Atorvas 10 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Atorvastatin
Available from:
Rowex Ltd
ATC code:
C10AA; C10AA05
INN (International Name):
Atorvastatin
Dosage:
10 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:
PA0711/180/001
Authorization date:
2010-09-03

Package leaflet: Information for the patient

Atorvas 10 mg film-coated tablets

Atorvas 20 mg film-coated tablets

Atorvas 40 mg film-coated tablets

Atorvas 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 Atorvas is and what it is used for

What you need to know before you take Atorvas

How to take Atorvas

Possible side effects

How to store Atorvas

Contents of the pack and other information

1.

What Atorvas is and what it is used for

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

Atorvas 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, Atorvas

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 Atorvas

DO NOT take Atorvas:

if you are allergic to atorvastatin or any of the other ingredients of this medicine (listed in section

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, pharmacist or nurse before taking

Atorvas:

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 Atorvas 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 Atorvas 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 Atorvas”).

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 Atorvas

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 Atorvas or their effect may be

changed by Atorvas. 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

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, letermovir 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 Atorvas 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

Atorvas. Taking Atorvas with fusidic acid may rarely lead to muscle weakness,

tenderness or pain (rhabdomyolysis). See more information regarding rhabdomyolysis

in section 4.

Atorvas with food, drink and alcohol

See section 3 for instructions on how to take Atorvas. 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 Atorvas.

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 Atorvas if you are pregnant, or if you are trying to become pregnant.

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

measures.

Do not take Atorvas if you are breast-feeding.

The safety of Atorvas 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.

Atorvas contains sodium. It contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to

say essentially ‘sodium-free’.

3.

How to take Atorvas

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

maintain also during therapy with Atorvas.

The usual starting dose of Atorvas 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 Atorvas is 80 mg

once a day.

Atorvas 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 or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

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

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

If you take more Atorvas than you should

If you accidently take too many Atorvas tablets (more than your usual daily dose), contact your doctor

or nearest hospital for advice.

If you forget to take Atorvas

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 Atorvas

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, tiredness, loss of

appetite, stomach pain, feeling sick, yellowing of your skin or eyes (jaundice), 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 Atorvas:

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

Inflammation of the nasal passages, pain in the throat, nosebleed

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, joint swelling, muscle pain, muscle spasms and back pain

Blood test results that show your liver function can become abnormal.

Uncommon (may affect up to 1 in 100 people):

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

should continue careful monitoring of your blood sugar levels)

Having nightmares, insomnia

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

change in sense of taste, loss of memory

Blurred vision

Ringing in the ears and/or head

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

leading to stomach pain)

Hepatitis (liver inflammation)

Rash, skin rash and itching, hives, hair loss

Neck pain, muscle fatigue

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

temperature

Urine tests that are positive for white blood cells.

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

Visual disturbance

Unexpected bleeding or bruising

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

Tendon injury.

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

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

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

Hearing loss

Gynaecomastia (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 HPRA Pharmacovigilance;

website: www.hpra.ie.. By reporting side effects you can help provide more information on the safety

of this medicine.

5.

How to store Atorvas

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 carton and the blister after “EXP”.

The expiry date refers to the last day of that month.

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

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 Atorvas contains

The active substance is atorvastatin (as calcium salt).

Each film-coated tablet contains 10 mg of atorvastatin (as calcium salt).

Each film-coated tablet contains 20 mg of atorvastatin (as calcium salt).

Each film-coated tablet contains 40 mg of atorvastatin (as calcium salt).

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

The other ingredients are sodium lauryl sulfate, microcrystalline cellulose, colloidal anhydrous silica,

maize starch pregelatinised, trometamol, iron oxide yellow (E172), magnesium stearate, talc, sodium

starch glycolate (type A), carmellose sodium, glycerol and hydroxyethylcellulose.

What Atorvas looks like and contents of the pack

10 mg film-coated tablets:

Light yellow, dappled, glossy, round biconvex film-coated tablets, debossed with “HLA 10” on one

side measuring 7.2 mm in diameter.

20 mg film-coated tablets:

Light yellow, dappled, glossy, round biconvex film-coated tablets, debossed with “HLA 20” on one

side measuring 9.2 mm in diameter.

40 mg film-coated tablets:

Light yellow, dappled, glossy, round biconvex film-coated tablets, debossed with “HLA 40” on one

side measuring 11.2 mm in diameter.

80 mg film-coated tablets:

Light yellow, dappled, glossy, oval biconvex film-coated tablets, debossed with “HLA 80” on one side

measuring 19.3 mm in length.

The film-coated tablets are packed in aluminium/aluminium blisters which are inserted in a carton

folder.

