ATOSTAT atorvastatin (as calcium) 40mg tablet blister pack

Main information

  • Trade name:
  • ATOSTAT atorvastatin (as calcium) 40mg tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATOSTAT atorvastatin (as calcium) 40mg tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 194109
  • Last update:
  • 21-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

194109

ATOSTAT atorvastatin (as calcium) 40mg 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

8/05/2012

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. ATOSTAT atorvastatin (as calcium) 40mg tablet blister pack

Product Type

Single Medicine Product

Effective date

18/01/2013

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

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. . Atorvastatin 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 to reduce the risk of non-fatal myocardial infarction and non-fatal 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

24 Months

Store below 25

degrees Celsius

Not recorded

Store at room

temperature

Pack Size/Poison information

Pack Size

Poison Schedule

30 tablets

(S4) Prescription Only Medicine

Components

1. ATOSTAT atorvastatin (as calcium) 40mg tablet blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

white oval biconvex tablet with "40" on one side and "A" on reverse.

Active Ingredients

Atorvastatin calcium

41.44 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 28.11.2017 at 06:13:57 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

Atostat PI Dec 2018

AUSTRALIAN PRODUCT INFORMATION – ATOSTAT® (atorvastatin

calcium)

1.

NAME OF THE MEDICINE

Atorvastatin calcium

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

ATOSTAT tablets contain atorvastatin calcium equivalent to 10, 20, and 40 mg

atorvastatin. The tablets also contain the following inactive ingredients: Mannitol,

Microcrystalline cellulose, Crospovidone, Sodium carbonate anhydrous, Povidone,

Methionine, Magnesium stearate, Talc and Opadry 03F28446 White (ARTG 107577).

3.

PHARMACEUTICAL FORM

ATOSTAT is available in three strengths:

10 mg: white oval biconvex tablet with “10” on one side and “A” on reverse.

20 mg: white oval biconvex tablet with “20” on one side and “A” on reverse.

40 mg: white oval biconvex tablet with “40” on one side and “A” on reverse.

4.

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

ATOSTAT 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.

ATOSTAT 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 CLINICAL TRIALS, Prevention of Cardiovascular Disease) to reduce the risk of

non-fatal myocardial infarction and non-fatal 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

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ATOSTAT can be administered within the dosage range of 10–80 mg/day as a single

daily dose. ATOSTAT 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 Dyslipidaemia

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.

Homozygous Familial Hypercholesterolaemia

Adults: In the 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%-42%).

Children: Treatment experience in a paediatric population (with doses of atorvastatin

up to 80 mg/day) is limited.

Dosage in Patients with 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

PHARMAKINETIC PROPERTIES and Section 4.4. SPECIAL WARNINGS AND

PRECAUTIONS FOR USE).

Dosage in Patients with Hepatic Impairment

Hepatic Insufficiency: 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 5.1 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 cyclosporin is necessary, the

dose of atorvastatin should not exceed 10 mg (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

Hypersensitivity to any component of this medication.

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Active liver disease or unexplained persistent elevations of serum transaminases

(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 FOR USE and Section 4.5 INTERACTIONS WITH

OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).

Concomitant

with

hepatitis

antivirals

glecaprevir/pibrentasvir

(see

Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

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 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

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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,

azole antifungals, colchicine, hepatitis C protease inhibitors (e.g. telaprevir,

boceprevir, elbasvir/prazoprevir), or the combination of tipranavir/ritonavir. Physicians

considering combined therapy with atorvastatin and fibric acid derivatives,

erythromycin, immunosuppressive drugs, azole antifungals, 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 maintenance

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

aforementioned drugs.

Atorvastatin must not be co-administered with fusidic acid. There have been reports

of rhabdomyolsis (including some fatalities) in patients receiving this combination. In

patients where the use of systemic fusidic acid is considered essential, statin

treatment should be discontinued throughout the duration of fusidic acid treatment.

