Lorstat

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Atorvastatin calcium trihydrate 10.844 mg equivalent to Atorvastatin 10 mg;  
Available from:
Viatris Limited
INN (International Name):
Atorvastatin calcium trihydrate 10.844 mg (equivalent to Atorvastatin 10 mg)
Dosage:
10 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Atorvastatin calcium trihydrate 10.844 mg equivalent to Atorvastatin 10 mg   Excipient: Arginine Colloidal silicon dioxide Croscarmellose sodium Hyprolose Lactose Magnesium stearate Microcrystalline cellulose Opadry white 85F18378 Opadry White OY-B-28920 AMB Sodium carbonate
Prescription type:
Prescription
Manufactured by:
Mylan Laboratories Limited
Therapeutic indications:
Lorstat is indicated as an adjunct to diet to reduce elevated total-C, LDL-C and TG levels in patients with primary hypercholesterolaemia or mixed dyslipidaemia where the primary abnormality is either elevated cholesterol or triglycerides when response to diet and other non-pharmacological measures is inadequate. Lorstat is also indicated to reduce total-C and LDL-C in patients with heterozygous and homozygous familial hypercholesterolaemia.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/ Aclar and aluminium - 10 tablets - 24 months from date of manufacture stored at or below 25°C protect from light and moisture - Blister pack, OPA/ Al/ PVC - 10 tablets - 36 months from date of manufacture stored at or below 25°C protect from light and moisture - Blister pack, PVC/ Aclar and aluminium - 30 tablets - 24 months from date of manufacture stored at or below 25°C protect from light and moisture - Blister pack, OPA/ Al/ PVC - 30 tablets - 36 months from date of manufacture stored at or below 25°C protect from light and moisture - Bottle, White opaque high density HDPE - 90 tablets - 36 months from date of manufacture stored at or below 25°C protect from light and moisture - Bottle, White opaque high density HDPE - 500 tablets - 36 months from date of manufacture stored at or below 25°C protect from light and moisture
Authorization number:
TT50-9651
Authorization date:
2014-10-28

Read the complete document

Page 1 of 5

NEW ZEALAND CONSUMER MEDICINE INFORMATION

LORSTAT

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

What is in this leaflet

Please read this leaflet carefully

before you start taking Lorstat.

This leaflet answers some common

questions about Lorstat.

It does not contain all the available

information. It does not take the

place of talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking Lorstat

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the

medicine. You may need to read it

again.

What Lorstat is used

for

Lorstat is used to treat lower high

cholesterol levels.

Lorstat is also used in people who

have high blood pressure and

coronary heart disease (CHD) or

who are at risk of CHD (for

example, if they have diabetes, a

history of stroke, or small blood

vessel disease). In these people,

Lorstat is used to reduce the risk of

having a heart attack or stroke.

How Lorstat works

Lorstat contains the active

ingredient atorvastatin calcium. It

belongs to a group of medicines

called HMG-CoA reductase

inhibitors (also known as “statins”)

It works by reducing the amount of

cholesterol made by the liver. More

specifically, Lorstat reduces the

amount of LDL (bad cholesterol)

and raises the amount of HDL

(good cholesterol). Lorstat also

helps to protect you from a heart

attack or stroke.

What is cholesterol

Everyone has cholesterol and

triglycerides in their blood. They

are types of blood fat needed by the

body for many things, such as

building cell walls, making bile acids

(which help to digest food) and

some hormones. However, too

much cholesterol and triglycerides

can be a problem.

Cholesterol is present in many

foods and is also made in your body

by the liver. If your body does not

balance the amount of cholesterol it

needs with the amount of

cholesterol eaten, then your

cholesterol becomes too high.

High cholesterol is more likely to

occur with certain diseases or if you

have a family history of high

cholesterol.

There are different types of

cholesterol, called LDL and HDL.

LDL cholesterol is the 'bad'

cholesterol that can block your

blood vessels. HDL cholesterol is

the 'good' cholesterol that is thought

to remove the 'bad' cholesterol from

the blood vessels.

When you have high levels of

cholesterol it may 'stick' to the

inside of your blood vessels instead

of being carried to the parts of the

body where it is needed. Over time,

this can form hard areas (called

plaques) on the walls of your blood

vessels, making it more difficult for

the blood to flow. This blocking of

your blood vessels can lead to

blood vessel disease, heart disease

(such as heart attack and angina)

and stroke.

There is another type of fat called

triglycerides. Triglycerides are an

energy source for the body.

However, as with cholesterol, high

levels of triglycerides in your blood

can be a problem.

In some patients, Lorstat is used to

treat high cholesterol and high

triglycerides together.

When you are taking Lorstat, you

also need to follow a low fat diet

and other measures, such as

exercise and weight control.

In most people there are no

symptoms of high cholesterol or

triglycerides. However, they can be

measured by a simple blood test,

which your doctor can do.

Your doctor may have prescribed

this medicine for another reason.

Ask your doctor if you have any

questions about why this

medicine has been prescribed for

you.

Lorstat has been studied to a very

limited extent in children. For more

information talk to your doctor.

This medicine is available only with

a doctor’s prescription.

There is no evidence that Lorstat is

addictive.

Before you take

Lorstat

When you must not take

it

Do not take Lorstat if you have an

allergy to:

any medicine containing

atorvastatin.

any of the ingredients listed

at the end of this leaflet.

Page 2 of 5

Some of the symptoms of an

allergic reaction may include:

shortness of breath; wheezing or

difficulty breathing; swelling of the

face, lips, tongue or other parts of

the body; rash, itching or hives on

the skin.

Do not take Lorstat if you have

active liver disease.

Do not take this medicine if you

are pregnant or intend to become

pregnant.

It may affect your unborn

developing baby if you take it during

pregnancy.

Women of child-bearing age who

are taking the medicine should

use a proven method of birth

control to avoid pregnancy.

Do not take the medicine if you

are breastfeeding or intend to

breastfeed.

The medicine may pass into breast

milk and affect your baby.

Do not take Lorstat if you are

taking the antibiotic fusidic acid,

which is used to treat infections.

Do not take this medicine after

the expiry date printed on the

pack or if the packaging is torn or

shows signs of tampering.

If it has expired or is damaged,

return it to your pharmacist for

disposal.

If you are not sure whether you

should start taking this medicine,

talk to your doctor.

Before you start to take

it

Tell your doctor if you have

allergies to any other medicines,

foods, preservatives or dyes.

Tell your doctor if you have or

have had any of the following

medical conditions:

any medical conditions

including:

liver problems

kidney problems

lung problems

hormonal problem

muscle pain, tenderness

or weakness from other

medicines used to treat

cholesterol or

triglycerides.

a history of haemorrhagic

stroke, or lacunar stroke.

drink alcohol regularly.

any allergies to any other

medicines or any other

substances, such as foods,

preservatives or dyes.

Tell your doctor if you are

pregnant or plan to become

pregnant or are breast-feeding.

Your doctor can discuss with you

the risks and benefits involved.

If you have not told your doctor

about any of the above, tell them

before you start taking Lorstat.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including medicines

that you buy without a

prescription from your pharmacy,

supermarket or health food shop.

You should also tell any health

professional who is prescribing a

new medication for you that you are

taking Lorstat.

Some medicines may interfere with

Lorstat. These include:

digoxin, a medicine used to

treat some heart problems.

antibiotics, such as

erythromycin,

clarithromycin, rifampicin

and fusidic acid.

phenytoin, a medicine used

to treat epilepsy.

oral contraceptives for birth

control.

other medicines used to

treat high cholesterol or

triglycerides.

antacids, medicines used to

treat reflux or ulcers.

ciclosporin, a medicine

used to suppress the

immune system.

protease inhibitors which

are used to treat HIV

infections, such as

efavirenz, ritonavir and

boceprevir, simeprevir, and

elbasvir/grazoprevir.

ketoconazole and

itraconazole, used to treat

certain fungal infections.

diltiazem, a medicine used

to treat angina.

spironolactone a medicine

used to treat high blood

pressure and certain types

of swelling.

vitamin B3.

colchicine, a medicine used

to treat gout, a disease with

painful, swollen joints

caused by uric acid

crystals.

ticagrelor, a medicine used

to reduce the risk of stroke

or heart attack.

letermovir, an antiviral

medicine used to treat CMV

infections.

These medicines may be affected

by Lorstat or may affect how well it

works. You may need different

amounts of your medicines, or you

may need to take different

medicines.

Your doctor can tell you what to do

if you are taking any of these

medicines.

