Atorvastatin Krka d.d. 40 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

04-11-2019

Produktens egenskaper Produktens egenskaper (SPC)

20-08-2019

Aktiva substanser:
atorvastatinkalciumtrihydrat
Tillgänglig från:
Krka d.d., Novo mesto
ATC-kod:
C10AA05
INN (International namn):
atorvastatin calcium trihydrate
Dos:
40 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
atorvastatinkalciumtrihydrat 43,38 mg Aktiv substans; laktosmonohydrat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 4 tabletter; Blister, 7 tabletter; Blister, 10 tabletter; Blister, 14 tabletter; Blister, 20 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 50 tabletter; Blister, 56 tabletter; Blister, 60 tabletter; Blister, 84 tabletter; Blister, 90 tabletter; Blister, 98 tabletter; Blister, 100 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
58095
Tillstånd datum:
2019-05-20

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

18-12-2020

Produktens egenskaper Produktens egenskaper - engelska

18-12-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

20-05-2019

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PACKAGE LEAFLET

Package leaflet: Information for the patient

Atorvastatin Krka d.d. 10 mg film-coated tablets

Atorvastatin Krka d.d. 20 mg film-coated tablets

Atorvastatin Krka d.d. 40 mg film-coated tablets

Atorvastatin Krka d.d. 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 <Invented name> is and what it is used for

What you need to know before you take <Invented name>

How to take <Invented name>

Possible side effects

How to store <Invented name>

Contents of the pack and other information

1.

What <Invented name> is and what it is used for

<Invented name> belongs to a group of medicines known as statins, which are lipid (fat) regulating

medicines.

<Invented name> 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, <Invented name> 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 <Invented name>

Do not take <Invented name>

if you are allergic to atorvastatin or to any of the other ingredients of this 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 <Invented name>:

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 <Invented name>

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 <Invented name> 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 <Invented name>”).

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 <Invented name>

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 <Invented name> or their effect

may be changed by <Invented name>. 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, fusidic acid

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.

Letermovir, a medicine that helps stop you from getting ill from cytomegalovirus

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 <Invented name> 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

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 <Invented name>. Taking

<Invented name> with fusidic acid may rarely lead to muscle weakness, tenderness or pain

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

Taking <Invented name> with food, drink and alcohol

See Section 3 for instructions on how to take <Invented name>. 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 <Invented name>.

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 <Invented name> if you are pregnant, or if you are trying to become pregnant.

Do not take <Invented name> if you are able to become pregnant unless you use reliable contraceptive

measures.

Do not take <Invented name> if you are breast-feeding.

The safety of <Invented name> during pregnancy and breast-feeding has not yet been proven. Ask

your doctor or pharmacist for advice before taking this 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.

<Invented name> contains lactose and sodium

If you have been told by your doctor that you have intolerance to some sugars, contact your doctor

before taking this product.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-

free’.

3.

How to take <Invented name>

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 <Invented name>.

The recommended 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

<Invented name> is 80 mg once daily.

<Invented name> 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 <Invented name> is determined by your doctor.

Please ask your doctor if you think that the effect of <Invented name> is too strong or too weak.

If you take more <Invented name> than you should

If you accidently take too many <Invented name> tablets (more than your usual daily dose), contact

your doctor or nearest hospital for advice.

If you forget to take <Invented name>

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 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 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:

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.

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

Other possible side effects with <Invented name>:

Common side effects (may affect up to 1 in 10 people) include:

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 side effects (may affect up to 1 in 100 people) include:

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 side effects (may affect up to 1 in 1,000 people) include:

visual disturbance

unexpected bleeding or bruising

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

tendon injury

Very rare side effects (may affect up to 1 in 10,000 people) include:

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

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 the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store <Invented name>

Keep this medicine out of the sight and reach of children.

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

date refers to the last day of that month.

Store in the original package in order to protect from moisture.

This medicine does not require any special temperature storage conditions.

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 <Invented name> contains

The active substance is atorvastatin.

<Invented name> 10 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

10 mg

atorvastatin.

<Invented name> 20 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

20 mg

atorvastatin.

<Invented name> 40 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

40 mg

atorvastatin.

<Invented name> 80 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

80 mg

atorvastatin.

The other ingredients (excipients) are calcium carbonate (E170), hydroxypropylcellulose

(E463), microcrystalline cellulose (E460), lactose monohydrate, croscarmellose sodium,

polysorbate 80 (E433) and magnesium stearate (E470b) in the tablet core and hypromellose

(E464), macrogol, titanium dioxide (E171) and talc (E553b) in the film coating. See section 2

"<Invented name> contains lactose and sodium".

What <Invented name> looks like and contents of the pack

<Invented name> 10 mg film-coated tablets

The tablets are white to almost white, round, biconvex, film-coated tablets with beveled edges and

engraved with a mark 10 on one side of the tablet. Tablet diameter: approximately 6 mm.