The patient should be advised to seek medical advice immediately if they experience

any symptoms of muscle weakness, pain or tenderness. Atorvastatin therapy may be

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

Periodic creatine kinase (CK) 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 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

rhabdomyolsis. Such patient 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 post-hoc analysis of a clinical study (SPARCL) in patients without known coronary

heart disease who had a recent stroke or 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

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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,

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 hemorrhagic 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 nor

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

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 are unknown. Caution should be exercised if

an HMG-CoA reductase inhibitor is administered concomitantly with other drugs that

may decrease the levels or activity of endogenous steroid hormones such as

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 4.8 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.

Before the treatment

Atorvastatin should be prescribed with caution in patients with pre-disposing factors

for rhabdomyolysis. A CK level should be measured before starting statin treatment

in the following situations:

Renal impairment

Hypothyroidism

Personal or familial history of hereditary muscular disorders

Previous history of muscular toxicity with a statin or fibrate

Previous history of liver disease and/or where substantial quantities of alcohol

are consumed

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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

increase

plasma

levels

occur,

such

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.

such

symptoms

occur

whilst

patient

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

elevated

ULN, treatment

discontinuation

should

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 (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 cholesterol in some patients may be blunted by raised Lp(a) levels.

Paediatric Use

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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.

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.

Effect on Laboratory Tests

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

and creatine kinase.

4.5

INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS

Atorvastatin is metabolised by cytochrome P450 3A4 and is a substrate of the

hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and

1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1.

Atorvastatin is also identified as a substrate of the multi-drug resistance protein 1

(MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal

absorption and biliary clearance of atorvastatin

.

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 been noted with HIV protease inhibitors

(fosamprenavir and combinations of 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 4.8 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 of hepatocyte uptake transporter

(OATP1B1), simultaneous co-administration of 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.

Atostat PI Dec 2018

Fusidic acid:

The risk of myopathy including rhabdomyolysis may be increased by

the concomitant administration of systemic fusidic acid 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 statins 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 Contraindications).

Colchicine: Although interaction studies with atorvastatin and colchicine have not

been conducted, cases of myopathy have been reported with atorvastatin co-

administered with colchicine, and caution should be exercised when prescribing

atorvastatin with colchicine.

Effect of Other Medicines on Atorvastatin

The following drugs have been shown to have an effect on the pharmacokinetics or

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 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.

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Grapefruit Juice: Contains one or more components that inhibit cytochrome P450

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 medicines have been shown to have their pharmacokinetics or

pharmacodynamics affected by atorvastatin:

Digoxin: When multiple doses of digoxin (0.25 mg once daily) 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 with an oral contraceptive containing

norethindrone and ethinyl oestradiol increased AUC values for norethindrone 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.

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 daily) did not alter the plasma concentrations of atorvastatin.

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

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 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

Atostat PI Dec 2018

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).

Use in 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 is a chronic

process and 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

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 at 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 of dilated renal pelvis,

increased postnatal mortality, suppression of pup 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.

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

Atostat PI Dec 2018

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.

Use in Lactation

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 reactions in nursing infants, women taking atorvastatin should not breast-

feed (see Section 4.3 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 effects have usually been mild and

transient. Less than 2% of patients were discontinued from clinical trials due to side

effects attributed to atorvastatin.

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

patients

participating

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.

Musculoskeletal and connective tissue disorders

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

swelling.

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.

Atostat PI Dec 2018

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.

Musculoskeletal and connective tissue disorders

Back pain, neck pain, muscle fatigue

Nervous system disorders

Paraesthesia.

Psychiatric disorders

Atostat PI Dec 2018

Insomnia, nightmare.

Reproductive system and breast disorders

Erectile dysfunction.

Respiratory, thoracic and mediastinal disorders

Asthma

Skin and subcutaneous tissue disorders

Rash, pruritus, urticarial, 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

recent

stroke

TIA,

showed

increased

risk

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=5,168) or placebo (n=5,137), the safety and

Atostat PI Dec 2018

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

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

above, regardless of causality, include the following:

Body as a Whole: allergic reactions (including anaphylaxis), chest pain, malaise,

fatigue

Musculoskeletal and connective tissue disorders: Immune mediated necrotising

myopathy,

rhabdomyolysis

which

fatal

(see

Section

CONTRAINDICATIONS, Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS

Section

INTERACTIONS

WITH

OTHER

MEDICINES

OTHER FORMS OF INTERACTIONS).