If you are not sure whether you

are taking any of these

medicines, check with your

doctor or pharmacist.

Your doctor and pharmacist have

more information on medicines to

be careful with or avoid while taking

this medicine.

How to take Lorstat

Follow all directions given to you

by your doctor or pharmacist

carefully.

They may differ from the information

contained in this leaflet.

If you do not understand the

instructions on the box, ask your

doctor or pharmacist for help.

How much to take

Take Lorstat only when prescribed

by your doctor.

The usual dose of Lorstat is

between 10-80 mg taken once a

day.

How to take it

Page 3 of 5

Swallow the tablets whole with a

full glass of water, with or

without food.

When to take it

Take your medicine at about the

same time each day.

Taking it at the same time each day

will have the best effect. It will also

help you remember when to take it.

How long to take it

Continue taking your medicine

for as long as your doctor tells

you.

Lorstat helps lower your cholesterol.

It does not cure your condition.

Therefore, you must continue to

take Lorstat as directed by your

doctor if you expect to lower your

cholesterol and keep it down.

Continue taking your medicine

until you finish the pack.

If you forget to take it

If it is almost time for your next

dose, skip the dose you missed

and take your next dose when

you are meant to.

Otherwise, take it as soon as you

remember, and then go back to

taking your medicine as you

would normally.

Do not take a double dose to

make up for the dose that you

missed.

This may increase the chance of

you getting an unwanted side effect.

If you are not sure what to do,

ask your doctor or pharmacist.

If you have trouble remembering to

take your medicine, ask your

pharmacist for some hints.

While you are taking

Lorstat

Things you must do

If you are about to be started on

any new medicine, tell your

doctor and pharmacist that you

are taking Lorstat.

Tell any other doctors, dentists,

and pharmacists who treat you

that you are taking this medicine.

If you are going to have surgery,

tell the surgeon or anaesthetist

that you are taking this medicine.

It may affect other medicines used

during surgery.

If you become pregnant while

taking Lorstat, stop taking the

medicine and contact your doctor

immediately.

If you are about to have any

blood tests, tell your doctor that

you are taking this medicine.

It may interfere with the results of

some tests.

Keep all of your doctor’s

appointments so that your

progress can be checked.

Your doctor may do some liver

function tests from time to time to

make sure the medicine is working

and to prevent unwanted side

effects.

Your cholesterol and

triglycerides levels also need to

be checked regularly while you

are taking Lorstat.

Things you must not do

Do not take Lorstat to treat any

other complaints unless your

doctor tells you to.

Do not give your medicine to

anyone else, even if they have

the same condition as you.

Do not stop taking your medicine

or lower the dosage without

checking with your doctor.

If you stop taking it suddenly, your

condition may worsen or you may

have unwanted side effects such as

If possible, your doctor will gradually

reduce the amount you take each

day before stopping the medicine

completely.

Things to be careful of

Be careful driving or operating

machinery until you know how

Lorstat affects you.

Lorstat generally does not cause

any problems with your ability to

drive a car or operate machinery.

However, as with many other

medicines, Lorstat may cause

dizziness in some people.

Avoid drinking large quantities of

alcohol.

Drinking large quantities of alcohol

may increase your chance of

Lorstat causing liver problems.

Avoid drinking large quantities of

grapefruit juice. Grapefruit juice

contains one or more components

that alter the metabolism of some

medicines, including Lorstat.

Therefore, drinking very large

quantities of grapefruit juice (over 1

litre) each day increases the chance

of Lorstat causing side effects.

If you feel light-headed, dizzy or

faint when getting out of bed or

standing up, get up slowly.

Standing up slowly, especially when

you get up from bed or chairs, will

help your body get used to the

change in position and blood

pressure. If this problem continues

or gets worse, talk to your doctor.

In case of overdose

If you take too much

(overdose)

Immediately telephone your

doctor or the National Poisons

Centre (telephone 0800 POISON

or 0800 764 766), or go to

accident and emergency at your

nearest hospital, if you think that

you or anyone else may have

taken too much Lorstat. Do this

even if there are no signs of

discomfort or poisoning. You may

need urgent medical attention.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not

feel well while you are taking

Lorstat.

This medicine helps most people

with high cholesterol, but it may

have unwanted side effects in a few

people.

All medicines can have side

effects. Sometimes they are

serious, most of the time they are

not. You may need medical

Page 4 of 5

treatment if you get some of the

side effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor or pharmacist if

you notice any of the following

and they worry you:

muscle and muscle

weakness

joint pain and swollen joints

constipation, diarrhoea

unusual tiredness or

weakness

stomach or belly pain,

nausea

heartburn, indigestion or

wind

headache

urine infection

nose bleeds, stuffy or runny

nose

rash

blurred vision

problems with breathing

such as breathlessness,

wheezing, chest tightness

and cough

erectile dysfunction

male breast enlargement

loss of appetite

nightmare

belching

symptoms of

hyperglycaemia, such as

increase urine, thirst, dry

mouth or skin

trouble sleeping

unusual hair loss

loss of memory

dizziness.

The above list includes the more

common side effects of your

medicine.

They are usually mild and short-

lived.

Tell your doctor as soon as

possible if you notice any of the

following:

symptoms of an allergy

such as skin rash, itching,

swelling of the face, lips,

mouth, tongue, throat or

neck which may cause

difficulty in swallowing and

breathing

chest pain

fever

yellowing of the skin and

eyes and dark colored urine

unexpected muscle pain,

tenderness or weakness

not caused by exercise

sudden severe headache

nausea

vomiting

loss of sensation

tingling in any parts of your

body

ringing in the ears

severe blisters and bleeding

of the lips, eyes, mouth,

nose or genitals.

The above list includes serious side

effects that may require medical

attention.

Tell your doctor or pharmacist if

you notice anything that is

making you feel unwell.

Other side effects not listed above

may also occur in some people. Tell

your doctor if you notice any other

effects.

Some of these side effects (for

example, cholesterol level) can only

be found when your doctor does

tests from time to time to check your

progress.

Do not be alarmed by this list of

possible side effects. You may

not experience any of them.

After taking Lorstat

Storage

Keep your tablets in the bottle

until it is time to take them.

If you take the tablets out of the

bottle they may not keep well.

Keep your tablets in a cool dry

place where the temperature

stays below 25°C.

Do not store Lorstat or any other

medicine in the bathroom or near a

sink. Do not leave it on a window sill

or in the car. Heat and dampness

can destroy some medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

medicine that is left over.

Product description

What it looks like

Lorstat tablets are available in 4

different strengths:

Lorstat 10 mg – White, oval,

biconvex, film coated tablet, plain

on one side and debossed “10” on

the other side.

Lorstat 20 mg - White, oval,

biconvex, film coated tablet, with

breakline on one side and debossed

“20” on the other side.

Lorstat 40 mg - White, oval,

biconvex, film coated tablet, with

breakline on one side and debossed

“40” on the other side.

Lorstat 80 mg – White, oval,

biconvex, film coated tablet, with

breakline on one side and debossed

“80” on the other side.

Ingredients

Active ingredient(s):

Lorstat contains 10, 20, 40, or 80

mg of atorvastatin calcium as the

active ingredient.

Inactive ingredient(s):

Lorstat also contains:

colloidal anhydrous silica

sodium carbonate

microcrystalline cellulose

L-arginine

lactose

croscarmellose sodium

hydroxypropyl cellulose

magnesium stearate

Opadry AMB White OY-B-

28920 (containing titanium

dioxide, talc, xanthan, gum,

polyvinyl alcohol and soya

lecithin).

Opadry II white 85F18378

(containing polyvinyl alcohol

– part hydrolysed, titanium

dioxide, macrogol and talc)

Page 5 of 5

Lortstat tablets may be coated with

either Opadry AMB White OY-B-

28920 or Opadry II white 85F18378.

If you want to know

more

Should you have any questions

regarding this product, please

contact your pharmacist or doctor.

Who supplies this

medicine

Lorstat is supplied in New Zealand

Mylan New Zealand Ltd,

PO Box 11183,

Ellerslie,

Auckland

NEW ZEALAND

Telephone: 0800 579 811

Date of Preparation

4 May 2021

(Based on datasheet dated 4 May

2021)

Read the complete document

Page 1 of 21

NEW ZEALAND DATA SHEET

LORSTAT

1. Product Name

Lorstat, 10 mg, 20 mg, 40 mg & 80 mg, film coated tablet.

2. Qualitative and Quantitative Composition

Each Lorstat tablet contains 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin as atorvastatin calcium

trihydrate.

