TOTALIP - PACKAGE LEAFLET - LEAFLETS

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Totalip - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Atorvastatin

TOTALIP 10 mg film-coated tablets

Totalip package inserts are available for pack sizes:

TOTALIP 10 mg film-coated tablets
TOTALIP 20 mg film-coated tablets
TOTALIP 40 mg film-coated tablets
TOTALIP 80 mg film-coated tablets
TOTALIP 5 mg chewable tablets
TOTALIP 10 mg chewable tablets
TOTALIP 20 mg chewable tablets
TOTALIP 40 mg chewable tablets

Indications Why is Totalip used? What is it for?

TOTALIP belongs to a class of medicines called statins, which regulate lipid (fat) levels.

TOTALIP is used to reduce blood lipid levels, known as cholesterol and triglycerides, when a low-fat diet and lifestyle changes have not been successful.

If you are at high risk of cardiovascular disease, TOTALIP can also be used to reduce this risk, even if your cholesterol levels are normal. A standard diet to reduce cholesterol should be continued during treatment.

Contraindications When Totalip should not be used

Do not take TOTALIP

if you are hypersensitive (allergic) to atorvastatin, or similar medicines used to lower blood lipids, or to any of the other ingredients of this medicine - see Section 6 for details.
if you have or have ever had a disease affecting the liver
if the results of liver function tests have shown unexplainably altered values
if you are a woman of childbearing age and do not use a reliable method of contraception
if you are pregnant or planning to become pregnant
if you are breastfeeding

Precautions for use What you need to know before taking Totalip

Take special care with TOTALIP

Below are the reasons why TOTALIP may not be suitable for you:

if you have had a previous stroke with brain haemorrhage or if you have low fluid reserves in the brain due to previous strokes
if you have kidney problems
if you have a poorly functioning thyroid gland (hypothyroidism)
if you have had repeated or unexplained muscle pain, a personal or family history of muscle problems
if you have had previous muscle problems during treatment with other lipid-lowering medicines (e.g. other medicines of the statin or fibrate class)
if you regularly consume large amounts of alcohol
if you have a history of liver disease
if you are over 70 years old

Check with your doctor or pharmacist before taking TOTALIP

If you suffer from severe respiratory failure

If any of these apply to you, your doctor will need to carry out a blood test before and possibly during treatment with TOTALIP to predict the risk of muscle-related side effects. The risk of muscle related side effects (eg rhabdomyolysis) is known to increase when certain medicines are taken at the same time (see Section 2 "Taking TOTALIP with other medicines")

While you are being treated with this medicine, your doctor will carefully check that you do not have diabetes or that you are not at risk of developing diabetes. You are at risk of developing diabetes if you have high blood sugar and fat levels, if you are overweight and have high blood pressure.

Interactions Which drugs or foods can modify the effect of Totalip

Taking TOTALIP with other medicines

Some medicines can alter the effect of TOTALIP or the effect of these medicines can be changed by TOTALIP. This type of interaction may reduce the effect of one or both medicines. Alternatively, it may increase the risk or severity of side effects including a wasting muscle condition known as rhabdomyolysis, described in Section 4:

Medicines used to change the way the immune system works, e.g. cyclosporine
Some antibiotics or antifungals, eg. erythromycin, clarithromycin, telithromycin, ketoconazole, itraconazole, voriconazole, fluconazole, posaconazole, rifampicin, fusidic acid
Other medicines used to regulate lipid levels, eg. gemfibrozil, other fibrates, colestipol
Some calcium channel blockers used for angina or high blood pressure, eg amlodipine, diltiazem; medicines to regulate heart rhythm, eg digoxin, verapamil, amiodarone
Medicines used to treat HIV, eg ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.
Other medicines known to interact with TOTALIP include ezetimibe (which lowers cholesterol), warfarin (reduces blood clot formation), oral contraceptives, stiripentol (an anticonvulsant for epilepsy), cimetidine (used for pain stomach and peptic ulcer), phenazone (pain reliever) and antacids (indigestion products containing aluminum and magnesium)
Medicines not subject to medical prescription: St. John's wort.

Always tell your doctor if you are taking or have recently taken any other medicines, even those without a prescription.

Taking TOTALIP with food and drink

See Section 3 for instructions on how to take TOTALIP. Note the following:

Grapefruit juice

You should not drink more than one or two small glasses of grapefruit juice a day as large amounts of grapefruit juice can alter the effects of TOTALIP.

