ATORVASTATIN ACTAVIS 10 atorvastatin (as calcium) 10 mg film-coated tablet blister pack

Main information

  • Trade name:
  • ATORVASTATIN ACTAVIS 10 atorvastatin (as calcium) 10 mg film-coated tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATORVASTATIN ACTAVIS 10 atorvastatin (as calcium) 10 mg film-coated tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 185027
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

185027

ATORVASTATIN ACTAVIS 10 atorvastatin (as calcium) 10 mg film-coated tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Medis Pharma Pty Ltd

Postal Address

PO Box 6127,North Sydney, NSW, 2059

Australia

ARTG Start Date

3/08/2012

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. ATORVASTATIN ACTAVIS 10 atorvastatin (as calcium) 10 mg film-coated tablet blister pack

Product Type

Single Medicine Product

Effective date

26/06/2015

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Atorvastatin is indicated as an adjunct to diet for the treatment of patients with hypercholesterolaemia.,Prior to initiating therapy with atorvastatin,

secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive

liver disease, other drug therapy and alcoholism) should be identified and treated.,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 to reduce the risk of nonfatal myocardial infarction and nonfatal stroke.,These effects do not replace the need to independently control known

causes of cardiovascular mortality and morbidity such as hypertension, diabetes and smoking.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

Al/Al

2 Years

Store below 25

degrees Celsius

Not recorded

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. ATORVASTATIN ACTAVIS 10 atorvastatin (as calcium) 10 mg film-coated tablet blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

oval, white, biconvex tablet, embossed with 10 on one side and A on the

other side

Active Ingredients

Atorvastatin calcium

10.36 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 03:55:37 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Atorvastatin Actavis – Product information

Page 1 of 20

AUSTRALIAN PRODUCT INFORMATION - ATORVASTATIN ACTAVIS

(ATORVASTATIN CALCIUM)

1.

NAME OF THE MEDICINE

Atorvastatin Calcium.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

ATORVASTATIN ACTAVIS tablets come in four strengths and contain 10 mg, 20 mg, 40 mg or 80 mg

of atorvastatin (calcium). The 10 mg, 20 mg and 40 mg tablets also contain: mannitol,

microcrystalline cellulose, crospovidone, sodium carbonate anhydrous, povidone, methionine,

magnesium

stearate,

Opadry

White

03F28466

(107577).

tablets

also

contain

microcrystalline

cellulose,

crospovidone,

sodium

carbonate

anhydrous,

povidone,

glycerol

dibehenate, magnesium stearate and Opadry white 03F28446 (107577). The tablets are gluten

free.

3.

PHARMACEUTICAL FORM

ATORVASTATIN ACTAVIS 10

Atorvastatin (as calcium) 10 mg; oval, white, biconvex tablet,

embossed with ‘10’ on one side and A on the other side.

ATORVASTATIN ACTAVIS 20

Atorvastatin (as calcium) 20 mg; oval, white, biconvex tablet,

embossed with ‘20’ on one side and A on the other side.

ATORVASTATIN ACTAVIS 40

Atorvastatin (as calcium) 40 mg; oval, white, biconvex tablet,

embossed with ‘40’ on one side and A on the other side. .

ATORVASTATIN ACTAVIS 80

Atorvastatin (as calcium) 80 mg; oval, white, biconvex tablet,

embossed with ‘80’ on one side and A on the other side.

4.

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

Atorvastatin

indicated

adjunct

diet

treatment

patients

with

hypercholesterolaemia.

Prior to initiating therapy with atorvastatin, secondary causes of hypercholesterolaemia (e.g.

poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias,

obstructive liver disease, other drug therapy and alcoholism) should be identified and treated.

Hypertensive patients with multiple risk factors for CHD which may include diabetes, history of

stroke or other cerebrovascular disease, peripheral vascular disease or existing asymptomatic CHD

(see Section 5.1 PHARMACODYNAMIC PROPERTIES, Clinical Trials, Prevention of cardiovascular

disease) to reduce the risk of nonfatal MI and nonfatal stroke.