Lorstat tablets contain lactose. For the full list of excipients, see section 6.1.

3. Pharmaceutical Form

Lorstat 10 mg: White, oval, biconvex, film coated tablet, plain on one side and debossed “10” on the

other side.

Lorstat 20 mg: White, oval, biconvex, film coated tablet, with breakline on one side and debossed

“20” on the other side.

Lorstat 40 mg: White, oval, biconvex, film coated tablet, with breakline on one side and debossed

“40” on the other side.

Lorstat 80 mg: White, oval, biconvex, film coated tablet, with breakline on one side and debossed

“80” on the other side.

The 20 mg, 40 mg and 80 mg tablets can be divided into equal doses.

4. Clinical Particulars

4.1

Therapeutic indications

Lorstat is indicated as an adjunct to diet to reduce elevated total cholesterol (total-C), low density

lipoprotein

cholesterol

(LDL-C)

triglycerides

(TG)

levels

patients

with

primary

hypercholesterolaemia or mixed dyslipidaemia where the primary abnormality is either elevated

cholesterol or triglycerides when response to diet and other non-pharmacological measures is

inadequate.

Lorstat is also indicated to reduce total-C and LDL-C in patients with heterozygous and homozygous

familial hypercholesterolaemia.

Lorstat is indicated to increase plasma high density lipoprotein cholesterol (HDL-C) and decrease

the LDL-C/HDL-C and total-C/HDL-C ratios.

Lorstat is indicated as an adjunct to diet for the treatment of patients with elevated serum triglyceride

levels (hypertriglyceridaemia), and for the treatment of patients with dysbetalipoproteinaemia who

do not respond adequately to diet.

Page 2 of 21

Lorstat is indicated for the reduction of cardiac ischaemic events in patients with asymptomatic or

mildly to moderately symptomatic coronary artery disease with a LDL-C of at least 3.0 mmol/L and

a triglyceride level of no more than 5.6 mmol/L.

Lorstat is indicated in hypertensive patients with multiple risk factors for coronary heart disease

(CHD), which may include diabetes, history of stroke or other cerebrovascular disease, peripheral

vascular disease or existing asymptomatic CHD (see section 5.2) to reduce the risk of non-fatal

myocardial infarction (MI) and non-fatal stroke.

Lorstat is also indicated in patients with type 2 diabetes, with at least one other risk factor for CHD,

to reduce the risk of coronary and cerebrovascular events.

These effects do not replace the need to independently control known causes of cardiovascular

mortality and morbidity such as hypertension, diabetes and smoking.

4.2

Dose and method of administration

Hypercholesterolaemia and mixed dyslipidaemia

Lorstat can be administered within the dosage range of 10-80 mg/day as a single daily dose. Lorstat

can be taken at any time of the day, with or without food. Therapy should be individualised according

to the target lipid levels, the recommended goal of therapy and the patient's response. After initiation

and / or upon titration of atorvastatin, lipid levels should be re-analysed within 4 weeks and dosage

adjusted according to the patient's response.

Primary hypercholesterolaemia and mixed hyperlipidaemia

The majority of patients are controlled with 10 mg atorvastatin once a day. A therapeutic response

is evident within two weeks, and the maximum response is usually achieved within four weeks. The

response is maintained during chronic therapy.

Intensive cholesterol lowering with atorvastatin 80 mg once a day should be considered in individuals

with stable coronary artery disease (see section 5.1).

Homozygous familial hypercholesterolaemia

Adults: In a compassionate-use study of patients with homozygous familial hypercholesterolaemia,

most patients responded to 80 mg of atorvastatin with a greater than 15% reduction in LDL-C (18%-

45%).

Children: Treatment experience in a paediatric population is limited to doses of atorvastatin up to 80

mg/day for 1 year in patients with homozygous familial hypercholesterolaemia (FH) (see section 4.4).

Hypertriglyceridaemia and dysbetalipoproteinaemia

The dosage of atorvastatin in this patient group is 10-80 mg daily as a single dose. Doses should be

individualised and adjusted according to the patient's response after 4 weeks.

Special populations

Renal impairment

Renal disease has no influence on the plasma concentrations or on the LDL-C reduction of

atorvastatin; thus no adjustment of the dose is required (see section 5).

Hepatic impairment

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver

disease (Childs-Pugh B). The benefits of therapy should be weighed against the risks when

atorvastatin is to be given to patients with hepatic insufficiency (see section 5 and section 4.3).

Page 3 of 21

Use in combination with other medicinal compounds

cases

where

co-administration

atorvastatin

with

ciclosporin,

telaprevir

glecaprevir/pibrentasvir is necessary, the dose of atorvastatin should not exceed 10 mg (see section

4.4 and section 4.5).

atorvastatin

recommended

patients

taking

letermovir

co-administered

with

ciclosporin.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active liver disease or unexplained persistent elevations of serum transaminases (see section 4.4).

Pregnancy and lactation (see section 4.6). Women of child-bearing potential, unless on an effective

contraceptive and highly unlikely to conceive.

Concomitant use with fusidic acid (see section 4.4 and 4.5).

4.4

Special warnings and precautions for use

Liver dysfunction

As with other lipid-lowering agents of the same class, moderate (> 3 x upper limit of normal [ULN])

elevations of serum transaminases have been reported following therapy with atorvastatin.

Persistent increases in serum transaminases > 3 x ULN occurred in 0.7% of patients who received

atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3%

for 10, 20, 40, and 80 mg respectively. Increases were generally not associated with jaundice or

other clinical signs or symptoms. When the dosage of atorvastatin was reduced, or drug treatment

interrupted or discontinued, transaminase levels returned to pre-treatment levels. Most patients

continued treatment on a reduced dose of atorvastatin without sequelae.

Liver function tests should be performed before the initiation of treatment and periodically

thereafter. Patients who develop increased transaminase levels should be monitored until

the abnormalities resolve. Should an increase in ALT or AST of > 3 x ULN persist, reduction

of dose or withdrawal of atorvastatin is recommended.

Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol

and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase

elevations are contraindications to the use of atorvastatin (see section 4.3).

Skeletal muscle

Uncomplicated myalgia has been reported in atorvastatin-treated patients (see section 4.8).

Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine

phosphokinase (CPK) values > 10 x ULN, should be considered in any patient with diffuse myalgias,

muscle tenderness or weakness and/or marked elevation of CPK. Patients should be advised to

report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by

malaise or fever. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur

or myopathy is diagnosed or suspected.

The risk of myopathy is increased with concurrent administration of drugs that increase the systemic

concentration of atorvastatin (see section 4.5). Physicians considering combined therapy with

atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals,

human immunodeficiency virus (HIV) / hepatitis C (HCV) protease inhibitors, HCV non-structural

protein 5A (NS5A)/5B (NS5B) inhibitors, letermovir, or lipid-lowering doses of niacin should carefully

weigh the potential benefits and risks and should carefully monitor patients for any signs and

symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy

and during any periods of upward dosage titration of either drug. Therefore, lower starting and

Page 4 of 21

maintenance doses of atorvastatin should also be considered when taken concomitantly with the

aforementioned drugs (see section 4.2).

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

concomitant fusidic acid and statins (see section 4.3 and section 4.5). In patients where the use of

systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the

duration of the fusidic acid treatment. The patient should be advised to seek medical advice

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

therapy may be reintroduced seven days after the last dose of fusidic acid.

Periodic creatine phosphokinase (CPK) determinations may be considered in such situations,

although there is no assurance that such monitoring will prevent the occurrence of severe myopathy

(see section 4.4).

As with other drugs in this class, rhabdomyolysis with acute renal failure, has been reported.

A history of renal impairment may be a risk factor for the development of rhabdomyolysis.

Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin therapy

should be temporarily withheld or discontinued in any patient with an acute, serious

condition suggestive of a myopathy or having a risk factor predisposing to the development

of renal failure secondary to rhabdomyolysis, (e.g. severe acute infection, hypotension, major

surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled

seizures).

Haemorrhagic stroke

A post-hoc analysis of a clinical study in patients without known coronary heart disease who had a

recent stroke or transient ischaemic attack (TIA) showed a higher incidence of haemorrhagic stroke

in patients on atorvastatin 80 mg (55/2365, 2.3%) compared to placebo (33/2366, 1.4%), (p=0.02).

Throughout the study, all cause mortality was numerically higher in the atorvastatin arm than the

placebo arm. At study end all cause mortality was 9.1% on atorvastatin vs. 8.9% on placebo.