Alcohol

Avoid drinking too much alcohol while taking this medicine. See Section 2 for more details. "Take special care with TOTALIP".

Warnings It is important to know that:

Pregnancy and breastfeeding

Do not take TOTALIP if you are pregnant or planning to become pregnant.

Do not take TOTALIP if you think you may get pregnant unless you are using an effective method of contraception.

Do not take TOTALIP if you are breastfeeding.

The safety of TOTALIP during pregnancy and lactation has not yet been demonstrated.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Usually this drug does not affect the ability to drive or use machines. However, do not drive if this medicine affects your ability to drive. Do not use tools or machines if your ability to use them is impaired by this medicine.

Important information about some of the ingredients of TOTALIP

If you have been told by your doctor that you are intolerant to some types of sugar, contact your doctor before taking this medicine.

Dose, Method and Time of Administration How to use Totalip: Posology

Before starting treatment, your doctor will prescribe a low cholesterol diet and you will also need to follow the diet while taking TOTALIP.

The usual starting dose of TOTALIP is 10 mg once a day in adults and children aged 10 years and over. If necessary, this dose can be increased by your doctor until the dose you need is reached. Your doctor will adjust the dosage at intervals of 4 or more weeks.The maximum dose of TOTALIP is 80 mg once a day for adults and 20 mg once a day for children.

TOTALIP tablets should be swallowed whole with water and can be taken at any time of the day, with or without food. However, try to take the tablets at the same time each day.

Always take TOTALIP exactly as your doctor has told you. If you are not sure, consult your doctor or pharmacist.

The duration of treatment with TOTALIP is determined by the doctor.

If you have the impression that the effect of TOTALIP is too strong or too weak, contact your doctor.

Overdose What to do if you have taken too much Totalip

If you take more TOTALIP than you should

If you accidentally take too many TOTALIP tablets (more than your usual daily dose), contact your doctor or the nearest hospital for advice.

If you forget to take TOTALIP

If you forget to take a dose, take your next dose at the correct time. Do not take a double dose to make up for a forgotten tablet.

If you stop taking TOTALIP

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Totalip

Like all medicines, TOTALIP can cause side effects, although not everybody gets them.

If you experience any of the following serious side effects, stop taking your tablets and tell your doctor immediately or go to the nearest hospital emergency department.

Rare side effects: present in 1 to 10 out of 10,000 patients:

Serious allergic reaction which causes swelling of the face, tongue and throat which can cause great difficulty in breathing.
Serious condition associated with severe peeling and swelling of the skin, blistering of the skin, mouth, eyes, genitals and fever. Skin rash with reddish patches, located especially on the palms of the hands or soles of the feet, which may blister
If you experience muscle weakness, achiness or pain and particularly if you feel unwell and have a high fever at the same time, this can be caused by abnormal muscle breakdown which can be fatal and can lead to kidney problems.

Very rare side effects: affecting less than 1 in 10,000 patients:

If you experience unexpected or unusual bleeding or bruising, this may suggest a liver disorder. You should see your doctor as soon as possible.

Other side effects that can occur with TOTALIP

Common side effects (1 to 10 out of 100 patients) include:

Inflammation of the nasal passages, pain in the throat, nose bleeding,
Allergic reactions
Increase in blood sugar levels (if you have diabetes you should continue to closely monitor your blood sugar levels), increase in blood creatinine kinase
Headache
Nausea, constipation, flatulence, indigestion, diarrhea,
Joint pain, muscle pain and back pain,
Abnormal laboratory tests for liver function

Uncommon side effects (1 to 10 out of 1000 patients) include:

Anorexia (loss of appetite), weight gain, decreased blood sugar levels (if you have diabetes you should continue to monitor your blood sugar closely)
Nightmares, insomnia
Dizziness, reduced sensation or tingling in the fingers and toes, reduced sensitivity to pain or touch, taste disturbance, memory loss
Blurred vision
Ringing in the ears and / or head
Vomiting, belching, upper and lower abdominal pain, pancreatitis (inflammation of the pancreas with stomach pain)
Hepatitis (inflammation of the liver)
Rash, skin rash and itching, hives, hair loss
Neck pain, muscle fatigue
Fatigue, malaise, weakness, chest pain, swelling especially in the ankles (edema), increased body temperature
urine test positive for white blood cells

Rare side effects (1 to 10 out of 10,000 patients) include:

visual disturbances
unexpected bleeding or hematoma
jaundice (yellowing of the skin and whites of the eyes)
damage to the tendons

Very rare side effects present in less than 1 in 10,000 patients include:

allergic reaction - symptoms may include sudden wheezing and chest pain or tightness in the chest, swelling of the eyelids, face, lips, mouth, tongue or throat, difficulty in breathing, collapse
hearing loss
gynecomastia (breast enlargement in men and women).

