LORSTAT 40 atorvastatin (as calcium) 40 mg tablets bottle

Main information

  • Trade name:
  • LORSTAT 40 atorvastatin (as calcium) 40 mg tablets bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • LORSTAT 40 atorvastatin (as calcium) 40 mg tablets bottle
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 181409
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

181409

LORSTAT 40 atorvastatin (as calcium) 40 mg tablets bottle

ARTG entry for

Medicine Registered

Sponsor

Alphapharm Pty Ltd

Postal Address

PO Box R1462,ROYAL EXCHANGE, NSW, 1225

Australia

ARTG Start Date

11/07/2012

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. LORSTAT 40 atorvastatin (as calcium) 40 mg tablets bottle

Product Type

Single Medicine Product

Effective date

5/12/2016

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

LORSTAT 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.,LORSTAT is indicated in hypertensive patients with multiple risk

factors for coronary heart disease (CHD) which may include diabetes, history of stroke or other cerebrovascular disease, peripheral vascular disease or

existing asymptomatic CHD (see Clinical Trials) 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

Bottle

HDPE

36 Months

Store below 25

degrees Celsius

Child resistant closure

Protect from Light

Protect from Moisture

Pack Size/Poison information

Pack Size

Poison Schedule

500 (for dispensing only)

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. LORSTAT 40 atorvastatin (as calcium) 40 mg tablets bottle

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

White, oval, biconvex, film coated tablet with break line on one side and

debossed '40' on the other side.

Active Ingredients

atorvastatin calcium trihydrate

43.376 mg

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

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Public Summary

Page 1 of

Produced at 14.11.2017 at 12:43:07 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

AUSTRALIAN PRODUCT INFORMATION

LORSTAT

®

Atorvastatin (as calcium trihydrate) tablets

1

NAME OF THE MEDICINE

Atorvastatin calcium trihydrate.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

LORSTAT contains atorvastatin (as calcium) and is available in four strengths:

Each LORSTAT 10 tablet contains atorvastatin calcium equivalent to 10 mg atorvastatin.

Each LORSTAT 20 tablet contains atorvastatin calcium equivalent to 20 mg atorvastatin.

Each LORSTAT 40 tablet contains atorvastatin calcium equivalent to 40 mg atorvastatin.

Each LORSTAT 80 tablet contains atorvastatin calcium equivalent to 80 mg atorvastatin.

Excipients with known effect:

Contains sugars (as lactose) and soya bean products.

For the full list of excipients, see Section 6.1 List of excipients.

3

PHARMACEUTICAL FORM

Oral. Film-coated tablets.

Presentations:

LORSTAT 10 – White, oval, biconvex, film coated tablet plain on one side and debossed ‘

10

’ on the other

side.

LORSTAT 20 – White, oval, biconvex, film coated tablet with break line on one side and debossed ‘

20

’ on

the other side.

LORSTAT 40 – White, oval, biconvex, film coated tablet with break line on one side and debossed ‘

40

’ on

the other side.

LORSTAT 80 - White, oval, biconvex, film coated tablet with break line on one side and debossed ‘

80

’ on

the other side.

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

LORSTAT 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.

LORSTAT is indicated in hypertensive patients with multiple risk factors for coronary heart disease (CHD)

which may include diabetes, history of stroke or other cerebrovascular disease, peripheral vascular disease

existing

asymptomatic

(see

section

5.1

Pharmacodynamic

properties,

Clinical

trials

-

Prevention of cardiovascular disease

) to reduce the risk of non-fatal myocardial infarction and non-fatal

stroke.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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

mortality and morbidity such as hypertension, diabetes and smoking.

4.2

DOSE AND METHOD OF ADMINISTRATION

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

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

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

upon titration of LORSTAT, 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 LORSTAT 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 tablets 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

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 sections

4.4 Special warnings and precautions for use and

5.2 Pharmacokinetic properties

Use in hepatic impairment

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

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

given to patients with hepatic insufficiency (see sections

4.3 Contraindications, 4.4 Special warnings and

precautions for use - Liver dysfunction, 5.1 Pharmacodynamic properties and 5.2 Pharmacokinetic

properties

Use in Combination with Other Medicines

cases

where

co-administration

atorvastatin

with

cyclosporine,

telaprevir,

combination

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

when co-prescribing atorvastatin with medicinal compounds that result in an increase in systematic

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

necessary dose of atorvastatin is employed (see

sections

4.4

Special warnings and precautions for use –

Skeletal muscle, 4.5 Interactions with other medicines and other forms of interactions

4.3

CONTRAINDICATIONS

Hypersensitivity to any component of this medication.