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

haemorrhagic stroke (15.6% for atorvastatin vs. 4.2% for placebo, hazard ratio (HR) 4.06; 95% CI

0.84 – 19.57) or prior lacunar infarct (2.8% for atorvastatin vs. 0.6% for placebo, HR 4.99; 95% CI

1.71 -14.61). All cause mortality was also increased in these patients with prior haemorrhagic stroke

(15.6% for atorvastatin vs. 10.4% for placebo) or prior lacunar infarct (10.9% for atorvastatin vs.

9.1% for placebo). The potential risk of a haemorrhagic stroke should be carefully considered before

initiating treatment with atorvastatin in patients with recent (1-6 months) stroke or TIA.

In 68% of patients who entered the study with neither a haemorrhagic stroke or lacunar infarct, the

risk of haemorrhagic stroke on atorvastatin vs. placebo was 2% vs. 1.8% (large vessel), 1.7% vs.

1.6% (TIA), 1.6% vs. 1.7% (unknown cause).

Endocrine function

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors interfere with cholesterol

synthesis and theoretically may blunt adrenal and/or gonadal steroid production. Clinical studies

have shown that atorvastatin does not reduce basal plasma cortisol concentration nor impair adrenal

reserve. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in

adequate numbers of patients. The effects, if any, on the pituitary gonadal axis in pre-menopausal

women

unknown.

Caution

should

exercised

HMG-CoA

reductase

inhibitor

administered concomitantly with other drugs that may decrease the levels or activity of endogenous

steroid hormones such as ketoconazole, spironolactone and cimetidine.

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. Risk factors for the development of diabetes include raised fasting blood glucose,

history of hypertension, raised triglycerides and raised body mass. Patients at risk should be

monitored both clinically and biochemically according to national guidelines.

Page 5 of 21

There is insufficient evidence to confirm or exclude an increased risk for any individual statin or a

dose-response relationship. The cardiovascular benefits of statin therapy continue to outweigh the

risk of diabetes.

Effect on ubiquinone levels (COQ

10

)

Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other

statins have been observed. The clinical significance of a potential long-term, statin-induced

deficiency of ubiquinone has not been established.

Effect on lipoprotein (a)

Like other HMG-CoA reductase inhibitors, atorvastatin has variable effects on lipoprotein(a) (Lp(a)).

It is unclear whether the beneficial effects of lowering LDL-C and total-C in some patients may be

blunted by raised Lp(a) levels.

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.

Special populations

Paediatrics

Treatment experience in a paediatric population is limited to doses of atorvastatin up to 80 mg/day

for 1 year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported

in these patients.

Elderly

Treatment experience in adults age ≥ 70 years with doses of atorvastatin up to 80 mg/day has been

evaluated in 221 patients. The safety and efficacy of atorvastatin in this population were similar to

those of patients < 70 years of age.

4.5

Interaction with other medicines and other forms of interaction

Atorvastatin is metabolised by cytochrome P450 3A4.

Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to

increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of

effects depends on the variability of effect on cytochrome P450 3A4. Pharmacokinetic drug

interactions that result in increased systemic concentration of atorvastatin have also been noted with

other HIV protease inhibitors (combinations of lopinavir/ritonavir and darunavir/ritonavir), HCV

protease

inhibitors

(boceprevir,

elbasvir/grazoprevir,

simeprevir),

NS5A/NS5B

inhibitors,

clarithromycin,

itraconazole,

letermovir.

Caution

should

used

when

co-prescribing

atorvastatin with medicinal compounds that result in an increase in systemic concentrations of

atorvastatin and appropriate clinical assessment is recommended to ensure that the lowest dose

necessary of atorvastatin is employed. Based on experience with other HMG-CoA reductase

inhibitors,

caution

should

exercised

when

atorvastatin

administered

with

inhibitors

cytochrome P450 3A4 (e.g. ciclosporin, macrolide antibiotics including erythromycin and azole

antifungals including itraconazole). The risk of myopathy during treatment with other HMG-CoA

reductase inhibitors is increased with concurrent administration of ciclosporin, fibric acid derivatives,

erythromycin, azole antifungals or niacin (see section 4.2 and section 4.4).

Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g. efavirenz,

rifampicin, phenytoin) can lead to variable reductions in plasma concentrations of atorvastatin. Due

to the dual interaction mechanism of rifampicin (cytochrome P450 3A4 induction and inhibition of

hepatocyte uptake transporter (OATP1B1)), simultaneous co-administration of atorvastatin with

Page 6 of 21

rifampicin is recommended, as delayed administration of atorvastatin after administration of

rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations.

Fusidic acid

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

of systemic fusdic acid with statins. Co-administration of this combination may cause increased

plasma

concentrations

both

agents.

mechanism

this

interaction

(whether

pharmacodynamics or pharmacokinetic, or both) is yet unknown.

Although interaction studies with atorvastatin and fusidic acid have not been conducted, there have

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

treatment with fusidic acid is necessary, statin treatment should be discontinued throughout the

duration of the fusidic acid treatment (see section 4.3 and 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 (see section 4.4).

Effects of other medicines on atorvastatin

following

drugs

have

been

shown

have

effect

pharmacokinetics

pharmacodynamics of atorvastatin:

Antacid

Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides

with atorvastatin decreased atorvastatin plasma concentrations approximately 35%, however, LDL-

C reduction was not altered.

Colestipol

Plasma concentrations of atorvastatin were lower (approximately 25%) when colestipol and

atorvastatin were co-administered. However, LDL-C reduction was greater when atorvastatin and

colestipol were co-administered than when either drug was given alone.

Transporter inhibitors

Atorvastatin is a substrate of the hepatic transporters (see section 5.2)

Concomitant administration of atorvastatin 10 mg and ciclosporin 5.2 mg/kg/day resulted in an

increase in exposure to atorvastatin (ratio of AUC: 8.7). Ciclosporin is an inhibitor of organic anion-

transporting polypeptide 1B1 (OATP1B1), OATP1B3, multi-drug resistance protein 1 (MDR1), and

breast cancer resistance protein (BCRP) as well as CYP3A4, thus it increases exposure to

atorvastatin. Do not exceed 10 mg atorvastatin daily) (see section 4.2).

Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they

increase exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see section 4.2).

Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase

in exposure to atorvastatin (ration of AUC: 3.29). Letermovir inhibits efflux transporters P-gp, BCRP,

MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do

not exceed 20 mg atorvastatin daily (see section 4.2).

The magnitude of CYPA3A- and OATP1B1/1B3-mediated drug interactions on co-administered

drugs may be different when letermovir is co-administered with ciclosporin. Use of atorvastatin is not

recommended in patients taking letermovir co-administered with ciclosporin.

Page 7 of 21

Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they

increase exposure to atorvastatin. Use with caution and lowest dose necessary (see section 4.2).

Erythromycin/clarithromycin

In healthy individuals, co-administration of atorvastatin (10 mg QD) and erythromycin (500 mg QID),

or clarithromycin (500 mg BID), known inhibitors of cytochrome P450 3A4, was associated with

higher plasma concentrations of atorvastatin (see section 4.4).

Protease inhibitors

Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4,

was associated with increased plasma concentrations of atorvastatin (see section 4.4).

Diltiazem hydrochloride

Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma

concentrations of atorvastatin.

Itraconazole

Concomitant administration of atorvastatin (20 to 40 mg) and itraconazole (200 mg) was associated

with an increase in atorvastatin AUC.

Ticagrelor

Co-administration of atorvastatin (80 mg) and ticagrelor (90 mg twice a day) increased atorvastatin

acid C

by 23% and AUC by 36%.

Grapefruit juice

Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of

atorvastatin, especially with excessive grapefruit juice consumption (> 1.2 L per day).

Effect of atorvastatin on other medicines

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

by atorvastatin.

Digoxin

When multiple doses of digoxin (0.25 mg QD) and 10 mg atorvastatin were co-administered,

steady-state plasma digoxin concentrations were unaffected. However, steady-state plasma digoxin

concentrations increased by approximately 20% following administration of digoxin with 80 mg

atorvastatin daily. Patients taking digoxin should be monitored appropriately.

Oral contraceptives

Co-administration of atorvastatin with an oral contraceptive containing norethisterone and ethinyl

oestradiol increased AUC values for norethisterone and ethinyl oestradiol by approximately 30% and

20%. These increases should be considered when selecting an oral contraceptive for a woman

taking atorvastatin.

Medicines shown not to interact with atorvastatin

Cimetidine

Atorvastatin plasma concentrations and LDL-C reduction were not altered by co-administration of

cimetidine.

Warfarin

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients

receiving chronic warfarin treatment.