Possible side effects reported with some statins (drugs of the same type):

sexual difficulties
depression
breathing difficulties including persistent cough and / or wheezing or fever
diabetes. It is more likely if you have high blood sugar and fat levels, are overweight and have high blood pressure. Your doctor will monitor you during treatment with this medicine.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

Keep out of the reach and sight of children. This medicinal product does not require any special storage conditions.

Do not use TOTALIP after the expiry date (EXP) which is stated on the label or carton. The expiry date refers to the last day of the month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What TOTALIP contains

The active ingredient of TOTALIP is atorvastatin.

Each tablet contains 10 mg of atorvastatin (as atorvastatin calcium trihydrate)

The other ingredients of TOTALIP are: calcium carbonate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, polysorbate 80, hyprolose and magnesium stearate.

TOTALIP tablet coating contains hypromellose, macrogol 8000, titanium dioxide (E171), talc, simethicone, emulsifiers stearates, thickening agents, benzoic acid and sorbic acid

Description of the appearance of TOTALIP and contents of the pack

TOTALIP film-coated tablets are white and round in shape. They are marked "10" on one side and "ATV" on the other.

TOTALIP tablets are available in blister packs of 4, 7, 10, 14, 20, 28, 30, 50, 56, 84, 98 and 100 film-coated tablets and in hospital packs of 200 (10x20) or 500 coated tablets. with film and bottles of 90 film-coated tablets.

This medicine is available as 5 mg, 10 mg, 20 mg, 40 mg chewable tablets and 10 mg, 20 mg, 40 mg and 80 mg film-coated tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Totalip can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TOTALIP 10 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg atorvastatin (as atorvastatin calcium trihydrate).

Excipients:

Each TOTALIP 10 mg tablet contains 27.25 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets

White, round shaped film-coated tablets marked "10" on one side and "ATV" on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Hypercholesterolemia

TOTALIP is indicated as an adjunct to diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides in adults, adolescents and children aged 10 years and over with primary hypercholesterolaemia including familial hypercholesterolemia (heterozygous variant) or mixed hyperlipemia (corresponding to Types IIa and IIb of the Fredrickson classification) when the response to diet and other non-pharmacological measures is inadequate.

TOTALIP is also indicated to reduce total cholesterol and LDL cholesterol in adults with homozygous familial hypercholesterolemia in addition to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not available.

Prevention of cardiovascular disease

Prevention of cardiovascular events in adult patients at high risk for a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.

04.2 Posology and method of administration

Dosage

The patient should be placed on a standard cholesterol-lowering low-fat diet prior to receiving TOTALIP and should continue the diet during treatment with TOTALIP.

Dosage should be individualized taking into account baseline LDL cholesterol levels, therapy goal and patient response.

The usual starting dose is 10 mg once a day. Dosage adjustments should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.

Primary hypercholesterolemia and mixed hyperlipemia

The majority of patients were controlled with TOTALIP 10 mg once daily. A therapeutic response is evident within two weeks and the maximum therapeutic response is usually achieved within 4 weeks. In the course of chronic therapy, the response is maintained.

Hypercholesterolemia heterozygous familial

Patients should start with TOTALIP 10 mg per day. The dosage should be individualized and adjusted every 4 weeks up to 40 mg per day. Thereafter, the dose can be increased to a maximum of 80 mg per day or a bile acid sequestering agent can be combined with 40 mg of atorvastatin once daily.

Homozygous familial hypercholesterolaemia

Only limited data are available (see section 5.1).

The dosage of atorvastatin in patients with homozygous familial hypercholesterolaemia ranges from 10 to 80 mg / day (see section 5.1). In these patients, atorvastatin should be used as an adjunct to other lipid-lowering treatments (eg LDL apheresis) or if such treatments are unavailable.

Prevention of cardiovascular disease

In the primary prevention studies a dose of 10 mg / day was used. To achieve the cholesterol (LDL) levels required by current guidelines, higher doses may be required.

Patients with renal insufficiency

No dosage adjustment is required (see section 4.4).