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

Atorvastatin Actavis – Product information

Page 2 of 20

Dosage and administration atorvastatin can be administered within the dosage range of 10 to

80 mg/day as a single daily dose. Atorvastatin 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 reanalysed within four weeks and dosage adjusted according

to the patient's response.

Primary hypercholesterolaemia and mixed dyslipidaemia

The majority of patients are controlled with atorvastatin 10 mg 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.

Homozygous familial hypercholesterolaemia

Adults

In the compassionate use study of patients with homozygous FH, most patients responded to

atorvastatin 80 mg with a greater than 15% reduction in LDL-C (18 to 42%).

Use in children

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

limited.

Use in 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 5.2 PHARMACOKINETIC

PROPERTIES and Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Use in hepatic impairment

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

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

atorvastatin

given

patients

with

hepatic

insufficiency

(see

Section

5.1

PHARMACODYNAMIC PROPERTIES, Section 4.3 CONTRAINDICATIONS and Section 4.4 SPECIAL

WARNINGS AND PRECAUTIONS FOR USE).

Use in combination with other medicinal compounds

In cases where co-administration of atorvastatin with cyclosporine, telaprevir, or the combination

tipranavir/ritonavir is necessary, the dose of atorvastatin should not exceed 10 mg. Caution

should be used when co-prescribing atorvastatin with medical compound 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 (see Section 4.4 SPECIAL

WARNINGS AND PRECAUTIONS FOR USE, Skeletal muscle and Section 4.5 INTERACTIONS WITH

OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).

4.3

CONTRAINDICATIONS

Known hypersensitivity to any of the ingredients.

Patients with active liver disease, or unexplained persistent elevations in serum transminases (see

Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Pregnancy and lactation (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Women of childbearing potential unless on an effective contraceptive and highly unlikely to

conceive.

Concomitant use with fusidic acid (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR

USE).

Atorvastatin Actavis – Product information

Page 3 of 20

Concomitant use with the hepatitis C antivirals glecaprevir/pibrentasvir (see Section 4.4 SPECIAL

WARNINGS AND PRECAUTIONS FOR USE).

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Liver effects

As with other lipid lowering agents of the same class, moderate (> 3 times upper limit of normal

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

Persistent increases in serum transaminases greater than three times 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

pretreatment 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. (see Section 4.2 Special Patient Populations, DOSE

AND METHOD OF ADMINISTRATION). Active liver disease or unexplained persistent transaminase

elevations

contraindications

atorvastatin

(see

Section

CONTRAINDICATIONS).

Skeletal muscle

Uncomplicated myalgia has been reported in atorvastatin treated patients (see Section 4.8

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)). Myopathy, defined as muscle aching or muscle

weakness in conjunction with increases in creatine kinase (CK) values > 10 x ULN, should be

considered in any patient with diffuse myalgias, muscle tenderness or weakness and/or marked

elevation of CK. 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 CK levels occur or myopathy is diagnosed or

suspected.

The risk of myopathy during treatment with other drugs in this class is increased with concurrent

administration of cyclosporin, fibric acid derivatives, erythromycin, niacin (nicotinic acid), azole

antifungals,

colchincine,

hepatistis

protease

inhibitors

(e.g.

telaprevir,

boceprevir,

elbasvir/prazoprevir) or the combination of tioranavir/ritonavir. Doctors considering combined

therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs,

azole antifungals or lipid lowering doses of niacin (nicotinic acid) 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 maintenance

doses

atorvastatin

should

also

considered

when

taken

concomitantly

with

aforementioned drugs.

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

concomitant fusidic acid and statins (see Section 4.3 CONTRAINDICATIONS and Section 4.5

INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS). In patients

where the use of systemic fusidic acid is considered essential, statin treatment should be

discontinued thoughout 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 re-introduced seven days after the last dose of fusidic acid.