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

4.6 Fertility, pregnancy and lactation – Use in pregnancy and

Use in lactation

). Women of childbearing potential, unless on an effective contraceptive and highly

unlikely to conceive.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

Concomitant use with fusidic acid (see sections

4.4 Special warnings and precautions for use –

Skeletal muscle and 4.5 Interactions with other medicines and other forms of interactions

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 LORSTAT is recommended.

Use in hepatic impairment

LORSTAT 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 ache 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. LORSTAT 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, azole antifungals, colchicine,

hepatitis C protease inhibitors (e.g. telaprevir, boceprevir) or the combination of tipranavir/ritonavir (see

section

4.5

Interactions with other medicines and other forms of interactions

). Physicians considering

combined therapy with LORSTAT 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. (see section

4.2

Dosage and administration, Use in

Combination with Other Medicinal Compounds

). Atorvastatin must not be co-administered with fusidic

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

concomitant fusidic acid and statins (see sections

4.3

Contraindications and 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 throughout the duration of the fusidic acid treatment. The

patient should be advised to seek medical advice immediately if they experience any symptoms of muscle

weakness, pain or tenderness. Statin therapy may be 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

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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. LORSTAT 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 Necrotising Myopathy

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

treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and

elevated serum creatinine kinase, which persists 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 transient ischaemic attack (TIA), showed a higher incidence of haemorrhagic stroke

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

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

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

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

haemorrhagic stroke (15.6% for atorvastatin vs. 4.2 % for placebo, 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

haemorrhagic stroke should be carefully considered before initiating treatment with atorvastatin in patients

with recent (1-6 months) stroke or TIA.

In 68% of patients who entered the study with neither a haemorrhagic stroke 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.

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.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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.

Use in the Elderly

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

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

<70 years of age.

Paediatric Use

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.

Effects 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.

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

systematic concentration of atorvastatin have been noted with HIV protease inhibitors (fosamprenavir and

combinations

lopinavir/ritonavir,

saquinavir/ritonavir,

darunavir/rotinavir,

fosamprenavir/ritonavir),

hepatitis C protease inhibitors (boceprevir), clarithromycin and intraconazole. Based on experience with

other HMG-CoA reductase inhibitors, caution should be exercised when LORSTAT 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 sections

4.2 Dose and method of administration, Use in

Combination with Other Medicinal Compounds

4.4 Special warnings and precautions for use,

Skeletal Muscle)

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

atorvastatin

with

rifampicin

recommended, as delayed administration of atorvastatin after administration of rifampicin has been

associated with a significant reduction in atorvastatin plasma concentrations.

Fusidic acid

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

systemic 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 atorvastatin and fusidic acid have not been conducted, there have been

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

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

Lorstat – AUSTRALIAN PRODUCT INFORMATION

acid treatment (see sections

4.3

Contraindications

4.4

Special warning and precautions for use,

Skeletal Muscle)

Colchicine

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

have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when

prescribing atorvastatin with colchicine (see section

4.4 Special warnings and precautions for use,

Skeletal Muscle

Effects of Other Medicines on atorvastatin

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

of atorvastatin tablets:

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

organic anion-

transporting polypeptide 1B1

(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, Use in combination with other medicines

Erythromycin/clarithromycin:

In healthy individuals, co-administration of atorvastatin (10 mg once

daily) with erythromycin (500 mg four times daily), 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, Skeletal Muscle

Protease inhibitors:

Co-administration of atorvastatin with protease inhibitors, known inhibitors of

cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin

(see section

4.4 Special Warnings and Precautions for Use, Skeletal Muscle

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 of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 L per

day).

Effects of atorvastatin on Other Medicines

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

by atorvastatin tablets:

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.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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

LDL-C

reduction

were

altered

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 with 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 with azithromycin (500 mg once 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 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.

LORSTAT 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

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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 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

LORSTAT should not breast-feed (see sections

4.3

Contraindications

4.4 Special warnings and

precautions for use

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Effects of ability to drive and operate machines on atorvastatin tablets have not been established.

4.8

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

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

Clinical Adverse Events

In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin; 7,311

placebo), treated for a median period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to

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

The most frequent (≥1%) adverse effects associated with atorvastatin tablet therapy, reported in patients

participating in controlled clinical studies include:

Gastrointestinal disorders:

dyspepsia, nausea, flatulence, diarrhoea.

Infections and infestations:

nasopharyngitis.

Investigations:

liver function test abnormal (hepatic enzyme increased, alanine aminotransferase increased,

aspartate

aminotransferase

increased,

blood

bilirubin

increased,

liver

function

test

abnormal

transaminases increased), blood creatine phosphokinase increased.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

Metabolism and nutrition disorders:

hyperglycaemia.

Musculoskeletal and connective tissue disorders:

myalgia, arthralgia, pain in extremity, musculoskeletal

pain, muscle spasms, joint swelling.