Patients with hepatic insufficiency

TOTALIP should be used with caution in patients with hepatic insufficiency (see sections 4.4 and 5.2). TOTALIP is contraindicated in patients with active liver disease (see section 4.3).

Use in the elderly

The efficacy and tolerability in patients over 70 years of age treated with the recommended doses are similar to those seen in the general population.

Pediatric use

Hypercholesterolemia

Pediatric use should only be undertaken by physicians experienced in the treatment of pediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.

For patients 10 years of age and older, the recommended starting dose of atorvastatin is 10 mg per day with titration up to 20 mg per day. Titration should be done based on the individual response and tolerability of pediatric patients. Safety information for pediatric patients treated with doses above 20 mg, corresponding to approximately 0.5 mg / kg, is limited.

Experience in children aged 6-10 years is limited (see section 5.1). Atorvastatin is not indicated for the treatment of patients less than 10 years of age.

Other pharmaceutical forms / strengths may be more appropriate for this patient population.

Method of administration

TOTALIP is for oral use. Each daily dose is given as a single dose and can be administered at any time of the day, regardless of meals.

04.3 Contraindications

TOTALIP is contraindicated in the following cases:

- Hypersensitivity to the active substance or to any of the excipients of the medicinal product listed in section 6.1

- Active liver disease or with unexplained persistent increases in transaminases, more than 3 times the upper limit of normal

- Pregnancy, lactation and in women of childbearing potential not using appropriate contraceptive measures (see section 4.6).

04.4 Special warnings and appropriate precautions for use

Effects on the liver

Liver function tests should be performed prior to initiation of treatment and periodically thereafter. Patients presenting with any signs or symptoms suggestive of liver damage should undergo liver function tests. Patients who develop elevated transaminases should be monitored until Normalization of values If an increase in transaminases of more than 3 times the upper limit of normal persists, dose reduction or discontinuation of TOTALIP is recommended (see section 4.8).

TOTALIP should be used with caution in patients who consume large quantities of alcohol and / or who have a history of liver disease.

Prevention of Stroke through Aggressive Reduction of Cholesterol Levels (SPARCL study)

A post-hoc analysis of stroke subtypes in patients without ischemic cardiomyopathy (CHD) who had had a stroke or a recent transient ischemic attack (TIA), found a higher incidence of haemorrhagic stroke in patients who started treatment with atorvastatin. 80 mg compared to the placebo group. The increased risk was particularly observed in patients with previous haemorrhagic stroke or lacunar infarction at study enrollment. For patients with previous haemorrhagic stroke or lacunar infarction, the benefit / risk balance of using atorvastatin 80 mg is uncertain and the potential risk of haemorrhagic stroke should be carefully considered before starting treatment (see section 5.1).

Effects on skeletal muscles

Atorvastatin, like other HMG-CoA reductase inhibitors, can on rare occasions affect skeletal muscle and can cause myalgia, myositis and myopathy that can progress to rhabdomyolysis, a potentially fatal condition characterized by marked increases in creatine phosphokinase (CPK). (> 10 times the ULN), myoglobinemia and myoglobinuria which can lead to renal failure.

Before the treatment

Atorvastatin should be prescribed with caution in patients with predisposing factors for rhabdomyolysis. Creatine phosphokinase (CPK) level should be measured before starting treatment in the presence of the following clinical conditions:

- Renal impairment

- Hypothyroidism

- Personal or family history of hereditary muscle disorders

- Previous history of muscle toxicity associated with the use of a statin or a fibrate

- Previous history of liver disease and / or when large quantities of alcoholic beverages are consumed

- In the elderly (age> 70 years) the need for these measurements should be assessed based on the presence of other predisposing factors for rhabdomyolysis

- Situations where increases in plasma levels occur, such as interactions (see section 4.5) and in specific patient groups including genetic subpopulations (see section 5.2)

In such situations, the risk of treatment should be weighed against the possible benefit and clinical monitoring is recommended.

If CPK levels are significantly elevated from baseline (> 5 times the ULN), treatment should not be initiated.

Measurement of creatine phosphokinase

Creatine phosphokinase (CPK) should not be measured after strenuous exercise or in the presence of any possible cause of increased CPK as this makes it difficult to interpret the value obtained.If CPK levels are significantly increased from baseline (> 5 times ULN), CPK levels should be re-measured within the next 5-7 days to confirm the results.

During the treatment

- Patients should be advised to promptly report muscle pain, cramps or weakness, particularly if associated with malaise or fever.