Atorvastatin Actavis – Product information

Page 4 of 20

Periodic creatine kinase (CK) determinations may be considered in such situations, although there

is no assurance that such monitoring will prevent the occurance of severe myopathy (see Section

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

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).

Immune-mediated necrotizing myopathy

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

after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle

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

treatment.

Haemorrhagic stroke

A posthoc analysis of a clinical study (SPARCL) in patients without known CHD who had a recent

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

patients on atorvastatin 80 mg (55/2,365, 2.3%) compared to placebo (33/2,366, 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 versus 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 versus 4.2% for placebo, hazard ratio (HR) 4.06;

95% confidence interval (CI) 0.84 to 19.57) or prior lacunar infarct (2.8% for atorvastatin versus

0.6% for placebo, HR 4.99; 95% CI 1.71 to 14.61). All cause mortality was also increased in these

patients with prior haemorrhagic stroke (15.6% for atorvastatin versus 10.4% for placebo) or prior

lacunar

infarct

(10.9%

atorvastatin

versus

9.1%

placebo).

potential

risk

haemorrhagic stroke should be carefully considered before initiating treatment with atorvastatin

in patients with recent (one to six months) stroke or TIA.

In 68% of patients who entered the study with neither a haemorrhagic stroke nor lacunar infarct,

the risk of haemorrhagic stroke on atorvastatin versus placebo was 2% versus 1.8% (large vessel),

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

Endocrine function

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 premenopausal women are unknown. Caution

should be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with other

drugs

that

decrease

levels

activity

endogenous

steroid

hormones,

e.g.

ketoconazole, spironolactone and cimetidine.

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase

inhibitors, including atorvastatin.

Interstitial lung disease

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

with

long

term

therapy

(see

Section

ADVERSE

EFFECTS

(UNDESIRABLE

EFFECTS)).

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.

Atorvastatin Actavis – Product information

Page 5 of 20

Before the treatment

Atorvastatin

should

prescribed

with

caution

patients

with

pre-disposing

factors

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 and special

populations including genetic subpopulations

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

clinical monitoring is recommended.

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

started.

Creatine kinase measurement

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

any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK

levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5

to 7 days later to confirm the results.

Whilst on treatment

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

accompanied by malaise or fever.

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

levels should be measured. If these levels are found to be significantly elevated (> 5 times

ULN), treatment should be stopped.

If muscular symptoms are severe and cause daily discomfort, even if the CK levels are

elevated to ≤ 5 x ULN, treatment discontinuation should be considered.

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

introduction of an alternative statin may be considered at the lowest dose and with close

monitoring.

Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x

ULN) occur, or if rhabdomyolysis is diagnosed or suspected.

Effect on ubiquinone levels (CoQ10)

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.

Paediatric use

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

80 mg/day for one year in eight patients with homozygous FH. No clinical or biochemical

abnormalities were reported in these patients.

Atorvastatin Actavis – Product information

Page 6 of 20

Use in the elderly

Treatment experience in adults aged ≥ 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.

Effects on laboratory tests

Atorvastatin can cause elevations in ALT/AST, alkaline phosphatase, γ-glutamyl transpeptidase

(GGT), bilirubin and creatine kinase.

4.5

INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS

Atorvastatin

metabolised

cytochrome

P450

substrate

hepatic

transporters,

organic

anion-transporting

polypeptide

(OATP1B1)

(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.

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

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

protease

inhibitors

(fosamprenavir

combinations

lopinavir/ritonavir,

darunavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir), hepatitis C protease inhibitors

(boceprevir, elbasvir/grazoprevir), clarithromycin and itraconazole.

Based on experience with other HMG-CoA reductase inhibitors caution should be exercised when

atorvastatin is administered with inhibitors of cytochrome P450 3A4 (e.g. cyclosporin, 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 cyclosporin, fibric acid derivatives, erythromycin, azole antifungals or niacin

(see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

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

hepatocyte

uptake

transporter

(OATP1B1)),

simultaneous

co-administration

atorvastatin with 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

risk

myopathy

including

rhabdomyolysis

increased

concomitant

administration of systemic fusidic acid and with statins. Co-administration of this combination

may cause increased plasma concentrations of both agents. The mechanism of this interaction

(whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown.

