Hypercholesterolaemia
AZTOLYP is indicated as an adjunct to diet for reduction of elevated total
cholesterol (total-C), LDL-cholesterol (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.
AZTOLYP is also indicated to reduce total-C and LDL-C in adults with
homozygous familial hypercholesterolaemia as an adjunct to other lipidlowering 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 AZTOLYP and should continue on this diet during
treatment with AZTOLYP.
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 AZTOLYP 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 AZTOLYP 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
AZTOLYP should be used with caution in patients with hepatic
impairment (see sections 4.4 and 5.2). AZTOLYP 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 reevaluated 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
AZTOLYP 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
It is recommended that liver function tests be performed before
treatment begins and thereafter when clinically indicated. 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
AZTOLYP is recommended (see section 4.8).
AZTOLYP 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 lifethreatening 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 predisposing 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 reintroduction 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.
Excipients
AZTOLYP 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 coadministration of these medicinal products with atorvastatin cannot be
4.5 Interaction with other medicinal products and other forms of
interaction
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 coadministration 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
AZTOLYP. However, lipid effects were greater when AZTOLYP 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 coadministered, steady-state digoxin concentrations increased slightly.
Patients taking digoxin should be monitored appropriately.
Oral contraceptives
Co-administration of AZTOLYP with an oral contraceptive produced
increases in plasma concentrations of norethindrone and ethinyl
oestradiol.
Warfarin
In a clinical study in patients receiving chronic warfarin therapy,
coadministration of atorvastatin 80 mg daily with warfarin caused a
small decrease of about 1.7 seconds in prothrombin time during the first
4 days of dosing which returned to normal within 15 days of atorvastatin
treatment. Although only very rare cases of clinically significant
anticoagulant interactions have been reported, prothrombin time should
be determined before starting atorvastatin in patients taking coumarin
anticoagulants and frequently enough during early therapy to ensure
that no significant alteration of prothrombin time occurs. Once a stable
prothrombin time has been documented, prothrombin times can be
monitored at the intervals usually recommended for patients on
coumarin anticoagulants. If the dose of atorvastatin is changed or
discontinued, the same procedure should be repeated. Atorvastatin
therapy has not been associated with bleeding or with changes in
prothrombin time in patients not taking anticoagulants.
Paediatric population
Drug-drug interaction studies have only been performed in adults. The
extent of interactions in the paediatric population is not known. The
above mentioned interactions for adults and the warnings in section 4.4
should be taken into account for the paediatric population.

* Contains one or more components that inhibit CYP3A4 and can
increase plasma concentrations of medicinal products metabolized by
CYP3A4. Intake of one 240 ml glass of grapefruit juice also resulted in a
decreased AUC of 20.4% for the active orthohydroxy metabolite. Large
quantities of grapefruit juice (over 1.2 l daily for 5 days) increased AUC
of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites).
^ Total atorvastatin equivalent activity
Increase is indicated as “↑”, decrease as “ ”
OD = once daily; SD = single dose; BID = twice daily; QID = four times
daily

Women of childbearing potential
Women of child-bearing potential should use appropriate contraceptive
measures during treatment (see section 4.3).
Pregnancy
AZTOLYP 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, AZTOLYP should not be used in women who are
pregnant, trying to become pregnant or suspect they are pregnant.
Treatment with AZTOLYP 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 AZTOLYP 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).
 

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

In the atorvastatin placebo-controlled clinical trial database of 16,066
(8755 Atorvastatin 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
AZTOLYP.
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.
Very rare: the potential for generally non-serious and reversible
cognitive side effects (memory loss, confusion, etc.)
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 AZTOLYP. 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 AZTOLYP. 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 AZTOLYP, similar to
other HMG-CoA reductase inhibitors in clinical trials. Levels above 10
times the normal upper range occurred in 0.4% AZTOLYP-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).
Rare:
• Increases in glycosylated hemoglobin (HbA1c) and fasting serum
glucose levels have been reported with statin use.
- To reports any side effect(s):
• Saudi Arabia
-The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Other GCC States:
- Please contact the relevant competent authority.
 

Specific treatment is not available for AZTOLYP 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.
 

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 HMG-CoA 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.
- Please contact the relevant competent authority.
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 lipid-lowering 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 predefined 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:

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, placebocontrolled 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:

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 LDL-C 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: LDL-cholesterol 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
 

The film coated tablets contain the following excipients:
Calcium carbonate - Microcrystalline cellulose - Lactose monohydrate -
Croscarmellose sodium – Polysorbate 80 - Hydroxypropyl cellulose -
Magnesium stearate - Opadry White 03F28421
 

Not applicable.
 

Store below 30°C.
Store in the original package
 

How supplied
Forming Aluminium / Aluminium blister pack.
Packs of 30 tablets.
 

No special requirements.