Hypercholesterolaemia
Astatin is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDLcholesterol
(LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and children aged 10
years or older with primary hypercholesterolaemia including familial hypercholesterolaemia
(heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of
the Fredrickson classification) when response to diet and other nonpharmacological measures is
inadequate.
Astatin is also indicated to reduce total-C and LDL-C in adults with homozygous familial
hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if
such treatments are unavailable.
Prevention of cardiovascular disease
Prevention of cardiovascular events in adult patients estimated to have a high risk for a first
cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.

Posology
The patient should be placed on a standard cholesterol-lowering diet before receiving Astatin and
should continue on this diet during treatment with Astatin

The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and
patient response.
The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4
weeks or more. The maximum dose is 80 mg once a day.
Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia
The majority of patients are controlled with Astatin 10 mg once a day. A therapeutic response is
evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks.
The response is maintained during chronic therapy.
Heterozygous familial hypercholesterolaemia
Patients should be started with Astatin 10 mg daily. Doses should be individualised and adjusted
every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg
daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily.
Homozygous familial hypercholesterolaemia
Only limited data are available (see section 5.1).
The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg
daily (see section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments
(e.g. LDL apheresis) in these patients or if such treatments are unavailable.
Prevention of cardiovascular disease
In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to
attain (LDL-) cholesterol levels according to current guidelines.
Renal impairment
No adjustment of dose is required (see section 4.4).
Hepatic impairment
Astatin should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2).
Astatin is contraindicated in patients with active liver disease (see section 4.3).
Use in the elderly

Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in
the general population.
Paediatric use
Hypercholesterolaemia:
Paediatric use should only be carried out by physicians experienced in the treatment of paediatric
hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.
For patients aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day
with titration up to 20 mg per day. Titration should be conducted according to the individual response
and tolerability in paediatric patients. Safety information for paediatric patients treated with doses
above 20 mg, corresponding to about 0.5 mg/kg, is limited.
There is limited experience in children between 6-10 years of age (see section 5.1). Atorvastatin is
not indicated in the treatment of patients below the age of 10 years.
Other pharmaceutical forms/strengths may be more appropriate for this population.
Method of administration
Astatin is for oral administration. Each daily dose of atorvastatin is given all at once and may be
given at any time of day with or without food.

Liver effects
Liver function tests should be performed before the initiation of treatment and periodically thereafter.
Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the
abnormality(ies) resolve. Should an increase in transaminases of greater than 3 times the upper limit
of normal (ULN) persist, reduction of dose or withdrawal of Astatin is recommended (see section
4.8).
Astatin should be used with caution in patients who consume substantial quantities of alcohol and/or
have a history of liver disease.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a
recent stroke or transient ischemic attack (TIA) there was a higher incidence of hemorrhagic stroke in
patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly
noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with
prior hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is
uncertain, and the potential risk of hemorrhagic stroke should be carefully considered before
initiating treatment (see section 5.1).
Skeletal muscle effects
Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal
muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a
potentially life-threatening condition characterised by markedly elevated creatine kinase (CK) levels
(> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.
Before the treatment
Atorvastatin should be prescribed with caution in patients with pre-disposing factors for
rhabdomyolysis. A CK level should be measured before starting statin treatment in the following
situations:
− Renal impairment
− Hypothyroidism
− Personal or familial history of hereditary muscular disorders
− Previous history of muscular toxicity with a statin or fibrate
− Previous history of liver disease and/or where substantial quantities of alcohol are consumed
− In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis
− Situations where an increase in plasma levels may occur, such as interactions (see section 4.5) and
special populations including genetic subpopulations (see section 5.2)
In such situations, the risk of treatment should be considered in relation to possible benefit, and
clinical monitoring is recommended.
If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.
Creatine kinase measurement
Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any
plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are
significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days
later to confirm the results.
Whilst on treatment
− Patients must be asked to promptly report muscle pain, cramps, or weakness especially if
accompanied by malaise or fever.
− If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels
should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment
should be stopped.
− If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to
5 x ULN, treatment discontinuation should be considered.
− If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or
introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
− Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x ULN)
occur, or if rhabdomyolysis is diagnosed or suspected.
Concomitant treatment with other medicinal products
Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain
medicinal products that may increase the plasma concentration of atorvastatin such as potent
inhibitors of CYP3A4 or transport proteins (e.g. ciclosporine, telithromycin, clarithromycin,
delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease
inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). The risk of myopathy
may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, erythromycin, niacin and ezetimibe. If possible, alternative (non-interacting) therapies should be
considered instead of these medicinal products.
In cases where co-administration of these medicinal products with atorvastatin is necessary, the
benefit and the risk of concurrent treatment should be carefully considered. When patients are
receiving medicinal products that increase the plasma concentration of atorvastatin, a lower
maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors,
a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these
patients is recommended (see section 4.5).
The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary
suspension of atorvastatin may be considered during fusidic acid therapy (see section 4.5).
Paediatric use
Developmental safety in the paediatric population has not been established (see section 4.8).
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with
long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough
and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has
developed interstitial lung disease, statin therapy should be discontinued.
Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of
future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate.
This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should
not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L,
BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and
biochemically according to national guidelines.
Excipients
Astatin contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp
lactose deficiency or glucose-galactose malabsorption should not take this medicine.