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

have

been

reports

rhabdomyolysis

(including

some

fatalities)

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 CONTRAINDICATIONS and

Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

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

Atorvastatin Actavis – Product information

Page 7 of 20

should be exercised when prescribing atorvastatin with colchicine (see Section 4.4 SPECIAL

WARNINGS AND PRECAUTIONS FOR USE).

Effects of other medicines

following

drugs

have

been

shown

have

effect

pharmacokinetics

pharmacodynamics of atorvastatin.

Antacids

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 and atorvastatin metabolites are substrates of the OATP1B1 transporter. Inhibitors

of the OATP1B1 (e.g. cyclosporin) can increase the bioavailability of atorvastatin. Concomitant

administration of atorvastatin 10 mg and cyclosporin 5.2 mg/kg/day resulted in an increase in

exposure to atorvastatin (see Section 4.2 DOSE AND METHOD OF ADMINISTRATION).

Erythromycin, clarithromycin

In healthy individuals, co-administration of atorvastatin (10 mg once daily) and erythromycin

(500 mg four times a day), or clarithromycin (500 mg twice daily), known inhibitors of cytochrome

P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Section 4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Protease inhibitors

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

3A4, was associated with increased plasma concentrations of atorvastatin.

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.

Grapefruit juice

Contains one or more components that inhibit cytochrome P450 3A4 and can increase plasma

concentrations

atorvastatin,

especially

with

excessive

grapefruit

juice

consumption

(> 1.2 L/day).

Effects of atorvastatin on other medicines.

The following medicines have been shown to have their pharmacokinetics or pharmacodynamics

affected by atorvastatin.

Digoxin

When

multiple

doses

digoxin

(0.25

once

daily)

atorvastatin

were

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

state plasma digoxin concentrations increased by approximately 20% following administration of

digoxin with atorvastatin 80 mg daily. Patients taking digoxin should be monitored appropriately.

Atorvastatin Actavis – Product information

Page 8 of 20

Oral contraceptives

Co-administration with an oral contraceptive containing norethindrone and ethinyloestradiol

increased AUC values for norethindrone and ethinyloestradiol 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.

Amlodipine

Atorvastatin pharmacokinetics were not altered by the co-administration of atorvastatin 80 mg

daily and amlodipine 10 mg daily at steady state. 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 once daily) did not alter

the plasma concentrations of atorvastatin.

Other concomitant therapy

clinical

studies,

atorvastatin

used

concomitantly

with

antihypertensive

agents

oestrogen replacement therapy without evidence of clinically significant adverse interactions.

Interaction studies with all specific agents have not been conducted.

4.6

FERTILITY, PREGNANCY AND LACTATION

Effects on Fertility

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

clinical studies. Dietary administration of atorvastatin 100 mg/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 two years (plasma AUC for enzyme

inhibitory activity 13 times higher than in humans).

Use in pregnancy (Category D)

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

Atorvastatin Actavis – Product information

Page 9 of 20

and possibly the synthesis of other biologically active substances derived from cholesterol, they

cause

foetal

harm

when

administered

pregnant

women.

Atorvastatin

should

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

fetus (see Section 4.3 CONTRAINDICATIONS).

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 and increased skeletal variations were observed in rats

dosed

mg/kg/day

rabbits

dosed

mg/kg/day.

perinatal/postnatal study, rats dosed at 225 mg/kg/day showed an increased incidence of

stillbirths, decreases in birthweight, an increased incidence of dilated renal pelvis, increased

postnatal

mortality,

suppression

growth,

retardation

physical

development

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.

In two series of 178 and 143 cases where pregnant women took an 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 fetus occurring after a pregnant woman is exposed to an 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 an HMG-CoA reductase inhibitor she should be informed of the possibility of foetal

injury and discuss the implications with her pregnancy specialist.