<Invented name> 20 mg film-coated tablets

The tablets are white to almost white, round, biconvex, film-coated tablets with beveled edges and

engraved with a mark 20 on one side of the tablet. Tablet diameter: approximately 8 mm.

<Invented name> 40 mg film-coated tablets

The tablets are white to almost white, round, biconvex, film-coated tablets with beveled edges and

engraved with a mark 40 on one side of the tablet. Tablet diameter: approximately 10 mm.

<Invented name> 80 mg film-coated tablets

The tablets are white to almost white, oval, biconvex, film-coated tablets engraved with a mark 80 on

one side of the tablet. Tablet dimension: approximately 18 mm x 9 mm.

<Invented name>

is available in boxes containing 4, 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 90, 98 or 100

film-coated tablets in blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

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

names:

Country1

Country2, Country3, Country4

This leaflet was last revised in

[To be completed nationally]

12/2020

Detailed information on this medicine is available on the website of {name of Member State Agency

(link)}

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Atorvastatin Krka d.d. 10 mg film-coated tablets

Atorvastatin Krka d.d. 20 mg film-coated tablets

Atorvastatin Krka d.d. 40 mg film-coated tablets

Atorvastatin Krka d.d. 80 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

<Invented name> 10 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

10 mg atorvastatin.

<Invented name> 20 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

20 mg atorvastatin.

<Invented name> 40 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

40 mg atorvastatin.

<Invented name> 80 mg film-coated tablets

Each film-coated tablet contains atorvastatin calcium trihydrate equivalent to

80 mg atorvastatin.

Excipient with known effect

10 mg tablets

20 mg tablets

40 mg tablets

80 mg tablets

Lactose monohydrate (mg/tablet)

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

<Invented name> 10 mg film-coated tablets

The tablets are white to almost white, round, biconvex, film-coated tablets with beveled edges and

engraved with a mark 10 on one side of the tablet. Tablet diameter: approximately 6 mm.

<Invented name> 20 mg film-coated tablets

The tablets are white to almost white, round, biconvex, film-coated tablets with beveled edges and

engraved with a mark 20 on one side of the tablet. Tablet diameter: approximately 8 mm.

<Invented name> 40 mg film-coated tablets

The tablets are white to almost white, round, biconvex, film-coated tablets with beveled edges and

engraved with a mark 40 on one side of the tablet. Tablet diameter: approximately 10 mm.

<Invented name> 80 mg film-coated tablets

The tablets are white to almost white, oval, biconvex, film-coated tablets engraved with a mark 80 on

one side of the tablet. Tablet dimension: approximately 18 mm x 9 mm.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hypercholesterolaemia

<Invented name> is indicated as an adjunct to diet for reduction of elevated total cholesterol

(total­C), 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

nonpharmacological measures is inadequate.

<Invented name> 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

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 <Invented

name> and should continue on this diet during treatment with <Invented name>.

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 <Invented name> 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 <Invented name> 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.

Homozygous familial hypercholesterolaemia

Only limited data are available (see section 5.1).

The dose of atorvastatin in patients with homozygous familial hypercholesterolemia 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.

Renal impairment

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

Hepatic impairment

<Invented name> should be used with caution in patients with hepatic impairment (see sections 4.4

and 5.2). <Invented name> 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).

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.

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

Co-administration with other medicines

In patients taking the hepatitis C antiviral agents elbasvir/grazoprevir or letermovir for

cytomegalovirus infection prophylaxis concomitantly with atorvastatin, the dose of atorvastatin should

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

Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin

(see sections 4.4 and 4.5).

Method of administration

<Invented name> 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.

4.3

Contraindications

<Invented name> 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 <Invented name> is recommended (see

section 4.8).

<Invented name> 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 hemorrhagic stroke in

patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted

in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with prior

hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is

uncertain, and the potential risk of hemorrhagic 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 predisposing 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.

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. ciclosporin, telithromycin, clarithromycin, delavirdine,

stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir and HIV protease

inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc). The

risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid

derivates, antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir,

elbasvir/grazoprevir), erythromycin, niacin, or 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).

<Invented name> 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 <Invented name> and fusidic acid should only

be considered on a case by case basis and under close medical supervision.

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).

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with

long term therapy (see 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.

Excipients

Lactose

<Invented name> contains lactose. Patients with rare hereditary problems of galactose intolerance,

total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-

free’.

4.5

Interaction with other medicinal products and other forms of interaction

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

sections 4.3 and 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 treatement 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

Inhibitors of transport proteins (e.g. ciclosporin, letermovir) 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).

Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin

(see section 4.4).

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.

Drug Interactions

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

Atorvastatin

Co-administered medicinal

product

and dosing regimen

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

Atorvastatin

Co-administered medicinal

product

and dosing regimen

Dose (mg)

Ratio of

&

Clinical Recommendation

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

Telaprevir 750 mg q8h, 10

days

20 mg, SD

Ciclosporin 5.2 mg/kg/day,

stable dose

10 mg OD for

28 days

In cases where co-administration

with atorvastatin is necessary, do

not exceed 10 mg atorvastatin

daily. Clinical monitoring of

these patients is recommended.