Atorvas 10 mg

Pack sizes: 7, 14, 28, 30, 56, 60, 63, 90, 91, 100 film-coated tablets

Atorvas 20 mg

Pack sizes: 7, 14, 28, 30, 56, 60, 63, 90, 91, 100 film-coated tablets

Atorvas 40 mg

Pack sizes: 7, 14, 28, 30, 56, 60, 63, 90, 91, 100 film-coated tablets

Atorvas 80 mg

Pack sizes: 7, 28, 30, 50, 60, 90, 98, 100 film-coated tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturers

Marketing Authorisation Holder

Rowex Ltd., Bantry, Co. Cork, Ireland.

Manufacturers

Lek Pharmaceuticals d.d., Verovškova 57, 1526 Ljubljana, Slovenia.

Lek S.A., ul, Domaniewska 50 C, 02-672 Warszawa, Poland.

Salutas Pharma GmbH, Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.

Lek Pharmaceuticals d.d., Trimlini 2D, 9220 Lendava, Slovenia.

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

names:

Austria

Atorvastatin Hexal 10 mg – Filmtabletten

Atorvastatin Hexal 20 mg – Filmtabletten

Atorvastatin Hexal 40 mg – Filmtabletten

Atorvastatin Hexal 80 mg – Filmtabletten

Germany

Atorvastatin HEXAL 10 mg Filmtabletten

Atorvastatin HEXAL 20 mg Filmtabletten

Atorvastatin HEXAL 40 mg Filmtabletten

Atorvastatin HEXAL 80 mg Filmtabletten

Ireland

Atorvas 10 mg film-coated tablets

Atorvas 20 mg film-coated tablets

Atorvas 40 mg film-coated tablets

Atorvas 80 mg film-coated tablets

Luxembourg

Atorvastatin HEXAL 10 mg Filmtabletten

Atorvastatin HEXAL 20 mg Filmtabletten

Atorvastatin HEXAL 40 mg Filmtabletten

Atorvastatin HEXAL 80 mg Filmtabletten

Slovak Republic

TULIP 10mg filmom abalené tablety

TULIP 20mg filmom abalené tablety

TULIP 40mg filmom abalené tablety

This leaflet was last approved in 04/2020.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Atorvas 10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg of atorvastatin (as calcium salt).

Excipient with known effect

Each film-coated tablet contains up to 1.52 mg of sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Light yellow, dappled, glossy, round biconvex film-coated tablets, debossed with "HLA 10" on one side measuring 7,2 mm in

diameter

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Hypercholesterolaemia

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

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

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

(Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological

measures is inadequate.

Atorvas 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 Atorvas and should continue on this diet

during treatment with Atorvas.

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 Atorvas 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.

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Heterozygous familial hypercholesterolaemia

Patients should be started with Atorvas 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 hypercholesterolaemia is 10 to 80 mg daily (see section 5.1).

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

treatments are unavailable.

Prevention of cardiovascular disease

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

levels according to current guidelines.

Co-administration with other medicinal products

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

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

Renal impairment

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

Hepatic impairment

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

Method of administration

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

or without food.

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4.3 Contraindications

Atorvas 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 Atorvas is recommended (see section 4.8).

Atorvas 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

ischaemic attack (TIA) there was a higher incidence of haemorrhagic stroke in patients initiated on atorvastatin 80 mg

compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or lacunar infarct at

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

80 mg is uncertain, and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment

(see section 5.1).

Skeletal muscle effects

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

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

markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal

failure.

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

statins. IMNM is clinically characterised 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

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

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

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

Whilst on treatment

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

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

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

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

discontinuation should be considered.

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

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

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

diagnosed or suspected.

Concomitant treatment with other medicinal products

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

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

telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, 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).

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

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

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

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

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

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

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

need for co-administration of Atorvas 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/m2, raised triglycerides, hypertension) should be monitored both clinically and

biochemically according to national guidelines.

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Atorvas contains sodium. It contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially

'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

Effect of co-administered medicinal products on atorvastatin

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

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

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

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

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

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

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

derivates and ezetimibe (see section 4.4).

CYP3A4 inhibitors

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

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

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

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

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

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

recommended (see Table 1).

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

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

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

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

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

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

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

CYP3A4 inducers

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

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

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

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

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

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

carefully monitored for efficacy.

Transport inhibitors

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).

Atorvastatin use in patients taking letermovir with ciclosporin is not recommended.

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

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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. Also see section 4.4.

Colchicine

Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported

with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with

colchicine.

Effect of atorvastatin on co-administered medicinal products

Digoxin

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

slightly. Patients taking digoxin should be monitored appropriately.

Oral contraceptives

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

and ethinyl oestradiol.

Warfarin

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

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

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

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

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

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

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

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

taking anticoagulants.

Paediatric population

Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not

known. The above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the

paediatric population.