Use in lactation

It is not known if atorvastatin is excreted in human milk. In rats, plasma concentrations of

atorvastatin are similar to those in milk. Because of the potential for adverse reactions in

breastfeeding

infants,

women

taking

atorvastatin

should

breastfeed

(see

Section

CONTRAINDICATIONS and Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

The effects of this medicine on a person's ability to drive and use machines were not assessed as

part of its registration.

4.8

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

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

Clinical Adverse Events

atorvastatin

placebo-controlled

clinical

trial

database

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.

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Infections and infestations

Nasopharyngitis.

Investigations

Liver function test abnormal

, blood creatine phosphokinase increased.

Metabolism and nutrition disorders

Hyperglycaemia.

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, joint swelling.

Respiratory, thoratic 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

, tinnitus

Eye disorders

Vision blurred.

Gastrointestinal disorders

Abdominal discomfort, abdominal pain, vomiting, pancreatitis, eructation.

General disorders and administration site conditions

Asthenia, malaise.

Hepatobiliary disorders

Hepatitis

Infections and infestations

Infection, influenza.

Investigations

White blood cells urine positive.

Metabolism and nutrition disorders

Anorexia.

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.

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Musculoskeletal and connective tissue disorders

Back pain, neck pain, muscle fatigue

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, alopecia

Rare (≥0.01%) and (<0.1%)

Eye disorders

Visual disturbance

General disorders and administration site conditions

Pyrexia.

Hepatobiliary disorders

Cholestasis.

Immune system disorders

Hypersensitivity (including anaphylaxis).

Infections and infestations

Sinusitis, pharyngitis.

Injury, poisoning and procedural complications

Injury.

Metabolism and nutrition disorders

Hypoglycaemia.

Musculoskeletal and connective tissue disorders

Myositis, myopathy

Nervous system disorders

Peripheral neuropathy.

Skin and subcutaneous tissue disorders

Angioedema

A post-hoc analysis of a clinical study (SPARCL) 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 SPECIAL WARNINGS AND

PRECAUTIONS FOR USE).

In ASCOT (see Section 5.1 PHARMACODYNAMIC PROPERTIES, Clinical Trials, Prevention of

cardiovascular disease) involving 10,305 participants treated with atorvastatin 10 mg daily (n =

Atorvastatin Actavis – Product information

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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.

Post marketing, Experience.

Adverse events that have been reported post marketing (which are not listed above), regardless

of causality, include the following.

Uncommon (≥0.1% and <1%)

General disorders and administration site conditions

Chest pain, fatigue, peripheral oedema

Investigations

Weight increased

Nervous system disorders

Hypoaesthesia, dizziness, amnesia, dysgeusia

Rare (≥0.01% and <0.1%)

Blood and lymphatic system disorders

Thrombocytopenia.

Hepatobiliary disorders

Hepatic failure.

Injury, poisoning and procedural complications

Tendon rupture.

Musculoskeletal and connective tissue disorders

Immune mediated necrotising myopathy (frequency unknown), rhabdomyolysis which may be

fatal

(see Section 4.3 CONTRAINDICATIONS, Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS

FOR USE and Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS).

Reproductive system and breast disorders

Gynaecomastia

Skin and subcutaneous tissue disorders

Bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal

necrolysis).

Paediatric Population

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Common: Abdominal pain

Investigations

Common: Alanine aminotransferase increased, blood creatine phosphokinase increased

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.

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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 SPECIAL WARNINGS

AND PRECAUTIONS FOR USE).

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is important. It

allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-

problems.

4.9

OVERDOSE

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

should

treated

symptomatically

supportive

measures

instituted

required.

symptomatic

patients,

monitor

serum

creatinine,

blood

urea

nitrogen

(BUN),

creatinine

phosphokinase

urine

myoglobin

indications

renal

impairment

secondary

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

necessary to maintain urine output. Urinary alkalinisation is not routinely recommended. Due to

extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance

atorvastatin clearance.

