbyantihypertensivebaselinetherapy.Theprimaryendpoint(fatalCHDplusnon-fatalMI)

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wassignificantlyreducedbyatorvastatininpatientstreatedwithamlodipine(HR0.47(0.32-0.69),p=0.00008),butnotinthose

treatedwithatenolol(HR0.83(0.59-1.17),p=0.287).

Theeffectofatorvastatinonfatalandnon-fatalcardiovasculardiseasewasalsoassessedinarandomized,double-blind,

multicenter,placebo-controlledtrial,theCollaborativeAtorvastatinDiabetesStudy(CARDS)inpatientswithtype2diabetes,

40-75yearsofage,withoutpriorhistoryofcardiovasculardisease,andwithLDL-C≤4.14mmol/l(160mg/dl)andTG≤6.78

mmol/l(600mg/dl).Allpatientshadatleast1ofthefollowingriskfactors:hypertension,currentsmoking,retinopathy,

microalbuminuriaormacroalbuminuria.

Patientsweretreatedwitheitheratorvastatin10mgdaily(n=1,428)orplacebo(n=1,410)foramedianfollow-upof3.9years.

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Event

RelativeRiskReduction(%)

No.ofEvents

(AtorvastatinvsPlacebo)

AbsoluteRisk

Reduction

1

(%)

p-value

Majorcardiovascularevents

(fatalandnon-fatalAMI,silent

MI,acuteCHDdeath,unstable

angina,CABG,PTCA,

revascularization,stroke)

37%

83vs.127

3.2%

0.0010

MI(fatalandnon-fatalAMI,silentMI)

42%

38vs64

1.9%

0.0070

Strokes(Fatalandnon-fatal)

21vs.39

1.3%

0.0163

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.9years.

AMI=acutemyocardialinfarction;CABG=coronaryarterybypassgraft;CHD=coronaryheartdisease;MI=myocardial

infarction;PTCA=percutaneoustransluminalcoronaryangioplasty.

Therewasnoevidenceofadifferenceinthetreatmenteffectbypatient’sgender,age,orbaselineLDL-Clevel.Afavourable

trendwasobservedregardingthemortalityrate(82deathsintheplacebogroupvs.61deathsintheatorvastatingroup,

p=0.0592).

Recurrent stroke

IntheStrokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)study,theeffectofatorvastatin80mgdailyor

placeboonstrokewasevaluatedin4731patientswhohadastrokeortransientischemicattack(TIA)withinthepreceding6

monthsandnohistoryofcoronaryheartdisease(CHD).Patientswere60%male,21-92yearsofage(averageage63years),

andhadanaveragebaselineLDLof133mg/dL(3.4mmol/L).ThemeanLDL-Cwas73mg/dL(1.9mmol/L)duringtreatment

withatorvastatinand129mg/dL(3.3mmol/L)duringtreatmentwithplacebo.Medianfollow-upwas4.9years.

Atorvastatin80mgreducedtheriskoftheprimaryendpointoffatalornon-fatalstrokeby15%(HR0.85;95%CI,0.72-1.00;

p=0.05or0.84;95%CI,0.71-0.99;p=0.03afteradjustmentforbaselinefactors)comparedtoplacebo.Allcausemortalitywas

9.1%(216/2365)foratorvastatinversus8.9%(211/2366)forplacebo.

Inapost-hocanalysis,atorvastatin80mgreducedtheincidenceofischemicstroke(218/2365,9.2%vs.274/2366,11.6%,

p=0.01)andincreasedtheincidenceofhemorrhagicstroke(55/2365,2.3%vs.33/2366,1.4%,p=0.02)comparedtoplacebo.

- Theriskofhemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorhemorrhagicstroke(7/45for

atorvastatinversus2/48forplacebo;HR4.06;95%CI,0.84-19.57),andtheriskofischemicstrokewassimilarbetweengroups

(3/45foratorvastatinversus2/48forplacebo;HR1.64;95%CI,0.27-9.82).

- Theriskofhemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorlacunarinfarct(20/708for

atorvastatinversus4/701forplacebo;HR4.99;95%CI,1.71-14.61),buttheriskofischemicstrokewasalsodecreasedinthese

patients(79/708foratorvastatinversus102/701forplacebo;HR0.76;95%CI,0.57-1.02).Itispossiblethatthenetriskofstroke

isincreasedinpatientswithpriorlacunarinfarctwhoreceiveatorvastatin80mg/day.

Allcausemortalitywas15.6%(7/45)foratorvastatinversus10.4%(5/48)inthesubgroupofpatientswithpriorhemorrhagic

stroke.Allcausemortalitywas10.9%(77/708)foratorvastatinversus9.1%(64/701)forplacebointhesubgroupofpatients

withpriorlacunarinfarct.

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Paediatric Population

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

An8-week,open-labelstudytoevaluatepharmacokinetics,pharmacodynamics,andsafetyandtolerabilityofatorvastatinwas

conductedinchildrenandadolescentswithgeneticallyconfirmedheterozygousfamilialhypercholesterolemiaandbaseline

LDL-C≥4mmol/L.Atotalof39childrenandadolescents,6to17yearsofage,wereenrolled.CohortAincluded15children,6

to12yearsofageandatTannerStage1.CohortBincluded24children,10to17yearsofageandatTannerStage≥2.

Theinitialdoseofatorvastatinwas5mgdailyofachewabletabletinCohortAand10mgdailyofatabletformulationin

CohortB.TheatorvastatindosewaspermittedtobedoubledifasubjecthadnotattainedtargetLDL-Cof<3.35mmol/Lat

Week4andifatorvastatinwaswelltolerated.

MeanvaluesforLDL-C,TC,VLDL-C,andApoBdecreasedbyWeek2amongallsubjects.Forsubjectswhosedosewasdoubled,

additionaldecreaseswereobservedasearlyas2weeks,atthefirstassessment,afterdoseescalation.Themeanpercent

decreasesinlipidparametersweresimilarforbothcohorts,regardlessofwhethersubjectsremainedattheirinitialdoseor

doubledtheirinitialdose.AtWeek8,onaverage,thepercentchangefrombaselineinLDL-CandTCwasapproximately40%

and30%,respectively,overtherangeofexposures.

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

Inadouble-blind,placebocontrolledstudyfollowedbyanopen-labelphase,187boysandpostmenarchalgirls10-17yearsof

age(meanage14.1years)withheterozygousfamilialhypercholesterolaemia(FH)orseverehypercholesterolaemiawere

randomisedtoatorvastatin(n=140)orplacebo(n=47)for26weeksandthenallreceivedatorvastatinfor26weeks.Thedosage

ofatorvastatin(oncedaily)was10mgforthefirst4weeksandup-titratedto20mgiftheLDL-Clevelwas>3.36mmol/l.

Atorvastatinsignificantlydecreasedplasmalevelsoftotal-C,LDL-C,triglycerides,andapolipoproteinBduringthe26week

double-blindphase.ThemeanachievedLDL-Cvaluewas3.38mmol/l(range:1.81-6.26mmol/l)intheatorvastatingroup

comparedto5.91mmol/l(range:3.93-9.96mmol/l)intheplacebogroupduringthe26-weekdouble-blindphase.

Anadditionalpaediatricstudyofatorvastatinversuscolestipolinpatientswithhypercholesterolaemiaaged10-18years

demonstratedthatatorvastatin(N=25)causedasignificantreductioninLDL-Catweek26(p<0.05)comparedwithcolestipol

(N=31).

Acompassionateusestudyinpatientswithseverehypercholesterolaemia(includinghomozygoushypercholesterolaemia)

included46paediatricpatientstreatedwithatorvastatintitratedaccordingtoresponse(somesubjectsreceived80mg

atorvastatinperday).Thestudylasted3years:LDL-cholesterolwasloweredby36%.