Respiratory, thoracic and mediastinal disorders:

pharyngolaryngeal pain, epistaxis.

Additional Adverse Events

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

been causally associated with atorvastatin therapy.

Common (≥1% and <10%)

Gastrointestinal disorders:

constipation.

Infections and infestations:

urinary tract infection.

Nervous system disorders:

headache.

Uncommon (≥0.1% and <1%)

Ear and labyrinth disorders:

deafness.

Eye disorders:

vision blurred.

Gastrointestinal disorders:

abdominal discomfort, abdominal pain, vomiting.

General disorders and administration site conditions:

asthenia, malaise.

Infections and infestations:

infection, influenza.

Metabolism and nutrition disorders:

anorexia.

Musculoskeletal and connective tissue disorders:

back pain, neck pain.

Nervous system disorders:

paraesthesia.

Psychiatric disorders:

insomnia, nightmare.

Reproductive system and breast disorders:

erectile dysfunction.

Respiratory, thoracic and mediastinal disorders:

asthma.

Skin and subcutaneous tissue disorders:

rash, pruritus, urticaria.

Rare (≥0.01% and <0.1%)

Ear and labyrinth disorders:

tinnitus.

Gastrointestinal disorders:

pancreatitis, eructation.

General disorders and administration site conditions:

pyrexia.

Hepatobiliary disorders:

hepatitis, cholestasis.

Immune system disorders:

hypersensitivity (including anaphylaxis).

Infections and infestations:

sinusitis, pharyngitis.

Injury, poisoning and procedural complications:

injury.

Investigations:

white blood cells urine positive.

Metabolism and nutrition disorders:

hypoglycaemia.

Musculoskeletal and connective tissue disorders:

immune mediated necrotising myopathy, myositis,

myopathy, muscle fatigue.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

Nervous system disorders:

peripheral neuropathy.

Skin and subcutaneous tissue disorders:

angioedema, alopecia.

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,

Clinical trials - Prevention of Cardiovascular Disease

involving 10,305 participants treated with atorvastatin 10 mg tablets daily (n=5,168) or placebo (n=5,137),

the safety and tolerability profile of the group treated with atorvastatin tablets 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:

Blood and lymphatic system disorders:

thrombocytopenia.

General disorders and administration site conditions:

chest pain, fatigue, peripheral oedema.

Hepatobiliary disorders:

hepatic failure.

Injury, poisoning and procedural complications:

tendon rupture.

Investigations:

weight increased.

Musculoskeletal and connective tissue disorders:

rhabdomyolysis which may be fatal

(see sections

4.3

Contraindications

4.4 Special warnings and Precautions for use

4.5 Interactions with other

medicines and other forms of interactions

Nervous system disorders:

hypoaesthesia, dizziness, amnesia, dysgeusia.

Reproductive system and breast disorders:

gynaecomastia.

Skin and subcutaneous tissue disorders:

bullous rashes (including erythema multiforme, Stevens-Johnson

syndrome and toxic epidermal necrolysis).

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 LORSTAT 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

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

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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), LDL-C and apolipoprotein B (apo B) promote human atherosclerosis

and are risk factors for developing cardiovascular disease. Similarly, decreased levels of 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), 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

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.

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

Clinical Trials

multicentre,

placebo-controlled,

double

blind

dose-response

study

patients

with

hypercholesterolaemia, atorvastatin was given as a single daily dose over 6 weeks. Atorvastatin (10-80 mg)

reduced total-C (30%-46%), LDL-C (41%-61%), apolipoprotein B (34%-50%) and triglycerides (14%-

Lorstat – AUSTRALIAN PRODUCT INFORMATION

33%) while producing variable increases in HDL-C and apolipoprotein A (TABLE 1). A therapeutic

response was seen within 2 weeks, and maximum response achieved within 4 weeks.

Table 1. Dose-response in patients with primary hypercholesterolaemia

a

Atorvastatin

dose (mg)

N

Total-C

LDL-C

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, TG 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

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

atorvastatin calcium tablets 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 calcium 10 mg tablets 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 levels greater than or equal to 5.5 mmol/L and less than 6.5

mmol/L; and 486 patients (9.4%) had total -C levels greater than or equal to 6.5 mmol/L. At baseline, 457

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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

10mg

N (%)

Placebo

N (%)

Absolute risk

reduction

a

% (95% CI)

Number

needed

to treat

per year

Relative risk

reduction %

(95% CI)

P value

Primary

Fatal CHD and

nonfatal MI

100 (1.9)

154 (3.0)

1.07

(0.47 to 1.67)

310.5

(17 to 50)

0.0005

Secondary

Total

cardiovascular

events including

revascularisation

procedures

389 (7.6)

483 (9.5)

(0.80 to 2.96)

176.0

(9 to 30)

0.0008

Total coronary

events

178 (3.5)

247 (4.8)

(0.60 to 2.14)

241.9

(14 to 41)

0.0006

Fatal and nonfatal

stroke

b

89 (1.7)

119 (2.3)

(0.05 to 1.14)

555.2

(2 to 44)

0.0332

Non-fatal MO

(excludes silent

MI) and fatal CHD

86 (1.7)

137 (2.7)

(0.42 to 1.56)

329.1

(19 to 53)

0.0005

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

Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p= 0.01), a favourable

trend was observed with a 26% relative risk reduction.