For information on the management of overdose, contact the Poisons Information Centre on 13 11

26 (Australia).

5.

PHARMACOLOGICAL PROPERTIES

5.1

PHARMACODYNAMIC PROPERTIES

Mode 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-methylglutaryl 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 pathological studies have demonstrated that elevated cholesterol and

lipoprotein levels of total cholesterol (total-C), LDL cholesterol (LDL-C) and apolipoprotein B (apo

B) promote human atherosclerosis and are risk factors for developing cardiovascular disease.

Similarly, decreased levels of high density lipoprotein (HDL) cholesterol (HDL-C) are associated

with the development of atherosclerosis. Epidemiological investigations have established that

cardiovascular morbidity and mortality vary directly with the levels of total-C and LDL-C and

inversely with the level of HDL-C.

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

homozygous

heterozygous

familial

hypercholesterolaemia

(FH),

nonfamilial

forms

hypercholesterolaemia and mixed dyslipidaemia. Atorvastatin also reduces very low density

lipoprotein

cholesterol

(VLDL-C)

produces

variable

increases

HDL-C

apolipoprotein A-1 (apo A-1). Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B and TG, and

increases

HDL-C

patients

with

isolated

hypertriglyceridaemia.

Atorvastatin

reduces

intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinaemia. In

animal models, atorvastatin limits the development of lipid enriched atherosclerotic lesions and

promotes the regression of pre-established atheroma.

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 DOSE AND

METHOD OF ADMINISTRATION).

Clinical Trials

multicentre,

placebo

controlled,

double

blind

dose

response

study

patients

with

hypercholesterolaemia, atorvastatin was given as a single daily dose over six weeks. Atorvastatin

(10 to 80 mg) reduced total-C (30 to 46%), LDL-C (41 to 61%), apo B (34 to 50%) and TGs (14 to

33%) while producing variable increases in HDL-C and apo A (see Table 1). A therapeutic response

was seen within two weeks and maximum response was achieved within four weeks.

Table 1: Dose-Response in Patients with primary hypercholesterolaemia

#

Atorvastatin

dose (mg)

N

Total-C

LDL-C

Apo B

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

124.9

-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,

nonfamilial

forms

hypercholesterolaemia

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 to 80 mg) were 5.0 to 7.8% in a non-dose

related manner.

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

simvastatin 10 mg and pravastatin 20 mg in reducing LDL-C, total-C, TG and apo B. 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/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 versus 27%) or pravastatin (65 versus 19%) reached their target LDL-C levels. Increasing the

dosage of atorvastatin resulted in more patients reaching target LDL-C goals.

Prevention of cardiovascular disease

In the lipid lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of

atorvastatin (calcium) on the composite endpoint of fatal coronary heart disease (CHD) and

nonfatal myocardial infarction (MI) was assessed in 10,305 hypertensive patients, 40 to 79 years

of age, without a history of symptomatic CHD and with total-C levels ≤ 6.5 mmol/L. Additionally

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patients were at moderate risk of CHD, having at least three of the predefined cardiovascular risk

factors (male gender (81%), age ≥ 55 years (84%), smoking (33%), noninsulin dependent diabetes

mellitus (25%), history of CHD in a first degree relative (26%), plasma total-C to HDL-C ratio ≥ 6

(14%), peripheral vascular disease (5%), left ventricular hypertrophy on echocardiography (14%),

past history of cerebrovascular event (10%), specific electrocardiogram (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

antihypertensive therapy (goal BP < 140/90 mmHg for nondiabetic 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 < 3.5 mmol/L; 2,340 patients (45.3%) had total-C levels ≥ 3.5 mmol/L

and < 5.5 mmol/L; 2,304 patients (44.6%) had total-C levels ≥ 5.5 mmol/L and < 6.5 mmol/L; and

486 patients (9.4%) had total-C levels ≥ 6.5 mmol/L. At baseline, 457 patients (9.8%) in the

atorvastatin group had LDL-C levels ≤ 2.5 mmol/L; 1,731 patients (37%) had LDL-C > 2.5 mmol/L

and < 3.4 mmol/L; and 2,495 patients (53.3%) had LDL-C levels ≥ 3.4 mmol/L. Median (25th and

75th percentile) changes from baseline after one 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.