Thelong-termefficacyofatorvastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthoodhasnotbeen

established.

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithatorvastatininchildrenaged0

tolessthan6yearsinthetreatmentofheterozygoushypercholesterolaemiaandinchildrenaged0tolessthan18yearsinthe

treatmentofhomozygousfamilialhypercholesterolaemia,combined(mixed)hypercholesterolaemia,primary

hypercholesterolaemiaandinthepreventionofcardiovascularevents(seesection4.2forinformationonpaediatricuse).

5.2 Pharmacokinetic properties

Absorption

Atorvastatinisrapidlyabsorbedafteroraladministration;maximumplasmaconcentrations(C

)occurwithin1to2hours.

Extentofabsorptionincreasesinproportiontoatorvastatindose.Afteroraladministration,atorvastatinfilm-coatedtabletsare

95%to99%bioavailablecomparedtotheoralsolution.Theabsolutebioavailabilityofatorvastatinisapproximately12%and

thesystemicavailabilityofHMG-CoAreductaseinhibitoryactivityisapproximately30%.Thelowsystemicavailabilityis

attributedtopresystemicclearanceingastrointestinalmucosaand/orhepaticfirst-passmetabolism

Distribution

Meanvolumeofdistributionofatorvastatinisapproximately381l.Atorvastatinis98%boundtoplasmaproteins.

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Biotransformation

AtorvastatinismetabolisedbycytochromeP4503A4toortho-andparahydroxylatedderivativesandvariousbeta-oxidation

products.Apartfromotherpathwaystheseproductsarefurthermetabolisedviaglucuronidation.Invitro,inhibitionof

HMG-CoAreductasebyortho-andparahydroxylatedmetabolitesisequivalenttothatofatorvastatin.Approximately70%of

circulatinginhibitoryactivityforHMG-CoAreductaseisattributedtoactivemetabolites.

Elimination

Atorvastatiniseliminatedprimarilyinbilefollowinghepaticand/orextrahepaticmetabolism.However,atorvastatindoesnot

appeartoundergosignificantenterohepaticrecirculation.Meanplasmaeliminationhalf-lifeofatorvastatininhumansis

approximately14hours.Thehalf-lifeofinhibitoryactivityforHMG-CoAreductaseisapproximately20to30hoursduetothe

contributionofactivemetabolites.

Atorvastatinisasubstrateofthehepatictransporters,organicanion-transportingpolypeptide1B1(OATP1B1)and1B3

(OATP1B3)transporter.MetabolitesofatorvastatinaresubstratesofOATP1B1.Atorvastatinisalsoidentifiedasasubstrateof

theeffluxtransportersmulti-drugresistanceprotein1(MDR1)andbreastcancerresistanceprotein(BCRP),whichmaylimitthe

intestinalabsorptionandbiliaryclearanceofatorvastatin.

Special populations

Elderly: Plasmaconcentrationsofatorvastatinanditsactivemetabolitesarehigherinhealthyelderlysubjectsthaninyoung

adultswhilethelipideffectswerecomparabletothoseseeninyoungerpatientpopulations.

Paediatric population: Inanopen-label,8-weekstudy,TannerStage1(N=15)andTannerStage≥2(N=24)paediatricpatients

(ages6-17years)withheterozygousfamilialhypercholesterolaemiaandbaselineLDL-C≥4mmol/Lweretreatedwith5or10

mgofchewableor10or20mgoffilm-coatedatorvastatintabletsoncedaily,respectively.Bodyweightwastheonlysignificant

covariateinatorvastatinpopulationPKmodel.Apparentoralclearanceofatorvastatininpaediatricsubjectsappearedsimilarto

adultswhenscaledallometricallybybodyweight.ConsistentdecreasesinLDL-CandTCwereobservedovertherangeof

atorvastatinando-hydroxyatorvastatinexposures.