Page 8 of 21

Amlodipine

In a drug-drug interaction study in healthy subjects, co-administration of atorvastatin 80 mg and

amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin which was not clinically

meaningful.

Azithromycin

Co-administration of atorvastatin 10 mg daily and azithromycin (500 mg QD) did not alter the plasma

concentrations of atorvastatin.

Antipyrine

Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other

drugs metabolised via the same cytochrome isozymes are not expected.

Other concomitant therapy

In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and oestrogen

replacement therapy without evidence of clinically significant adverse interactions. Interaction

studies with specific agents have not been conducted.

Effects on laboratory tests

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

phosphokinase.

4.6

Fertility, pregnancy and lactation

Pregnancy (Category D)

The definition of Pregnancy Category D is drugs which have caused, are suspected to have caused

or may be expected to cause, an increased incidence of human foetal malformations or irreversible

damage. These drugs may also have adverse pharmacological effects.

Atorvastatin

is

contraindicated

in

pregnancy.

Atherosclerosis

chronic

process

discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of

long-term therapy of primary hypercholesterolaemia. Cholesterol and other products of cholesterol

biosynthesis are essential components for foetal development (including synthesis of steroids and

cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly

the synthesis of other biologically active substances derived from cholesterol, they may cause foetal

harm when administered to pregnant women. Atorvastatin should be administered to women of

childbearing age only when such patients are highly unlikely to conceive and have been informed of

the potential. If the patient becomes pregnant while taking this drug, therapy should be discontinued

and the patient apprised of the potential hazard to the foetus (see section 4.3).

Atorvastatin crosses the rat placenta and reaches a level in foetal liver equivalent to that in maternal

plasma. Animal reproduction studies showed no evidence of teratogenic activity in rats or rabbits at

oral doses up to 300 mg/kg/day and 100 mg/kg/day respectively. Increased post-implantation loss,

decreased

foetal

weight

increased

skeletal

variations

were

observed

rats

dosed

100-300 mg/kg/day and rabbits dosed at 50-100 mg/kg/day. In a peri/post natal study, rats dosed at

225 mg/kg/day showed an increased incidence of stillbirths, decreases in birthweight, an increased

incidence

dilated

renal

pelvis,

increased

postnatal

mortality,

suppression

growth,

retardation of physical development and abnormal behavioural development; some of these effects

were also observed at the non-maternotoxic dose of 100 mg/kg/day; the plasma AUC for HMG-CoA

reductase inhibitory activity at the no effect dose level of 20 mg/kg/day was similar to that in humans

dosed at 80 mg/day.

HMG-CoA reductase inhibitors are contraindicated in pregnancy. The risk of foetal injury outweighs

the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.

Page 9 of 21

In two series of 178 and 143 cases where pregnant women took a HMG-CoA reductase inhibitor

(statin) during the first trimester of pregnancy serious foetal abnormalities occurred in several cases.

These included limb and neurological defects, spontaneous abortions and foetal deaths. The exact

risk of injury to the foetus occurring after a pregnant woman is exposed to HMG-CoA reductase

inhibitor has not been determined. The current data do not indicate that the risk of foetal injury in

women exposed to HMG-CoA reductase inhibitors is high. If a pregnant woman is exposed to a

HMG-CoA reductase inhibitor she should be informed of the possibility of foetal injury and discuss

the implications with her pregnancy specialist.

Breast-feeding

It is not known whether this drug is excreted in human milk. In rats, plasma concentrations of

atorvastatin are similar to those in milk. Because of the potential for adverse effects in nursing infants,

women taking atorvastatin should not breast-feed (see section 4.3 and section 4.4).

Fertility

The effects of atorvastatin on spermatogenesis and human fertility have not been investigated in

clinical studies. Dietary administration of 100 mg atorvastatin/kg/day to rats caused a decrease in

spermatid concentration in the testes, a decrease in sperm motility and an increase in sperm

abnormalities. Similar effects, however, were not observed in male rats dosed by gavage to

175 mg/kg/day (plasma AUC for HMG-CoA reductase inhibitory activity 14 times higher than in

humans dosed at 80 mg/day) and male fertility was not affected in either study. No adverse effects

on fertility or reproduction were observed in female rats given doses up to 225 mg/kg/day (plasma

AUC for enzyme inhibitory activity 56 times higher than in humans dosed at 80 mg/day). Atorvastatin

caused no adverse effects on sperm or semen parameters, or on reproductive organ histopathology

in dogs given doses of 10, 40, or 120 mg/kg for 2 years (plasma AUC for enzyme inhibitory activity

13 times higher than in humans).

4.7

Effects on ability to drive and use machines

None known.

4.8

Undesirable effects

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

Clinical adverse events

In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin;

7,311 placebo), treated for a median period of 53 weeks, 5.2% of patients on atorvastatin

discontinued due to adverse reactions compared to 4.0% of the patients on placebo.

The most frequent (≥ 1%) adverse events that may be associated with atorvastatin therapy, reported

in patients participating in placebo-controlled clinical studies include:

Gastrointestinal disorders: dyspepsia, nausea, flatulence, diarrhoea.

Infections and infestations: nasopharyngitis.

Investigations: liver function test abnormal

, blood creatine phosphokinase increased.

Metabolism and nutrition disorders: hyperglycaemia.

Refers to the following preferred terms: hepatic enzyme increased, alanine aminotransferase

increased, aspartate aminotransferase increased, blood bilirubin increased, liver function test

abnormal and transaminases increased.

Page 10 of 21

Musculoskeletal

and

connective

tissue

disorders:

myalgia,

arthralgia,

pain

extremity,

musculoskeletal pain, muscle spasms, joint swelling.

Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, epistaxis.

Additional adverse events

The following have been reported in clinical trials of atorvastatin, however, not all the events listed

have been causally associated with atorvastatin therapy.

Common (≥ 1% and < 10%)

Gastrointestinal disorders: constipation.

Infections and infestations: urinary tract infection.

Nervous system disorders: headache.

Uncommon (≥ 0.1% and < 1%)

Ear and labyrinth disorders: deafness.

Eye disorders: vision blurred.

Gastrointestinal disorders: abdominal discomfort, abdominal pain, vomiting.

General disorders and administration site conditions: asthenia, malaise.

Infections and infestations: infection, influenza.

Metabolism and nutrition disorders: anorexia.

Musculoskeletal and connective tissue disorders: back pain, neck pain.

Nervous system disorders: paraesthesia.

Psychiatric disorders: insomnia, nightmare.

Reproductive system and breast disorders: erectile dysfunction.

Respiratory, thoracic and mediastinal disorders: asthma.

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria.

Rare (≥ 0.01% and <0.1%)

Ear and labyrinth disorders: tinnitus.

Gastrointestinal disorders: pancreatitis, eructation.

General disorders and administration site conditions: pyrexia.

Hepatobiliary disorders: hepatitis, cholestasis.

Immune system disorders: hypersensitivity (including anaphylaxis).

Infections and infestations: sinusitis, pharyngitis.

Injury, poisoning and procedural complications: injury.

Investigations: white blood cells urine positive.

Page 11 of 21

Metabolism and nutrition disorders: hypoglycaemia.

Musculoskeletal and connective tissue disorders: myositis, myopathy, muscle fatigue.

Nervous system disorders: peripheral neuropathy.

Skin subcutaneous tissue disorders: angioedema and alopecia.

A post-hoc analysis of a clinical study in patients without known coronary heart disease who had a

recent stroke or TIA, showed an increased risk of haemorrhagic stroke in patients with prior

haemorrhagic stroke or prior lacunar infarct (see section 4.4).

In a study (see section 5.1) involving 10,305 hypertensive participants treated with atorvastatin

10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated

with atorvastatin was comparable to that of the group treated with placebo during a median of 3.3

years of follow-up.

Another study (see section 5.1) included 2,838 patients with type 2 diabetes, and participants

received atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410). The overall incidence of adverse

events or serious adverse events in the atorvastatin treated group was similar to that of the placebo-

group following a median duration of treatment of 3.9 years.

Post-marketing experience

Rare adverse events that have been reported post-marketing which are not listed above, regardless

of causality, include the following:

Blood and lymphatic system disorders: thrombocytopenia.

General disorders and administration site conditions: chest pain, fatigue, peripheral oedema.

Hepatobiliary disorders: hepatic failure.

Injury, poisoning and procedural complications: tendon rupture.

Investigations: weight increased.

Musculoskeletal and connective tissue disorders: lupus-like syndrome, muscle rupture, immune

mediated necrotising myopathy, rhabdomyolysis which may be fatal

(see section 4.3, section 4.4

and section 4.5).