Lopinavir 400 mg BID/

Ritonavir 100 mg BID,

14 days

20 mg OD for

4 days

Clarithromycin 500 mg BID,

9 days

80 mg OD for

8 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

.

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

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

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

.

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.

Letermovir 480 mg OD, 10

days

20 mg SD

3.29

The dose of atorvastatin should

not exceed a daily dose of 20

mg during co-administration

with products containing

letermovir.

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.

Atorvastatin

Co-administered medicinal

product

and dosing regimen

Dose (mg)

Ratio of

&

Clinical Recommendation

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 weeks

10 mg OD for

2 weeks

1.00

No specific recommendation.

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

Rifampin 600 mg OD, 5 days

(doses separated)

40 mg SD

0.20

If co-administration cannot be

avoided, simultaneous co-

administration of atorvastatin

with rifampin is recommended,

with clinical monitoring.

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

Co-administered medicinal product

dosing regimen

Medicinal product/Dose (mg)

Ratio of

&

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.

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.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment

(see section 4.3).

Pregnancy

<Invented name> is contraindicated during pregnancy (see section 4.3). Safety in pregnant women has

not been established. 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, <Invented name> should not be used in women who are pregnant, trying to become

pregnant or suspect they are pregnant. Treatment with <Invented name> should be suspended for the

duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3.)

Breastfeeding

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 <Invented name> should not

breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during breastfeeding (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

<Invented name> 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 atorvastatin 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 table

presents the adverse reaction profile for atorvastatin.

Estimated frequencies of reactions are ranked according to the following convention: common

(≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 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.

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, muscle rupture, tendonopathy, sometimes complicated by

rupture.

Very rare: lupus-like syndrome.

Frequency not known: immune-mediated necrotizing myopathy (see section 4.4).

Reproductive system and breast disorders

Very rare: gynecomastia.

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 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/m2, raised triglycerides, history of hypertension).

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 the national reporting system

listed in Appendix V.

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:

C10AA05

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 catabolized primarily through the receptor

with high affinity to LDL (LDL receptor).

Pharmacodynamic effects

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.

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 medicinal products.

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, nonfamilial 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 risk for

cardiovascular events and cardiovascular mortality.

Clinical efficacy and safety

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 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 randomized,

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 pre-defined 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 anti-hypertensive 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

p-value

Fatal CHD plus non-fatal MI

Total cardiovascular events and

revascularization procedures

Total coronary events

100 vs. 154

389 vs. 483

178 vs 247

1.1%

1.9%

1.4%

0.0005

0.0008

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

randomized, double-blind, multicenter, 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

p-value

Major cardiovascular events

(fatal and non-fatal AMI, silent

MI, acute CHD death, unstable

angina, CABG, PTCA,

revascularization, stroke)

MI (fatal and non-fatal AMI,

silent MI)

Strokes (Fatal and non-fatal)

83 vs. 127

38 vs 64

21 vs. 39

3.2%

1.9%

1.3%

0.0010

0.0070

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 4731 patients who had a stroke or

transient ischemic 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% (216/2365) for atorvastatin versus 8.9%

(211/2366) for placebo.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2%

vs. 274/2366, 11.6%, p=0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs.

33/2366, 1.4%, p=0.02) compared to placebo.

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

hemorrhagic stroke (7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-

19.57), and the risk of ischemic stroke was similar between groups (3/45 for atorvastatin versus

2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).

The risk of hemorrhagic 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 ischemic 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 hemorrhagic 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 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 completing 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.

Distribution

Mean volume of distribution of atorvastatin is approximately 381 l. Atorvastatin is ≥ 98% bound to

plasma proteins.

Biotransformation

Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and

various beta-oxidation products. Apart from other pathways these products are further metabolized 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.

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

(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: approx. 20% higher for C

and approx. 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 (approx. 16-fold in C

and approx. 11-fold in AUC) in patients with chronic alcoholic liver

disease (Child-Pugh B).

SLCO1B1 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 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 AUC

0-24h

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

Calcium carbonate (E170)

Hydroxypropylcellulose (E463)

Cellulose, microcrystalline (E460)

Lactose monohydrate

Croscarmellose sodium

Polysorbate 80 (E433)

Magnesium stearate (E470b)

Film coating

Hypromellose (E464)

Macrogol

Titanium dioxide (E171)

Talc (E553b)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

Store in the original package in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

6.5

Nature and contents of container

Blister (OPA/Alu/PVC-Alu foil): 4, 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 90, 98 or 100 film-coated

tablets, in a box.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements for disposal.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

[To be completed nationally]

12/2020

Detailed information on this medicinal product is available on the website of {name of Member State

Agency (link)}

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