Table 2: Summary of Risk Reductions in Primary Prevention Patients

Endpoint

Atorvastatin

10 mg

N (%)

Placebo

N (%)

Absolute Risk

Reduction

#

% (95% CI)

Number

Needed to

Treat

Per Year

Relative

Risk

Reduction

% (95% CI)

P Value

Primary

Fatal CHD

Non-fatal MI

100 (1.9)

(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)

(9.5)

(0.80 to 2.96)

176.0

20 (9 to 30)

0.0008

Total Coronary

Events

178 (3.5)

(4.8)

(0.60 to 2.14)

241.9

29 (14 to 41)

0.0006

Fatal and Non-fatal

Stroke*

89 (1.7)

(2.3)

(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)

(2.7)

(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

favourite trend was observed with a 26% relative risk reduction.

The primary endpoint examined in ASCOT was the rate of fatal CHD or nonfatal MI infarction over

3.3 years. These coronary events occurred in 1.9% of atorvastatin treated patients compared to

3% of placebo treated patients, a relative risk reduction of 36% (p = 0.0005) (Table 2). 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 left ventricular

hypertrophy (LVH), previous vascular disease 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.

Noninsulin dependent diabetes mellitus

A 26 week randomised, double blind, comparator study in noninsulin dependent diabetes mellitus

(NIDDM) subjects showed that atorvastatin is effective in dyslipidaemic patients with NIDDM. A

Atorvastatin Actavis – Product information

Page 16 of 20

dose of atorvastatin 10 mg produced a 34% reduction in LDL-C, 27% reduction in total-C, a 24%

reduction in TGs 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

usually

responded

other

lipid

lowering

medication.

uncontrolled

compassionate use study, 29 patients aged 6 to 37 years with homozygous FH received maximum

daily doses of atorvastatin 20 to 80 mg. 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 to 53%, median 24%).

Five of the 29 patients had absent LDL receptor function, three of whom responded

atorvastatin with a mean LDL-C reduction of 22%. Experience in paediatric patients has been

limited to patients with homozygous FH.

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 TG by 31 to 40%.

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

80 mg) reduced serum TG 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 and 80 mg/day

produced significantly greater reductions in TG levels than placebo (see Table 3).

Table 3: Efficacy in patients with Hypertriglyceridaemia

#

Atorvastatin

Dose

(mg)

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 IDL-C (range 28 to

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

open

label,

randomised,

crossover

study

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

1,200

mg/day

significantly

greater

mean

percent

decreases

than

simvastatin 40 mg/day (see Table 4).

Table 4: Efficacy in Patients with Dysbetalipoproeinaemia

#^

Treatment

N

IDL-C+VLDL-C

IDL-C

Total-C

TG

VLDL-C

Apo B

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

Atorvastatin Actavis – Product information

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5.2

PHARMACOKINETIC PROPERTIES

Absorption

Rapidly absorbed after oral administration; maximum plasma concentrations occur within one to

two hours. A constant proportion of atorvastatin is absorbed intact. The absolute bioavailability

is 14%. The low systemic availability is attributed to presystemic 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 Cmax and area under

the plasma concentration time curve (AUC), LDL-C reduction is similar whether atorvastatin is

given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for

Cmax and 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 DOSE

AND METHOD OF ADMINISTRATION).

Distribution

The mean volume of distribution of atorvastatin is about 400 L. 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 4.6 FERTILITY, PREGNANCY AND LACTATION, Use in

lactation).

Metabolism

In humans atorvastatin is extensively metabolised to o- and p-hydroxylated derivatives. In vitro

inhibition of HMG-CoA reductase by o- and p-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

cytochrome

P450

3A4,

consistent

with

increased

plasma

concentrations

atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this

isozyme (see Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS). In animals, the o-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.