Effect of co-administered medicinal products on atorvastatin
Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate to transport proteins e.g. the hepatic uptake transporter OATP1B1. Concomitant administration of medicinal
products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma
concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at
concomitant administration of atorvastatin with other medicinal products that have a potential to
induce myopathy, such as fibric acid derivates and ezetimibe (see section 4.4).
CYP3A4 inhibitors
Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of
atorvastatin (see Table 1 and specific information below). Co-administration of potent CYP3A4
inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole,
voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir,
atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration
of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses
of atorvastatin should be considered and appropriate clinical monitoring of the patient is
recommended (see Table 1).
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase
plasma concentrations of atorvastatin (see Table 1).. An increased risk of myopathy has been
observed with the use of erythromycin in combination with statins. Interaction studies evaluating the
effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and
verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result
in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be
considered and appropriate clinical monitoring of the patient is recommended when concomitantly
used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after
initiation or following dose adjustments of the inhibitor.
CYP3A4 inducers
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. efavirenz,
rifampin, St. John's Wort) can lead to variable reductions in plasma concentrations of atorvastatin.
Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A induction and inhibition of
hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with
rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin
has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of
rifampin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant
administration cannot be avoided, patients should be carefully monitored for efficacy.
Transport protein inhibitors
Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin
(see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in
hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1).
Gemfibrozil / fibric acid derivatives
The use of fibrates alone is occasionally associated with muscle related events, including
rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid
derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of
atorvastatin to achieve the therapeutic objective should be used and the patients should be
appropriately monitored (see section 4.4).
Ezetimibe
The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The
risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin.
Appropriate clinical monitoring of these patients is recommended.
Colestipol
Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) when
colestipol was co-administered with Astatin . However, lipid effects were greater when Astatin and
colestipol were co-administered than when either medicinal product was given alone.
Fusidic acid
Interaction studies with atorvastatin and fusidic acid have not been conducted. As with other statins,
muscle related events, including rhabdomyolysis, have been reported in post-marketing experience
with atorvastatin and fusidic acid given concurrently. The mechanism of this interaction is not
known. Patients should be closely monitored and temporary suspension of atorvastatin treatment may
be appropriate.
Effect of atorvastatin on co-administered medicinal products
Digoxin
When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin
concentrations increased slightly. Patients taking digoxin should be monitored appropriately.
Oral contraceptives
Co-administration of Astatin with an oral contraceptive produced increases in plasma concentrations
of norethindrone and ethinyl oestradiol.
Warfarin

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

Pregnancy
Astatin is contraindicated during pregnancy (see section 4.3). Safety in pregnant women has not
been established. No controlled clinical trials with atorvastatin have been conducted in pregnant
women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA
reductase inhibitors have been received. Animal studies have shown toxicity to reproduction (see
section 5.3).
Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor
of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of
lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk
associated with primary hypercholesterolaemia.
For these reasons, Astatin should not be used in women who are pregnant, trying to become
pregnant or suspect they are pregnant. Treatment with Astatin should be suspended for the duration
of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3.)
Breastfeeding
It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma
concentrations of atorvastatin and its active metabolites are similar to those in milk (see section 5.3).
Because of the potential for serious adverse reactions, women taking Astatin should not breast-feed
their infants (see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).
Fertility
In animal studies atorvastatin had no effect on male or female fertility (see section 5.3).