The primary endpoint examined in 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

also

been

shown

reduce

LDL-C

patients

with

homozygous

familial

hypercholesterolaemia (FH), a population that has not usually responded to other lipid-lowering medication.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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

a

Atorvastatin

dose (mg)

N

TG

Total-C

LDL-C

VLDL-C

ApoB

HDL-C

Placebo

-5.3

+0.3

+1.4

-2.0

+2.7

+2.4

-33.6*

-33.1*

-31.1*

-46.0*

-32.7*

+10.6

-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

patients

with

dysbetalipoproteinaemia,

atorvastatin

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

a b

Treatment

N

IDL-C +

VLDL-C

IDL-C

Total-C

TG

VLDL-C

Apo B

HDL-C

Atorvastatin

10mg/day

Atorvastatin

80mg/day

Gemfibrozil

1200mg/day

-33*

-13*^

-34*

-52+

-35*

-53*

Simvastatin

40mg/day

-28*

-27*

-41*

-36*

-26*

-52*

Adjusted mean % change from baseline

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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

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

4.4 Special

warnings and

Precautions for use

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.

Excretion

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:

Plasma concentrations of atorvastatin are higher (approximately 40% for C

and 30% for AUC)

in healthy elderly subjects (age ≥65 years) than in young adults. Lipid effects are comparable to that seen

in younger patient populations given equal doses of atorvastatin.

Children and Adolescents

: Pharmacokinetic studies have not been conducted in the paediatric population.

Gender:

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

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

with atorvastatin between men and women.

Lorstat – AUSTRALIAN PRODUCT INFORMATION

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 sections

4.2

Dose

and method of administration and 4.4 Special warnings and precautions for use

Haemodialysis:

While

studies

have

been

conducted

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 sections

4.2 Dose and method of administration, 4.3 Contraindications

4.4 Special warnings

and

precautions for use

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

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

The tablets also contain the following inactive ingredients: colloidal anhydrous silica, sodium carbonate

anhydrous,

microcrystalline

cellulose,

arginine,

lactose

anhydrous,

croscarmellose

sodium,

hydroxypropylcellulose, magnesium stearate and Opadry AMB white OY-B-28920 (Proprietary Ingredient

ID no. 10274).

6.2

INCOMPATIBILITIES

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

6.3

SHELF LIFE

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

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

Lorstat – AUSTRALIAN PRODUCT INFORMATION

6.4

SPECIAL PRECAUTIONS FOR STORAGE

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

6.5

NATURE AND CONTENTS OF CONTAINER

LORSTAT tablets are available in blister packs (OPA/AL/PVC or PVC/Aclar) of 10 or 30 tablets or bottle

(HDPE) of 10, 30 or 90 tablets. Bottle (HDPE) of 500 tablets is for dispensing only.

Some strengths, pack sizes and/or pack types may not be marketed.

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL

Discard blister pack 30 days after the first tablet is taken and discard bottle 90 days after opening.

In Australia, any unused medicine or waste material should be disposed of by taking it to your local

pharmacy.

6.7

PHYSICOCHEMICAL PROPERTIES

Atorvastatin calcium trihydrate is a white to off-white powder that is practically insoluble in aqueous

solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4

phosphate buffer, and acetonitrile, slightly soluble in ethanol and freely soluble in methanol.

Chemical Structure

CAS Number

344423-98-9

7

MEDICINE SCHEDULE (POISONS STANDARD)

S4 (Prescription Only Medicine)

8

SPONSOR

Alphapharm Pty Limited

Level 1, 30 The Bond

30 – 34 Hickson Road

Lorstat – AUSTRALIAN PRODUCT INFORMATION

Millers Point NSW 2000

ABN 93 002 359 739

www.mylan.com.au

9

DATE OF FIRST APPROVAL

11/07/2012

10 DATE OF REVISION

28/09/2018

Summary Table of Changes

Section Changed

Summary of New Information

All section

Align with new PI format and update references to correct section subheader

section 2

Qualitative and

Quantitative

Composition

Include lactose and soya bean products declaration

section 4.4 Special

warnings and

precautions for use

Include information on

Immune Mediated Necrotising Myopathy

LORSTAT_pi\Sep18/00