Special populations

Elderly ≥ 65 years

Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC)

in healthy elderly subjects (≥ 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 Cmax 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 4.4 SPECIAL

WARNINGS

AND

PRECAUTIONS

FOR

USE

Section

4.2

DOSE

AND

METHOD

OF

ADMINISTRATION).

Atorvastatin Actavis – Product information

Page 18 of 20

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 Cmax and

11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B) (see Section 4.3

CONTRAINDICATIONS, Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE and Section

4.2 DOSE AND METHOD OF ADMINISTRATION).

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 phosphoribosyl transferase (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 two 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 eleven times higher than the highest human dose (80 mg/kg) based on

AUC (0 to 24) values. In a two 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 to 24) values. Other HMG-CoA reductase inhibitors have been

reported to induce hepatocellular tumours in mice and rats.

6.

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

Refer to Section 2 – QUALITATIVE AND QUANTITATIVE COMPOSITION.

6.2

INCOMPATIBILITIES

Incompatibilities were either not assessed or not identified as part of the registration of this

medicine. Refer to Section 4.5 – INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS.

6.3

SHELF LIFE

In Australia, information on the shelf life can be found on the public summary of the Australia

Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4

SPECIAL PRECAUTIONS FOR STORAGE

Store below 25°C in original container. Protect from light.

6.5

NATURE AND CONTENTS OF CONTAINER

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Page 19 of 20

ATORVASTATIN ACTAVIS 10

Atorvastatin (as calcium) 10 mg; oval, white, biconvex tablet,

embossed with ‘10’ on one side and A on the other side.

Al/Al blister packs of 10 and 30 tablets.

ATORVASTATIN ACTAVIS 20

Atorvastatin (as calcium) 20 mg; oval, white, biconvex tablet,

embossed with ‘20’ on one side and A on the other side.

Al/Al blister packs of 10 and 30 tablets.

ATORVASTATIN ACTAVIS 40

Atorvastatin (as calcium) 40 mg; oval, white, biconvex tablet,

embossed with ‘40’ on one side and A on the other side.

Al/Al blister packs of 10 and 30 tablets.

ATORVASTATIN ACTAVIS 80

Atorvastatin (as calcium) 80 mg; oval, white, biconvex tablet,

embossed with ‘80’ on one side and A on the other side.

Al/Al blister packs of 10 and 30 tablets and HDPE bottle packs

of 90 or 100 tablets.

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL

In Australia, any unused medicine or waste material should be disposed of in accordance with

local requirements.

6.7

PHYSICOCHEMICAL PROPERTIES

Atorvastatin calcium is a white to off-white powder, in either amorphous or crystalline form, that

is practically insoluble in aqueous solutions of pH 4 and below. It is very slightly soluble in

distilled water, pH 7.4 phosphate buffer and acetonitrile, slightly soluble in ethanol and freely

soluble in methanol.

The chemical name for atorvastatin calcium is[R-(R*,R*)]-2-(4-fluorophenyl)- β,δ-dihydroxy- 5-(1-

methylethyl)- 3-phenyl- 4-[(phenylamino)carbonyl]- 1H-pyrrole- 1-heptanoic acid, calcium salt.

Chemical Structure

Ca.3H

Molecular weight: 1,209.42

CAS No.: 344423-98-9

7.

MEDICINE SCHEDULE (POISONS STANDARD)

PRECRIPTION ONLY MEDICINES - S4

8.

SPONSOR

Medis Pharma Pty Ltd

Suite 1002, Level 10

Atorvastatin Actavis – Product information

Page 20 of 20

53 Walker Street,

North Sydney, NSW 2060

9.

DATE OF FIRST APPROVAL

3 August 2012

10.

DATE OF REVISION

17 May 2019

Summary table of changes

Section

changed

Summary of new information

Reformatted in line with the revised Australian form for providing

product information

4.4, 4.5

PI updated with additional safety changes in accordance with CCSI

Sponsor name an address updated