There

have

been

very

rare

reports

immune-mediated

necrotising

myopathy

(IMNM),

autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle

weakness and elevated serum creatine kinase, which persists despite discontinuation of statin

treatment;

muscle

biopsy

showing

necrotising

myopathy

without

significant

inflammation;

improvement with immunosuppressive agents (see section 4.4).

Nervous system disorders: hypoaesthesia, dizziness, amnesia, dysgeusia.

Reproductive system and breast disorders: gynaecomastia.

Skin

and

subcutaneous

tissue

disorders:

bullous

rashes

(including

erythema

multiforme,

Stevens-Johnson syndrome and toxic epidermal necrolysis).

Examples of signs and symptoms are muscle weakness, muscle swelling, muscle pain, dark urine,

myoglobinuria, elevated serum creatine kinase, acute renal failure and cardiac arrhythmia.

Page 12 of 21

The following adverse events have been reported with some statins: Exceptional cases of interstitial

lung disease, especially with long term therapy (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked

to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

There is no specific treatment for atorvastatin overdosage. Should an overdose occur, the patient

should be treated symptomatically, and supportive measures instituted as required. In symptomatic

patients, monitor serum creatinine, BUN, creatinine phosphokinase, and urine myoglobin for

indications of renal impairment secondary to rhabdomyolysis. Liver function tests should be

performed in symptomatic patients.

If there has been significant ingestion, consider administration of activated charcoal. Activated

charcoal is most effective when administered within 1-hour of ingestion. In patients who are not fully

conscious or have impaired gag reflex, consideration should be given to administering activated

charcoal via nasogastric tube once the airway is protected. For rhabdomyolysis, administer sufficient

0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Diuretics may be necessary to maintain urine

output. Urinary alkalinization is not routinely recommended. Due to extensive drug binding to plasma

proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.

For further advice on management of overdose please contact the National Poisons Information

Centre (0800 POISON or 0800 764 766).

5. Pharmacological Properties

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA reductase inhibitor.

ATC code: C10AA05.

Pharmacodynamic effects

Atorvastatin and its metabolites are responsible for pharmacological activity in humans. The liver is

its primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dose

rather than systemic drug concentration correlates better with LDL-C reduction. Individualisation of

drug dose should be based on therapeutic response (see section 4.2).

Mechanism of action

Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of HMG-CoA reductase,

the rate-limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a

precursor of sterols, including cholesterol. Triglycerides (TG) and cholesterol in the liver are

incorporated into very low density lipoprotein (VLDL) and released into the plasma for delivery to

peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolised primarily

through the high affinity LDL receptor.

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

cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-

surface to enhance uptake and catabolism of LDL. Atorvastatin reduces LDL production and the

number of LDL particles. Atorvastatin produces a marked and sustained increase in LDL receptor

activity coupled with a beneficial change in the quality of circulating LDL particles.

A variety of clinical and pathologic studies have demonstrated that elevated cholesterol and

lipoprotein levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C) and

apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing

Page 13 of 21

cardiovascular disease (CVD). Similarly, decreased levels of high density lipoprotein cholesterol

(HDL-C) are associated with the development of atherosclerosis. Epidemiological investigations

have established that cardiovascular morbidity and mortality vary directly with the level of total-C and

LDL-C and inversely with the level of HDL-C.

Atorvastatin reduces total-C, LDL-C, and apo B in both normal volunteers and in patients with

homozygous and heterozygous

FH, non-familial

forms of hypercholesterolaemia, and mixed

dyslipidaemia. Atorvastatin also reduces very low-density lipoprotein cholesterol (VLDL-C) and TG

and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin reduces total-C,

LDL-C, VLDL-C, apo B and TG, and increases HDL-C in patients with isolated hypertriglyceridaemia.

Atorvastatin

reduces

intermediate

density

lipoprotein

cholesterol

(IDL-C)

patients

with

dysbetalipoproteinaemia. In animal models, atorvastatin limits the development of lipid-enriched

atherosclerotic lesions and promotes the regression of pre-established atheroma.

5.2

Pharmacokinetic properties

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur

within 1 to 2 hours. A constant proportion of atorvastatin is absorbed intact. The absolute

bioavailability is 14%. The low systemic availability is attributed to pre-systemic clearance in

gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and

extent of drug absorption by approximately 25% and 9% respectively as assessed by C

and AUC,

LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin

concentrations

lower

(approximately

AUC)

following

evening

drug

administration compared with morning. However, LDL-C reduction is the same regardless of the time

of day of drug administration (see section 4.2).

Distribution

The mean volume of distribution of atorvastatin is approximately 381 litres. Atorvastatin is ≥ 98%

bound to plasma proteins. A red blood cell/plasma ratio of approximately 0.25 indicates poor drug

penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted

in human milk (see section 4.4).

Biotransformation

In humans, atorvastatin is extensively metabolised to ortho- and para-hydroxylated derivatives. In

vitro inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to

that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is

attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism

by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans

following co-administration with erythromycin, a known inhibitor of this isozyme (see section 4.4). In

animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Elimination

Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism;

however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination

half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for

HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2%

of a dose of atorvastatin is recovered in urine following oral administration.

Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter.

Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate

of the efflux transporters MDR1 and BCRP, which may limit the intestinal absorption and biliary

clearance of atorvastatin.

Special populations

Page 14 of 21

Elderly (≥ 65 years): Plasma concentrations of atorvastatin are higher (approximately 40% for C

and 30% for AUC) in healthy elderly subjects (age ≥ 65 years) than in young adults. Lipid effects are

comparable to that seen in younger patient populations given equal doses of atorvastatin.

Children and adolescents: Pharmacokinetic studies have not been conducted in the paediatric

population.

Gender: Plasma concentrations of atorvastatin in women differ (approximately 20% higher for C

and 10% lower for AUC) from those in men; however, there is no clinically significant difference in

lipid effects with atorvastatin between men and women.

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

atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary (see section

4.2 and section 4.4).

Haemodialysis: While studies have not been conducted in patients with end-stage renal disease,

haemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is

extensively bound to plasma proteins.

Hepatic impairment: Plasma concentrations of atorvastatin are markedly increased (approximately

16-fold in C

and 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh B)

(see section 4.2, section 4.3 and section 4.4).

Clinical trials

multicentre,

placebo-controlled,

double-blind

dose-response

study

patients

with

hypercholesterolaemia, atorvastatin was given as a single daily dose over 6 weeks. Atorvastatin (10-

reduced

total-C

(30%-46%),

LDL-C

(41%-61%),

apolipoprotein

(34%-50%)

triglycerides (14%-33%) while producing variable increases in HDL-C and apolipoprotein A (Table

1). A therapeutic response was seen within 2 weeks, and maximum response achieved within 4

weeks.

Table 1. Dose-response in Patients with Primary Hypercholesterolaemia

a

Atorvastatin

Dose (mg)

N

Total C

LDL-C

ApoB

TG

HDL-C

Placebo

-0.7

-2.5

10

-30.3

-41.0

-34.4

-14.2

20

-34.5

-44.3

-36.3

-33.2

12.1

40

-37.8

-49.7

-40.9

-24.9

-2.6

80

-45.7

-61.0

-50.3

-27.2

Adjusted mean % change from baseline

In three further trials, 1,148 patients with either heterozygous familial hypercholesterolaemia, non-

familial forms of hypercholesterolaemia, or mixed dyslipidaemia were treated with atorvastatin for

one year. The results were consistent with those of the dose response study and were maintained

for the duration of therapy.

In patients with primary hypercholesterolaemia and mixed dyslipidaemia (Fredrickson Types IIa and

IIb), data pooled from 24 controlled trials demonstrated that the adjusted mean percent increases

from baseline in HDL-C for atorvastatin (10-80 mg) were 5.0% to 7.8% in a non-dose-related manner.

Additionally, analysis of this pooled data demonstrated significant dose related decreases in total-

C/HDL-C and LDL-C/HDL-C ratios, ranging from -29% to -44% and -37% to -55%, respectively.

Clinical studies demonstrate that the starting dose of 10 mg atorvastatin is more effective than

simvastatin 10 mg, and pravastatin 20 mg in reducing LDL-C, total-C, TG and apo B.