Gender: Concentrationsofatorvastatinanditsactivemetabolitesinwomendifferfromthoseinmen(Women:approx.20%

higherforC

max

andapprox.10%lowerforAUC).Thesedifferenceswereofnoclinicalsignificance,resultinginnoclinically

significantdifferencesinlipideffectsamongmenandwomen.

Renal impairment: Renaldiseasehasnoinfluenceontheplasmaconcentrationsorlipideffectsofatorvastatinanditsactive

metabolites.

Hepatic impairment: Plasmaconcentrationsofatorvastatinanditsactivemetabolitesaremarkedlyincreased(approx.16-foldin

max

andapprox.11-foldinAUC)inpatientswithchronicalcoholicliverdisease(Child-PughB).

SLOC1B1 polymorphism: HepaticuptakeofallHMG-CoAreductaseinhibitorsincludingatorvastatin,involvestheOATP1B1

transporter.InpatientswithSLCO1B1polymorphismthereisariskofincreasedexposureofatorvastatin,whichmayleadtoan

increasedriskofrhabdomyolysis(seesection4.4).PolymorphisminthegeneencodingOATP1B1(SLCO1B1c.521CC)is

associatedwitha2.4-foldhigheratorvastatinexposure(AUC)thaninindividualswithoutthisgenotypevariant(c.521TT).A

geneticallyimpairedhepaticuptakeofatorvastatinisalsopossibleinthesepatients.Possibleconsequencesfortheefficacyare

unknown.

5.3 Preclinical safety data

Atorvastatinwasnegativeformutagenicandclastogenicpotentialinabatteryof4invitrotestsand1invivoassay.

Atorvastatinwasnotfoundtobecarcinogenicinrats,buthighdosesinmice(resultingin6-11foldtheAUC0-24hreachedin

humansatthehighestrecommendeddose)showedhepatocellularadenomasinmalesandhepatocellularcarcinomasin

females.

ThereisevidencefromanimalexperimentalstudiesthatHMG-CoAreductaseinhibitorsmayaffectthedevelopmentof

embryosorfoetuses.Inrats,rabbitsanddogsatorvastatinhadnoeffectonfertilityandwasnotteratogenic,however,at

maternallytoxicdosesfoetaltoxicitywasobservedinratsandrabbits.Thedevelopmentoftheratoffspringwasdelayedand

post-natalsurvivalreducedduringexposureofthedamstohighdosesofatorvastatin.Inrats,thereisevidenceofplacental

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transfer.Inrats,plasmaconcentrationsofatorvastatinaresimilartothoseinmilk.Itisnotknownwhetheratorvastatinorits

metabolitesareexcretedinhumanmilk.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Mannitol

Cellulosemicrocrystalline

Crospovidone

Sodiumcarbonate

Povidone

Methionine

Magnesiumstearate

Coating:

Hypromellose6cP

Titaniumdioxide(E171)

Macrogol

Talc

6.2 Incompatibilities

Notapplicable.

6.3 Shelf life

2 years

Shelflifeafterfirstopeningofthetabletcontaineris100days.

6.4 Special precautions for storage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5 Nature and contents of container

Aluminium/aluminiumblisterpacks.

Tabletcontainers(HDPE)closedwithsnap-oncap(LDPE)withatamperevidentringandwithadesiccant(silicagel).

Packsizes:

Blisters:

Atorvastatin20 mgfilm‑coatedtablets:10,20,28,30,50, 90,98,100 tablets.

Tabletcontainer:

Atorvastatin20 mgfilm‑coatedtablets:30,100,250,500 tablets.

Notallpacksizesmaybemarketed.

6.6 Special precautions for disposal and other handling

Nospecialrequirements.

Anyunusedmedicinalproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7 MARKETING AUTHORISATION HOLDER

ActavisGroupPTCehf

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Reykjavikurvegi76-78

220Hafnarfjördur

Iceland

8 MARKETING AUTHORISATION NUMBER

PA1380/017/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Dateoffirstauthorisation:18thSeptember2009

Dateoflastrenewal:23rdMay2012

10 DATE OF REVISION OF THE TEXT

September2019

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