Astatin has negligible influence on the ability to drive and use machines.

In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Astatin vs. 7311
placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued
due to adverse reactions compared to 4.0% of the patients on placebo.
Based on data from clinical studies and extensive post-marketing experience, the following table
presents the adverse reaction profile for Astatin .
Estimated frequencies of reactions are ranked according to the following convention: common (
1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare

1/10,000).
Infections and infestations:
Common: nasopharyngitis.
Blood and lymphatic system disorders
Rare: thrombocytopenia.
Immune system disorders
Common: allergic reactions.
Very rare: anaphylaxis.
Metabolism and nutrition disorders
Common: hyperglycaemia.
Uncommon: hypoglycaemia, weight gain, anorexia
Psychiatric disorders
Uncommon: nightmare, insomnia.
Nervous system disorders
Common: headache.
Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.
Rare: peripheral neuropathy.
Eye disorders
Uncommon: vision blurred.
Rare: visual disturbance.
Ear and labyrinth disorders

Uncommon: tinnitus
Very rare: hearing loss.
Respiratory, thoracic and mediastinal disorders:
Common: pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders
Common: constipation, flatulence, dyspepsia, nausea, diarrhoea.
Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.
Hepatobiliary disorders
Uncommon: hepatitis.
Rare: cholestasis.
Very rare: hepatic failure.
Skin and subcutaneous tissue disorders
Uncommon: urticaria, skin rash, pruritus, alopecia.
Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson
syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders
Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.
Uncommon: neck pain, muscle fatigue.
Rare: myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture.
Reproductive system and breast disorders
Very rare: gynecomastia.
General disorders and administration site conditions

Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.
Investigations
Common: liver function test abnormal, blood creatine kinase increased.
Uncommon: white blood cells urine positive.
As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in
patients receiving Astatin . These changes were usually mild, transient, and did not require
interruption of treatment. Clinically important (> 3 times upper normal limit) elevations in serum
transaminases occurred in 0.8% patients on Astatin . These elevations were dose related and were
reversible in all patients.
Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in
2.5% of patients on Astatin , similar to other HMG-CoA reductase inhibitors in clinical trials. Levels
above 10 times the normal upper range occurred in 0.4% Astatin -treated patients (see section 4.4).
Paediatric Population
The clinical safety database includes safety data for 249 paediatric patients who received atorvastatin,
among which 7 patients were < 6 years old, 14 patients were in the age range of 6 to 9, and 228
patients were in the age range of 10 to 17.
Nervous system disorders
Common: Headache
Gastrointestinal disorders
Common: Abdominal pain
Investigations
Common: Alanine aminotransferase increased, blood creatine phosphokinase increased
Based on the data available, frequency, type and severity of adverse reactions in children are
expected to be the same as in adults. There is currently limited experience with respect to long-term
safety in the paediatric population.
The following adverse events have been reported with some statins:

• Sexual dysfunction.
• Depression.
• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4).
• Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood
glucose 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).

Specific treatment is not available for Astatin overdose. Should an overdose occur, the patient
should be treated symptomatically and supportive measures instituted, as required. Liver function
tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin
binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin
clearance.

Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors, ATC code:
C10AA05
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme
responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a
precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated
into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral
tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily through
the receptor with high affinity to LDL (LDL receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMGCoA
reductase and subsequently cholesterol biosynthesis in the liver and increases the number of
hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a
profound and sustained increase in LDL receptor activity coupled with a beneficial change in the
quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with
homozygous familial hypercholesterolaemia, a population that has not usually responded to lipidlowering
medicinal products.
Atorvastatin has been shown to reduce concentrations of 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 A1 in a dose response study. These results are consistent in patients with
heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed
hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for
cardiovascular events and cardiovascular mortality.
Homozygous familial hypercholesterolaemia
In a multicenter 8 week open-label compassionate-use study with an optional extension phase of
variable length, 335 patients were enrolled, 89 of which were identified as homozygous familial
hypercholesterolaemia patients. From these 89 patients, the mean percent reduction in LDL-C was
approximately 20%. Atorvastatin was administered at doses up to 80 mg/day.
Atherosclerosis
In the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study (REVERSAL), the effect of
intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with
pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS),
during angiography, in patients with coronary heart disease. In this randomised, double- blind,
multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502
patients. In the atorvastatin group (n=253), there was no progression of atherosclerosis.
The median percent change, from baseline, in total atheroma volume (the primary study criteria) was
-0.4% (p=0.98) in the atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249).
When compared to pravastatin the effects of atorvastatin were statistically significant (p=0.02). The
effect of intensive lipid lowering on cardiovascular endpoints (e. g. need for revascularisation, non
fatal myocardial infarction, coronary death) was not investigated in this study.
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30)
from baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced
to a mean of 2.85 mmol/l ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 26)
(p<0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin: -18.4%,
p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by
39.1% (pravastatin: -22.0%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin:
+5.6%, p=NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a
5.2% reduction in the pravastatin group (p<0.0001).
Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to
the lower dose strengths.
The safety and tolerability profiles of the two treatment groups were comparable. The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this
study. Therefore, the clinical significance of these imaging results with regard to the primary and
secondary prevention of cardiovascular events is unknown.
Acute coronary syndrome
In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n=1,538;
placebo n=1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina). Treatment
was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks.
Treatment with atorvastatin 80 mg/day increased the time to occurrence of the combined primary
endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris
with evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16%
(p=0.048). This was mainly due to a 26% reduction in re-hospitalisation for angina pectoris with
evidence of myocardial ischaemia (p=0.018). The other secondary endpoints did not reach statistical
significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).
The safety profile of atorvastatin in the MIRACL study was consistent with what is described in
section 4.8.
Prevention of cardiovascular disease
The effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomized,
double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid
Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous
myocardial infarction or treatment for angina, and with TC levels 6.5 mmol/l (251 mg/dl). All
patients had at least 3 of the pre-defined cardiovascular risk factors: male gender, age 55 years,
smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C >6, peripheral vascular
disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality,
proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a first
cardiovascular event.
Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol-based regimen)
and either atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137).
The absolute and relative risk reduction effect of atorvastatin was as follows:
Event Relative Risk
Reduction
(%)
No. of
Events
(Atorvastatin
vs Placebo)
Absolute
Risk
Reduction1
(%)
p-value
Fatal CHD plus non-fatal MI 36% 100 vs. 154 1.1% 0.0005

Total cardiovascular events and
revascularization procedures
20% 389 vs. 483 1.9% 0.0008
Total coronary events 29% 178 vs 247 1.4% 0.0006
1Based on difference in crude events rates occurring over a median follow-up of 3.3 years.
CHD = coronary heart disease; MI = myocardial infarction.
Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events,
p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% females),
a beneficial effect of atorvastatin was seen in males but could not be established in females possibly
due to the low event rate in the female subgroup. Overall and cardiovascular mortality were
numerically higher in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically
significant. There was significant treatment interaction by antihypertensive baseline therapy. The
primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by atorvastatin in patients
treated with amlodipine (HR 0.47 (0.32-0.69), p=0.00008), but not in those treated with atenolol (HR
0.83 (0.59-1.17), p=0.287).
The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a
randomized, double-blind, multicenter, placebo-controlled trial, the Collaborative Atorvastatin
Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history
of cardiovascular disease, and with LDL-C 4.14 mmol/l (160 mg/dl) and TG 6.78 mmol/l (600
mg/dl). All patients had at least 1 of the following risk factors: hypertension, current smoking,
retinopathy, microalbuminuria or macroalbuminuria.
Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410) for a
median follow-up of 3.9 years.
The absolute and relative risk reduction effect of atorvastatin was as follows:
Event Relative Risk
Reduction
(%)
No. of
Events
(Atorvastatin
vs Placebo)
Absolute
Risk
Reduction1
(%)
p-value
Major cardiovascular events(fatal and
non-fatal AMI, silent MI, acute CHD
death, unstable angina, CABG, PTCA,
revascularization, stroke)
37% 83 vs. 127 3.2% 0.0010
MI (fatal and non-fatal AMI, silent 42% 38 vs 64 1.9% 0.0070