Page 15 of 21

In several multicentre, double-blind studies in patients with hypercholesterolaemia, atorvastatin was

compared to other HMG-CoA reductase inhibitors. After randomisation, patients were treated with

atorvastatin 10 mg per day or the recommended starting dose of the comparative agent. At week 16

a greater proportion of atorvastatin treated patients than those treated with simvastatin (46% vs 27%)

or pravastatin (65% vs 19%) reached their target LDL-C levels. Increasing the dosage of atorvastatin

resulted in more patients reaching target LDL-C goals.

Coronary artery disease

In a randomised, parallel-group, open-label study, the effect of aggressive cholesterol lowering on

ischaemic events was assessed in a population referred for angioplasty (based on angiogram

showing at least 50% stenosis in 1 or more coronary arteries which had not previously been

subjected to interventional treatment). A total of 341 patients (aged 18-80 years) with asymptomatic

or mildly to moderately symptomatic coronary artery disease (Canadian Cardiovascular Society

class 1 or 2) with a LDL-C level of at least 3.0 mmol/L and a triglyceride level of no more than 5.6

mmol/L, in the absence of left main coronary or triple-vessel disease and congestive heart failure

(New York Heart Association classes III or IV), were randomised to either receive atorvastatin 80

mg/day or undergo angioplasty, with or without stents, followed by usual care (UC). Patients were

also excluded if they had an episode of unstable angina or a MI within the previous 2 weeks or an

ejection fraction < 40%. Lipid lowering therapy was included in UC, with 73% of patients in the

angioplasty/UC group receiving lipid lowering medication at some time during the trial. In both

treatment groups, approximately 80% of the patients had a history of hyperlipidaemia. After 18

months, atorvastatin 80 mg/day had a lower mean LDL-C plasma level than angioplasty/usual care

(1.98 mmol/L vs 3.07 mmol/L, p<0.05). Patients treated with atorvastatin who achieved reductions

in LDL-C values of > 40% experienced significantly fewer ischaemic events than patients whose

LDL-C values decreased by ≤ 40% (p=0.014).

Compared to the angioplasty/UC group, 36% fewer atorvastatin treated patients experienced

ischaemic events [22 (13%) vs 37 (21%); p=0.048 versus an adjusted significance level of 0.045]

(Table 2) and there was a significant delay in time to first cardiac ischaemic event (p=0.027) (Figure

1). The analysis of the occurrence of an ischaemic event was repeated after excluding coronary

artery bypass grafts and angioplasties that were not per protocol ("per-protocol" analysis). The per-

protocol analysis revealed that 48% fewer atorvastatin treated patients experienced ischaemic

events compared to the angioplasty/UC group (9% vs 18%; p=0.022).

Table 2. Number (%) of Patients who Experienced an Ischaemic Event

Ischaemic Event

Atorvastatin

N = 164

Angioplasty/UC

N = 177

Cardiac Death

1 (0.6%)

1 (0.6%)

Resuscitated Cardiac Arrest

0 (0.0%)

0 (0.0%)

Nonfatal Myocardial Infarction

4 (2.4%)

5 (2.8%)

Cardiovascular Accident

0 (0.0%)

0 (0.0%)

Coronary Artery Bypass Graft

2 (1.2%)

9 (5.1%)

Angioplasty

18 (11.0%)

21 (11.9%)

Worsening

Angina

with

Objective

Evidence

Resulting

Hospitalisation

11 (6.7%)

25 (14.1%)

Any Ischaemic Event

22 (13.4%)

37 (20.9%)

Page 16 of 21

Figure 1. Kaplan-Meier Curve of Time to First Ischaemic Event

Prevention of cardiovascular disease

In the lipid lowering arm of a cardiac outcomes trial, the effect of atorvastatin on the composite

endpoint of fatal coronary heart disease and non-fatal MI was assessed in 10,305 hypertensive

patients, 40-79 years of age, without a history of symptomatic coronary heart disease and with total-

C levels ≤ 6.5 mmol/L. Additionally patients were at moderate risk of coronary heart disease, having

at least 3 of the predefined cardiovascular risk factors [male gender (81%), age ≥ 55 years (84%),

smoking (33%), type 2 diabetes (25%), history of CHD in a first-degree relative (26%), plasma total-

C to HDL-C ratio ≥ 6 (14%), peripheral vascular disease (PVD) (5%), left ventricular hypertrophy

(LVH) on echocardiography (14%), past history of cerebrovascular event (10%), specific ECG

abnormality (14%), proteinuria/albuminuria (62%)]. Patients with a history of previous MI or angina

were excluded.

this

randomised,

double-blind,

placebo-controlled

study,

patients

were

treated

with

anti-

hypertensive therapy (Goal BP < 140/90 mmHg for non-diabetic patients, < 130/80 mmHg for

diabetic patients) and either atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137) and followed

for a median duration of 3.3 years. At baseline, in the atorvastatin group, 38 patients (0.7%) had

total-C levels less than 3.5 mmol/L; 2,340 patients (45.3%) had total-C levels greater than or equal

to 3.5 mmol/L and less than 5.5 mmol/L; 2,304 patients (44.6%) had total-C levels greater than or

equal to 5.5 mmol/L and less than 6.5 mmol/L; and 486 patients (9.4%) had total-C levels greater

than or equal to 6.5 mmol/L. At baseline, 457 patients (9.8%) in the atorvastatin group had LDL-C

levels less than or equal to 2.5 mmol/L; 1,731 patients (37%) had LDL-C greater than 2.5 mmol/L

and less than 3.4 mmol/L; and 2,495 patients (53.3%) had LDL-C levels greater than or equal to 3.4

mmol/L. Median (25th & 75th percentile) changes from baseline after 1 year of atorvastatin treatment

in total-C, LDL-C, TG and HDL-C were -1.40 mmol/L (-1.80, -0.90), -1.27 mmol/L (-1.66, -0.84), -

0.20 mmol/L (-0.60, 0.10) and 0.00 mmol/L (-0.10, 0.10). Blood pressure control throughout the trial

was similar in patients assigned to atorvastatin and placebo.

Atorvastatin significantly reduced the rate of coronary events (fatal coronary heart disease and

nonfatal MI) by 36% [154 events in the placebo group vs. 100 events in the atorvastatin group,

p=0.0005 (see Table 3)]. A reduction in coronary events emerged in the first year of follow up. The

risk reduction was consistent across baseline total-C levels, age, smoking status, obesity, presence

of LVH, previous PVD, presence of diabetes, renal dysfunction or presence of metabolic syndrome.

Page 17 of 21

Table 3. Summary of Risk Reductions in Primary Prevention Patients

Endpoint

Atorvastatin

10mg

N (%)

Placebo

N (%)

Absolute Risk

Reduction*

% (95% CI)

Number

Needed

to Treat

Per Year

Relative

Risk

Reduction

% (95% CI)

P

value

Primary

Fatal CHD and

nonfatal MI

100 (1.9%)

154 (3.0%)

1.07 (0.47 to 1.67)

310.5

36 (17 to 50)

0.0005

Secondary

Total

cardiovascular

events including

revascularisation

procedures

389 (7.6%)

483 (9.5%)

1.9 (0.80 to 2.96)

176.0

20 (9 to 30)

0.0008

Total coronary

events

178 (3.5%)

247 (4.8%)

1.4 (0.60 to 2.14)

241.9

29 (14 to 41)

0.0006

Fatal and nonfatal

stroke

89 (1.7%)

119 (2.3%)

0.6 (0.05 to 1.14)

555.2

26 (2 to 44)

0.0332

Non-fatal MI

(excludes silent

MI) and fatal CHD

86 (1.7%)

137 (2.7%)

1.0 (0.42 to 1.56)

329.1

38 (19 to 53)

0.0005

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

Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level

(p=0.01), a favourable trend was observed with a 26% relative risk reduction.

The primary endpoint examined in this study was the rate of fatal coronary heart disease or non-fatal

MI over 3.3 years. These coronary events occurred in 1.9% of atorvastatin-treated patients

compared with 3% of placebo-treated patients, a relative risk reduction of 36% (p=0.0005) (Table 3).

Although this difference was statistically significant for the whole trial population, this difference was

not statistically significant in specified subgroups such as diabetes, patients with LVH, PVD or

metabolic syndrome.

There was no statistically significant reduction in the rate of total mortality, cardiovascular mortality

or heart failure in the atorvastatin-treated group compared to placebo.

In another study, the effect of atorvastatin on fatal and non-fatal coronary and cerebrovascular

disease was assessed in 2,838 patients with type 2 diabetes aged 40 - 75 years, without prior history

of cardiovascular disease and with LDL < 4.14 mmol/L and TG < 6.78 mmol/L. Additionally, all

patients had at least one of the following risk factors: hypertension, current smoking, retinopathy,

microalbuminuria or macroalbuminuria.

