Composition:

Active substance:

Atorvastatin calcium;

Each film-coated tablet contains:

Atorvastatin calcium equivalent to Atorvastatin…………10 mg/20 mg

Additional ingredients: Lactose monohydrate, Microcrystalline cellulose, calcium

carbonate, Povidone (K 30), Croscarmellose sodium, Colloidal anhydrous silica,

Magnesium stearate, Opadry Pink 03F84827, Isopropyl alcohol, Purified water

Indications:

Hypercholesterolaemia

Lolip 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.

Lolip 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, as an adjunct to correction of other risk factors.

Administration and Dosage:

The patient should be placed on a standard cholesterol-lowering diet before receiving Lolip

and should continue on this diet during treatment with Lolip.

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.

Lolip 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.

Side effects:

In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Lolip 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 Lolip.

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:

Neadache.

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:

Iiver 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 Lolip. 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 Lolip. 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 Lolip, similar to other HMG-CoA reductase inhibitors in

clinical trials. Levels above 10 times the normal upper range occurred in 0.4% Lolip-treated

patients.

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.

Adverse Drug reaction*:

”Inform doctors about unexpected reactions after using drugs”.

Drug Interactions:

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.

CYP3A4 inhibitors

Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of

atorvastatin. 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 avoided lower

starting and maximum doses of atorvastatin should be considered and appropriate clinical

monitoring of the patient is recommended.

Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole)

may increase plasma concentrations of atorvastatin. 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 coadministration

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.

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.

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 Lolip. However, lipid effects were greater

when Lolip 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 postmarketing

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 Lolip 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.

Precautions in usage:

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 abnormalities resolve. Should an increase in transaminases of

greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or

withdrawal of Lolip is recommended.

Lolip 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.

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

and special populations including genetic subpopulations.

 In such situations, the risk of treatment should be considered in relation to

possible benefit, and clinical monitoring is recommended.

 If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment

should not be started.

Creatine kinase measurement

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

presence of any plausible alternative cause of CK increase as this makes value interpretation

difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should

be remeasured within 5 to 7 days later to confirm the results.

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.

The concurrent use of atorvastatin and fusidic acid is not recommended, therefore,

temporary suspension of atorvastatin may be considered during fusidic acid therapy.

Paediatric use

Developmental safety in the paediatric population has not been established.

Interstitial lung disease

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

especially with long term therapy. 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.

Contraindications:

Lolip is contraindicated in patients:

 With hypersensitivity to the active substance or to any of the excipients of this

medicinal product

 With active liver disease or unexplained persistent elevations of serum transaminases

exceeding 3 times the upper limit of normal

 During pregnancy, while breast-feeding and in women of child-bearing potential not

using appropriate contraceptive measures.

Overdosage:

Specific treatment is not available for Lolip 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.

Pharmaceutical Form: Tablets.

Pharmacotherapeutic group: Lipid lowering agent

ATC code: C10AA05

Pharmacologic properties:

Pharmacodynamics:

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.

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.

Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for

cardiovascular events and cardiovascular mortality.

Pharmacokinetics:

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.