Nervous system disorders: hypoesthesia, dizziness, amnesia, dysgeusia

Ear and Labyrinth Disorders: tinnitus

Skin and Appendages: bullous rashes (including erythema multiforme, Stevens-

Johnson syndrome and toxic epidermal necrolysis), urticaria

Metabolic and Nutritional Disorders: peripheral oedema

Investigations: weight gain

Blood and lymphatic system disorders: thrombocytopenia

Hepatobiliary disorders: Hepatic failure

Injury, Poisoning and Procedural Complications: tendon rupture

Reproductive System and Breast Disorders: gynaecomastia.

Exceptional cases of interstitial lung disease adverse events have been reported with

some statins, 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

asked

report

suspected

adverse

reactions at www.tga.gov.au/reporting-problems

4.9

OVERDOSE

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.

Atostat PI Dec 2018

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 information on the management of overdose, contact the Poisons Information

Centre on 13 11 26 (Australia).

5.

PHARMACOLOGICAL PROPERTIES

5.1

PHARMACODYNAMIC PROPERTIES

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 cardiovascular disease. 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 familial hypercholesterolaemia (FH),

Atostat PI Dec 2018

non-familial forms of hypercholesterolaemia, and mixed dyslipidaemia. Atorvastatin

also reduces 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) in patients with

dysbetalipoproteinaemia. In animal models, atorvastatin limits the development of

lipid-enriched atherosclerotic lesions and promotes the regression of pre-established

atheroma.

CLINICAL TRIALS

In a multicentre, placebo-controlled, double blind dose-response study in patients

with hypercholesterolaemia, atorvastatin was given as a single daily dose over 6

weeks. Atorvastatin (10-80 mg) reduced total-C (30%-46%), LDL-C (41%-61%),

apolipoprotein B (34%-50%) and triglycerides (14%-33%) while producing variable

increases in HDL-C and apolipoprotein 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*

Atorvastatin dose (mg)

N

Total-C

LDL-C

Apo B

TG

HDL-C

Placebo

-0.7

-2.5

-30.3

-41.0

-34.4

-14.2

-34.5

-44.3

-36.3

-33.2

12.1

-37.8

-49.7

-40.9

-24.9

-2.6

-45.7

-61.0

-50.3

-27.2

* Adjusted mean % change from baseline

In three further trials, 1148 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.

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,

triglycerides 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 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.

Prevention of Cardiovascular Disease

Atostat PI Dec 2018

In the lipid lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial

(ASCOT), the effect of atorvastatin (atorvastatin calcium) on the composite endpoint

of fatal coronary heart disease and non-fatal myocardial infarction was assessed in

10,305 hypertensive patients, 40-79 years of age, without a history of symptomatic

coronary heart disease and with TC 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%), non insulin dependent diabetes mellitus (25%), history of CHD in a first-

degree relative (26%), plasma TC to HDL cholesterol ratio ≥ 6 (14%), peripheral

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

history of cerebrovascular event (10%), specific ECG abnormality (14%),

proteinuria/albuminuria (62%)]. Patients with a history of previous myocardial

infarction or angina were excluded.

In 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; 2340

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 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.

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 and Non-fatal

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

Total Coronary Events

Fatal and Non-fatal

Stroke

Non-fatal MI (excludes

Silent MI) and Fatal CHD

389 (7.6)

178 (3.5)

89 (1.7)

86 (1.7)

483 (9.5)

247 (4.8)

119 (2.3)

137 (2.7)

1.9 (0.80 to 2.96)

1.4 (0.60 to 2.14)

0.6 (0.05 to 1.14)

1.0 (0.42 to 1.56)

176.0

241.9

555.2

329.1

20 (9 to 30)

29 (14 to 41)

26 (2 to 44)

38 (19 to 53)

0.0008

0.0006

0.0332

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.