Drug interactions

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

Co-administer

ed medicinal

product

Atorvastatin ​

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and dosing

regimen

Dose

(mg)

Ratio of AUC

&

Clinical Recommendation

Tipranavir 500

mg BID/

Ritonavir 200

mg BID, 8 days

(days 14 to 21)

40 mg

day 1,

10 mg

day 20

In cases where co-administration with atorvastatin is necessary, do not exceed 10

mg atorvastatin daily. Clinical monitoring of these patients is recommended. ​

Telaprevir 750

mg q8h, 10

days

20 mg,

Ciclosporin 5.2

mg/kg/day,

stable dose

10 mg

for 28

days

Glecaprevir

400 mg OD/

Pibrentasvir

120 mg OD, 7

days

10 mg

for 7

days

Co-administration with products containing glecaprevir or pibrentasvir is

contraindicated (see section 4.3).

Lopinavir 400

mg BID/

Ritonavir 100

mg BID, 14

days

20 mg

for 4

days

In cases where co-administration with atorvastatin is necessary, lower maintenance

doses of atorvastatin are recommended. At atorvastatin doses exceeding 20 mg,

clinical monitoring of these patients is recommended.

Clarithromycin

500 mg BID, 9

days

80 mg

for 8

days

Saquinavir 400

mg BID/

Ritonavir (300

mg BID from

days 5-7,

increased to

400 mg BID on

day 8), days

4-18, 30 min

after

atorvastatin

dosing

40 mg

for 4

days

In cases where co-administration with atorvastatin is necessary, lower maintenance

doses of atorvastatin are recommended. At atorvastatin doses exceeding 40 mg,

clinical monitoring of these patients is recommended.

​ ​ ​

Darunavir 300

mg BID/

Ritonavir 100

mg BID, 9 days

10 mg

for 4

days

Itraconazole

200 mg OD, 4

days

40 mg

Fosamprenavir

700 mg BID/

Ritonavir 100

mg BID, 14

days

10 mg

for 4

days

Fosamprenavir

1400 mg BID,

14 days

10 mg

for 4

days

Nelfinavir 1250

10 mg

1.74

No specific recommendation.

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mg BID, 14

days

for 28

days

Grapefruit

juice, 240 mL

40 mg,

1.37

Concomitant intake of large quantities of grapefruit juice and atorvastatin is not

recommended.

Diltiazem 240

mg OD, 28

days

40 mg,

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,

1.33

Lower maximum dose and clinical monitoring of these patients is recommended.

Amlodipine 10

mg, single

dose

80 mg,

1.18

No specific recommendation.

Cimetidine 300

mg QID, 2

weeks

10 mg

for 2

weeks

1.00

No specific recommendation.

Colestipol 10 g

BID, 24 weeks

40 mg

for 8

weeks

0.74**

No specific recommendation.

Antacid

suspension of

magnesium

and aluminium

hydroxides, 30

mL QID, 17

days

10 mg

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-administer

40 mg

1.12

If co-administration cannot be avoided, simultaneous co-administration of

atorvastatin with rifampin is recommended, with clinical monitoring. ​

Rifampin 600

mg OD, 5 days

(doses

separated)

40 mg

0.20

Gemfibrozil

600 mg BID, 7

days

40 mg

1.35

Lower starting dose and clinical monitoring of these patients is recommended.

Fenofibrate

160 mg OD, 7

days

40 mg

1.03

Lower starting dose and clinical monitoring of these patients is recommended.

Boceprevir 800

mg TID, 7 days

40 mg

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.

Elbasvir 50 mg

Grazoprevir

mg OD, 13

days

10 mg

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

mgonce a day,

10 days

20 mg

​3.29

When used together with preparations that containletermovir, atorvastatin daily

dose should not exceed 20 mg.

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& Represents ratio of treatments (co-administered medicinal product 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

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

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

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

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

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

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

Atorvastatin and dosing regimen ​

Co-administered medicinal product ​

Medicinal product/Dose (mg)

Ratio of AUC

&

Clinical

Recommenda

tion

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 microg

1.28

1.19

No specific

recommendat

ion.

80 mg OD for 15 days

* Phenazone, 600 mg SD

1.03

No specific

recommendat

ion.

10 mg, SD

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

1.08

No specific

recommendat

ion.

10 mg, OD for 4 days

Fosamprenavir 1400 mg BID, 14 days

0.73

No specific

recommendat

ion.

10 mg OD for 4 days

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

0.99

No specific

recommendat

ion.

& Represents ratio of treatments (co-administered medicinal product plus atorvastatin versus atorvastatin alone).

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

phenazone.

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

Atorvas is contraindicated during pregnancy (see section4.3). 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. Studies in animals have shown toxicity

to reproduction (see section5.3).

Maternal treatment with atorvastatin may reduce the foetal 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, Atorvas should not be used in women who are pregnant, trying to become pregnant or suspect they are

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

woman is not pregnant (see section4.3.)

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Breast-feeding

It is unknown 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 Atorvas should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during

breast-feeding (see section 4.3).

Fertility

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

4.7 Effects on ability to drive and use machines

Atorvas 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 (8,755 atorvastatin vs. 7,311 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 to < 1/10); uncommon

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

available data).

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Rare: thrombocytopenia.

Immune system disorders

Common: allergic reactions.

Very rare: anaphylaxis.

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

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