In this randomized, double blind, multicentre, placebo-controlled trial, 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.

This study was terminated 2 years earlier than anticipated when the analysis of the primary efficacy

parameter

reached

pre-specified

significance

level

(p<0.0005,

one-sided)

favour

atorvastatin.

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

Page 18 of 21

Table 4. Summary of Risk Reductions in Primary Prevention Patients

Endpoint

Number of Patients

with Endpoint (%)

Absolute

Risk

Reduction

a

% (95% CI)

Number

Needed to

Treat per

Year

Hazard

Ratio

% (95%

CI)

P

value

Atorvastatin

10 mg

Placebo

Primary

Major cardiovascular

events (fatal and nonfatal

AMI, silent MI, CHD death,

unstable angina, CABG,

PTCA, revascularisation,

stroke)

83 (5.8)

127 (9.0)

(1.3 to 5.1)

0.63

(0.48 to

0.83)

0.0010

MI (fatal and nonfatal AMI

infarction, silent MI)

38 (2.7)

64 (4.5)

(0.5 to 3.2)

0.58

(0.39 to

0.86)

0.0070

Stroke (fatal and nonfatal)

21 (1.5)

39 (2.8)

(0.2 to 2.4)

0.52

(0.31 to

0.89)

0.0163

Secondary

Death due to all causes

61 (4.3)

82 (5.8)

1.5 (0.0, 3.2)

0.73

(0.52 to

1.01)

0.0592

Based on difference in crude event rates occurring over a median follow-up of 4.0 years.

There was no evidence of a difference in the primary efficacy treatment effect by patient's gender,

age, or baseline LDL-C level.

Type 2 diabetes

A 26 week randomised, double blind, comparator study in type 2 diabetic subjects showed that

atorvastatin is effective in dyslipidaemic patients with type 2 diabetes. A 10 mg dose of atorvastatin

produced a 34% reduction in LDL-C, 27% reduction in total-C, a 24% reduction in TG and a 12%

rise in HDL-C.

Homozygous familial hypercholesterolaemia

Atorvastatin has also been shown to reduce LDL-C in patients with homozygous FH, a population

that has not usually responded to other lipid-lowering medication. In an uncontrolled compassionate-

use study, 29 patients aged 6 to 37 years with homozygous FH received maximum daily doses of

20 mg to 80 mg of atorvastatin. The mean LDL reduction in this study was 18%. 25 patients with a

reduction in LDL-C had a mean response of 20% (range 7%-53%, median 24%). 5 of the 29 patients

had absent LDL-receptor function, three of whom responded to atorvastatin with a mean LDL-C

reduction of 22%. Experience in paediatric patients has been limited to patients with homozygous

Hypertriglyceridaemia

In patients with hypertriglyceridaemia (baseline TG ≥ 2.26 mmol/L and LDL-C <4.14 mmol/L)

atorvastatin (10 to 80 mg) reduced serum triglycerides by 31% to 40%.

In patients with severe hypertriglyceridaemia (baseline TG > 5.7 mmol/L), atorvastatin (10 to 80 mg)

reduced serum triglycerides by 30% to 56%.

randomised,

placebo-controlled,

double-blind,

multicentre

study

patients

with

hypertriglyceridaemia (TG ≥ 3.95 mmol/L, LDL-C ≤ 4.1 mmol/L), atorvastatin 20 mg/day and 80

mg/day produced significantly greater reductions in triglyceride levels than placebo (Table 5).

Page 19 of 21

Table 5. Efficacy in patients with hypertriglyceridaemia

a

Atorvastatin

Dose (mg)

N

TG

Total-C

LDL-C

VLDL-C

ApoB

HDL-C

Placebo

-5.3

+0.3

+1.4

-2.0

+2.7

+2.4

20

-33.6*

-33.1*

-31.1*

-46.0*

-32.7*

+10.6

80

-42.4*

-41.3*

-36.1*

-54.2*

-38.7*

+11.8*

Adjusted mean % change from baseline

*significantly different from placebo, p<0.05

Dysbetalipoproteinaemia

In patients with dysbetalipoproteinaemia, atorvastatin (10 to 80 mg) reduced intermediate density

lipoprotein (IDL-C) (range 28% to 52%) and IDL-C + VLDL-C (range 34% to 58%).

In an open-label, randomised, cross-over study in patients with dysbetalipoproteinaemia, treatment

with atorvastatin 80 mg/day resulted in significantly greater mean percent decreases in IDL-C +

VLDL-C, IDL-C, total-C, VLDL-C and Apo B than either simvastatin 40 mg/day or gemfibrozil 1200

mg/day and significantly greater mean percent decreases in triglycerides than simvastatin 40 mg/day

(Table 6).

Table 6. Efficacy in patients with dysbetalipoproteinaemia

a b

Treatment

N

IDL-C+VLDL-C

IDL-C

Total-C

TG

VLDL-C

ApoB

HDL-C

Atorvastatin

10 mg/day

]Atorvastatin

80 mg/day

Gemfibrozil

1200 mg/day

-33*

-13*+

-34*

-52+

-35*

-53*

Simvastatin

40 mg/day

-28*

-27*

-41*

-36*

-26*

-52*

Adjusted mean % change from baseline

Comparisons other than atorvastatin 80 mg/day versus simvastatin 40 mg/day were ad hoc

*significantly different from atorvastatin 80 mg/day, p<0.05

+significantly different from atorvastatin 10 mg/day, p<0.05

5.3

Preclinical safety data

Genotoxicity

Atorvastatin did not demonstrate mutagenic or clastogenic potential in an appropriate battery of

assays. It was negative in the Ames test with Salmonella typhimurium and Escherichia coli, and in

the in vitro hypoxanthine-guanine phosphoribosyltransferase (HGPRT) forward mutation assay in

Chinese hamster lung cells. Atorvastatin did not produce significant increases in chromosomal

aberrations in the in vitro Chinese hamster lung cell assay and was negative in the in vivo mouse

micronucleus test.

Carcinogenicity

In a 2-year study in rats given 10, 30 or 100 mg/kg/day, the incidence of hepatocellular adenoma

was marginally, although not significantly, increased in females at 100 mg/kg/day. The maximum

dose used was 11 times higher than the highest human dose (80 mg/kg) based on AUC (0-24)

values. In a 2-year study in mice given 100, 200 or 400 mg/kg, incidences of hepatocellular adenoma

in males and hepatocellular carcinoma in females were increased at 400 mg/kg. The maximum dose

used was 14 times higher than the highest human dose (80 mg/kg) based on AUC (0-24) values.

Page 20 of 21

Other HMG-CoA reductase inhibitors have been reported to induce hepatocellular tumours in mice

and rats.

6. Pharmaceutical Particulars

6.1

List of excipients

colloidal anhydrous silica

sodium carbonate

microcrystalline cellulose

L-arginine

lactose

croscarmellose sodium

hydroxypropyl cellulose

magnesium stearate

opadry AMB White OY-B-28920 (containing titanium dioxide, talc, xanthan gum, polyvinyl

alcohol and soya lecithin).

opadry II white 85F18378 (containing polyvinyl alcohol – part hydrolysed, titanium dioxide,

macrogol and talc)

Lorstat tablets may be coated with either Opadry AMB White OY-B-28920 or Opadry II white

85F18378.

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years for HDPE bottle and OPA/Al/PVC/Al cold form blister packs.

2 years for Aclar/Al/PVC blister pack.

6.4

Special precautions for storage

Store at or below 25°C. Protect from light and moisture.

6.5

Nature and contents of container

HDPE bottle with a child-resistant closure. Pack-sizes of 90 or 500 film-coated tablets.

OPA/Al/PVC/Al cold form blister strip in cardboard outer carton. Pack size of 10 or 30 film-coated

tablets.

Aclar/Al/PVC blister strip in cardboard carton. Pack size of 10 or 30 film-coated tablets.

Not all pack types and sizes may be marketed.

6.6

Special precautions for disposal

Not applicable.

7. Medicines Schedule

Prescription Medicine

Page 21 of 21

8. Sponsor Details

Mylan New Zealand Ltd

PO Box 11-183

Ellerslie

AUCKLAND

Customer Services Freephone: 0800 579 811

9. Date of First Approval

16 July 2015

10. Date of Revision of the Text

4 May 2021

Sections

4.4, 4.5

Safety update for interaction with HCV NS5A/NS5B inhibitors.

Minor editorial update.

Removed gluten free statement.

Sponsor contact phone number updated.

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