MI)
Strokes (Fatal and non-fatal) 48% 21 vs. 39 1.3% 0.0163
1Based on difference in crude events rates occurring over a median follow-up of 3.9 years.
AMI = acute myocardial infarction; CABG = coronary artery bypass graft; CHD = coronary heart
disease; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.
There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline
LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo
group vs. 61 deaths in the atorvastatin group, p=0.0592).
Recurrent stroke
In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect
of atorvastatin 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or
transient ischemic attack (TIA) within the preceding 6 months and no history of coronary heart
disease (CHD). Patients were 60% male, 21-92 years of age (average age 63 years), and had an
average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L)
during treatment with atorvastatin and 129 mg/dL (3.3 mmol/L) during treatment with placebo.
Median follow-up was 4.9 years.
Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR
0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline
factors) compared to placebo. All cause mortality was 9.1% (216/2365) for atorvastatin versus 8.9%
(211/2366) for placebo.
In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2%
vs. 274/2366, 11.6%, p=0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs.
33/2366, 1.4%, p=0.02) compared to placebo.
• The risk of hemorrhagic stroke was increased in patients who entered the study with prior
hemorrhagic stroke (7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57), and
the risk of ischemic stroke was similar between groups (3/45 for atorvastatin versus 2/48 for placebo;
HR 1.64; 95% CI, 0.27-9.82).
• The risk of hemorrhagic stroke was increased in patients who entered the study with prior lacunar
infarct (20/708 for atorvastatin versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk
of ischemic stroke was also decreased in these patients (79/708 for atorvastatin versus 102/701 for
placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients
with prior lacunar infarct who receive atorvastatin 80 mg/day.

All cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in the subgroup of patients
with prior hemorrhagic stroke. All cause mortality was 10.9% (77/708) for atorvastatin versus 9.1%
(64/701) for placebo in the subgroup of patients with prior lacunar infarct.
Paediatric Population
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old
An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and
tolerability of atorvastatin was conducted in children and adolescents with genetically confirmed
heterozygous familial hypercholesterolemia and baseline LDL-C 4 mmol/L. A total of 39 children
and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of
age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage
2.
The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a
tablet formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not
attained target LDL-C of <3.35 mmol/L at Week 4 and if atorvastatin was well tolerated.
Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For
subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first
assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for
both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial
dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately
40% and 30%, respectively, over the range of exposures.
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old
In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and
postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial
hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to atorvastatin
(n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks.. The dosage
of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C
level was >3.36 mmol/l. Atorvastatin significantly decreased plasma levels of total-C, LDL-C,
triglycerides, and apolipoprotein B during the 26 week double-blind phase. The mean achieved LDLC
value was 3.38 mmol/l (range: 1.81-6.26 mmol/l) in the atorvastatin group compared to 5.91
mmol/l (range: 3.93-9.96 mmol/l) in the placebo group during the 26-week double-blind phase.
An additional paediatric study of atorvastatin versus colestipol in patients with hypercholesterolaemia
aged 10-18 years demonstrated that atorvastatin (N=25) caused a significant reduction in LDL-C at
week 26 (p<0.05) compared with colestipol (N=31).