Atostat PI Dec 2018

The primary endpoint examined in ASCOT was the rate of fatal coronary heart

disease or non-fatal myocardial 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.

Non Insulin Dependent Diabetes Mellitus (NIDDM)

A 26 week randomised, double blind, comparator study in NIDDM subjects showed

that atorvastatin is effective in dyslipidaemic patients with NIDDM. A 10 mg dose of

atorvastatin produced a 34% reduction in LDL-cholesterol, 27% reduction in total

cholesterol, a 24% reduction in triglycerides and a 12% rise in HDL cholesterol.

Homozygous Familial Hypercholesterolaemia

Atorvastatin has also been shown to reduce LDL-C in patients with homozygous

familial hypercholesterolaemia (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 to 80 mg of atorvastatin. The mean LDL reduction in this study was 18%. Twenty-

five patients with a reduction in LDL-C had a mean response of 20% (range 7%-53%,

median 24%). Five 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 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 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%.

In a randomized, placebo-controlled, double blind, multicentre study in 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 3).

Table 3 Efficacy in Patients with Hypertriglyceridaemia*

Atorvastatin Dose (mg)

N

TG

Total-C

LDL-C

VLDL-

C

Apo B

HDL-C

Placebo

-5.3

+0.3

+1.4

-2.0

+2.7

+2.4

-33.6

-33.1

-31.1

-46.0

-32.7

+10.6

Atostat PI Dec 2018

-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, randomized, 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 4).

Table 4 Efficacy in Patients with Dysbetalipoproteinaemia

Treatment

N

IDL-C+

VLDL-C

IDL-

C

Total-

C

TG

VLDL-

C

Apo B

HDL-C

Atorvastatin 10 mg/day 15

Atorvastatin 80 mg/day 16

Gemfibrozil 1200

mg/day

-33*

-13*

-34*

-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

5.2

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 are lower (approximately 30% for C

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

Atostat PI Dec 2018

The mean volume of distribution of atorvastatin is about 400 litres. Atorvastatin is

≥98% bound to plasma proteins. A RBC/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).

Metabolism

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 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). 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.

Pharmacodynamics

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).

Special Populations

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 & 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.

Atostat PI Dec 2018

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 DOSE AND METHOD OF ADMINISTRATION).

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 DOSE AND METHOD OF

ADMINISTRATION, Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR

USE and Section 4.3 CONTRAINDICATIONS).

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 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. 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.

Atostat PI Dec 2018

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

6.5

NATURE AND CONTENTS OF CONTAINER

ATOSTAT is available in three strengths:

10 mg: white oval biconvex tablet with “10” on one side and “A” on reverse.

20 mg: white oval biconvex tablet with “20” on one side and “A” on reverse.

40 mg: white oval biconvex tablet with “40” on one side and “A” on reverse.

ATOSTAT tablets are available in foil blister and bottle

packs of 30.

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 amorphous powder. Atorvastatin calcium

is very slightly soluble in water, slightly soluble in ethanol and freely soluble in

methanol.

Chemical name:

[R-(R*,R*)]-2-(4-fluorophenyl)-ß,δ- dihydroxy-5-(1-methylethyl)-3-phenyl-4-

[(phenylamino) carbonyl] -1H-pyrrole -1-heptanoic acid, calcium salt (2:1).

Chemical Structure:

Not marketed in Australia

Atostat PI Dec 2018

Molecular formula: (C

Molecular weight: 1155.3

CAS No.: 134523-03-8

7.

MEDICINE SCHEDULE (POISONS STANDARD)

S4 - Prescription only medicine

8.

SPONSOR

Medis Pharma Pty Ltd

Suite 1002, Level 10

53 Walker Street,

North Sydney, NSW 2060

9.

DATE OF FIRST APPROVAL

30 March 2011

10.

DATE OF REVISION

17 May 2019

Atostat PI Dec 2018

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

Section updated to align with other Medis Atorvastatin PI’s

Sponsor name an address updated