A compassionate use study in patients with severe hypercholesterolaemia (including homozygous
hypercholesterolaemia) included 46 paediatric patients treated with atorvastatin titrated according to
response (some subjects received 80 mg atorvastatin per day). The study lasted 3 years: LDLcholesterol
was lowered by 36%.
The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
The European Medicines Agency has waived the obligation to submit the results of studies with
atorvastatin in children aged 0 to less than 6 years in the treatment of heterozygous
hypercholesterolaemia and in children aged 0 to less than 18 years in the treatment of homozygous
familial hypercholesterolaemia, combined (mixed) hypercholesterolaemia, primary
hypercholesterolaemia and in the prevention of cardiovascular events (see section 4.2 for information
on paediatric use).

Absorption
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax)
occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral
administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral
solution. The absolute bioavailability of atorvastatin is approximately 12% and the systemic
availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic
availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass
metabolism
Distribution
Mean volume of distribution of atorvastatin is approximately 381 l. Atorvastatin is 98% bound to
plasma proteins.
Biotransformation
Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and
various beta-oxidation products. Apart from other pathways these products are further metabolized
via glucuronidation. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated
metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity
for HMG-CoA reductase is attributed to active metabolites.
Excretion Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism.
However, atorvastatin does not appear to undergo significant enterohepatic recirculation. Mean
plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of
inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution
of active metabolites.
Special populations
Elderly: Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly
subjects than in young adults while the lipid effects were comparable to those seen in younger patient
populations.
Paediatric: In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage 2 (N=24)
paediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline
LDL-C 4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated
atorvastatin tablets once daily, respectively. Body weight was the only significant covariate in
atorvastatin population PK model. Apparent oral clearance of atorvastatin in paediatric subjects
appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C
and TC were observed over the range of atorvastatin and o-hydroxyatorvastatin exposures.
Gender: Concentrations of atorvastatin and its active metabolites in women differ from those in men
(Women: approx. 20% higher for Cmax and approx. 10% lower for AUC). These differences were of
no clinical significance, resulting in no clinically significant differences in lipid effects among men
and women.
Renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of
atorvastatin and its active metabolites.
Hepatic insufficiency: Plasma concentrations of atorvastatin and its active metabolites are markedly
increased (approx. 16-fold in Cmax and approx. 11-fold in AUC) in patients with chronic alcoholic
liver disease (Child-Pugh B).
SLOC1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including
atorvastatin, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a
risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis
(see section 4.4). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated
with a 2.4-fold higher atorvastatin exposure (AUC) than in individuals without this genotype variant
(c.521TT). A genetically impaired hepatic uptake of atorvastatin is also possible in these patients.
Possible consequences for the efficacy are unknown.

Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1
in vivo assay. Atorvastatin was not found to be carcinogenic in rats, but high doses in mice (resulting
in 6-11 fold the AUC0-24h reached in humans at the highest recommended dose) showed
hepatocellular adenomas in males and hepatocellular carcinomas in females.
There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect
the development of embryos or fetuses. In rats, rabbits and dogs atorvastatin had no effect on fertility
and was not teratogenic, however, at maternally toxic doses fetal toxicity was observed in rats and
rabbits. The development of the rat offspring was delayed and post-natal survival reduced during
exposure of the dams to high doses of atorvastatin. In rats, there is evidence of placental transfer. In
rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether
atorvastatin or its metabolites are excreted in human milk.

Ludipress
Calcium Carbonate
Crospovidone
Hydroxypropylcellulose
Maize Starch
Starch 1500 (Pregelatinised starch
Magnesium Stearate
Aerosil (Colloidal Silicon Dioxide)
Coating Material
Opadry white
Propylene glycol
Polysorbate 80
Simethicone
Purified Water

Not applicable.

Do not store above 30 °C.

Immediate Container: Alu-Alu Color printed blister.

Outer Individual Carton: 260g/m2 grammage paper, dimension
124 X 52 X 22 mm, Colored Printed Carton, text & Color Similar to
approved artwork.

Insert/Leaflet; 55 g/m2 paper, both side printed.
Dimensions LXB: 280 X 160 mm.

No special instructions needed.