- If these symptoms occur when a patient is being treated with atorvastatin, their CPK levels should be measured. If these levels are significantly increased (> 5 times the ULN), treatment should be stopped.

- If muscle symptoms are severe and cause daily discomfort, even if CPK levels are ≤ 5 times ULN, treatment discontinuation should be considered.

- If symptoms resolve and CPK levels normalize, restarting atorvastatin or another statin at the lower dose and careful monitoring may be considered.

- Atorvastatin should be discontinued if clinically significant increases in CPK levels (> 10 x ULN) occur or if rhabdomyolysis is diagnosed or suspected.

Concomitant treatment with other medicinal products

The risk of rhabdomyolysis is increased when atorvastatin is co-administered with certain medicinal products that may increase plasma concentrations of atorvastatin such as potent CYP3A4 inhibitors or transport proteins (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, itraconazole) and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) The risk of myopathy may also increase with the concomitant use of gemfibrozil and other fibric acid derivatives, boceprevir, erythromycin, niacin, ezetimibe , telaprevir or the tipranavir / ritonavir combination If possible, alternative (non-interacting) therapies should be considered as alternatives to these medicinal products.

There have been very rare reports of immune-mediated necrotizing myopathy (Immune-Mediated Necrotizing Myopathy, IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

In cases where concomitant administration of these medicinal products and atorvastatin is necessary, the risks and benefits of treatment should be carefully weighed. When patients are taking medicinal products that increase the plasma concentration of atorvastatin, a lower starting dose of atorvastatin is recommended. In addition, in case of concomitant treatment with potent CYP3A4 inhibitors, a higher starting dose should be considered. of atorvastatin and appropriate clinical monitoring of these patients is recommended (see section 4.5).

Concomitant use of atorvastatin and fusidic acid is not recommended and therefore temporary withdrawal of atorvastatin may be considered during fusidic acid therapy (see section 4.5).

Pediatric use

The developmental safety of the pediatric 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 may include dyspnoea, non-productive cough, and deteriorating health (fatigue, weight loss, and fever). If a patient is suspected of developing interstitial lung disease, statin therapy should be discontinued.

Diabetes mellitus

Some evidence suggests that statins, as a class effect, increase blood glucose and in some patients, at high risk of developing diabetes, may induce a level of hyperglycemia such that antidiabetic therapy is appropriate. This risk, however, is outweighed by the reduction in vascular risk with the use of statins and therefore should not be a reason for discontinuation of treatment. Patients at risk (fasting glucose 5.6 - 6.9 mmol / l, BMI> 30kg / m2, elevated triglyceride levels, hypertension) must be monitored both clinically and biochemically in accordance with national guidelines.

Excipients

TOTALIP contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Effects of other medicinal products on atorvastatin

Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the transport proteins, namely the hepatic transporter OATP1B1. increased risk of myopathy. The risk may also be increased with concomitant administration of atorvastatin with other medicinal products that may induce myopathy, such as fibric acid derivatives 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). Concomitant administration of potent CYP3A4 inhibitors (eg cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinovir, atazanavir, etc.) possible, should be avoided. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided, lower initial and maximum doses should be considered and adequate clinical monitoring of these patients 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 CYP34A and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore the lowest maximum dose should be considered and clinical monitoring of the patient is recommended. when moderate CYP3A4 inhibitors are used concomitantly. Appropriate clinical monitoring is recommended after initiation of therapy or after dose adjustment of the inhibitor.

CYP3A4 inducers

Concomitant administration of atorvastatin and inducers of cytochrome P450 3A (e.g. efavirenz, rifampicin, St. John's wort) may result in variable reductions in plasma concentrations of atorvastatin. Due to the dual mechanism of interaction of rifampicin (induction of cytochrome P450 3A and inhibition of the transporter OATP1B1 in the hepatocyte), concomitant administration of atorvastatin and rifampicin is recommended, as delayed administration of atorvastatin following rifampicin administration has been associated with a significant decrease in plasma concentrations of atorvastatin. The effect of rifampicin on atorvastatin concentrations in hepatocytes is however unknown and if co-administration cannot be avoided patients should be carefully monitored for efficacy.

Transport protein inhibitors

Transport protein inhibitors (eg cyclosporine) may increase the systemic exposure of atorvastatin (see Table 1). The effects of inhibition of the uptake of liver transporters on atorvastatin concentrations in hepatocytes are not known. If co-administered. cannot be avoided, dose reduction and clinical monitoring for efficacy are 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 concomitant administration of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin should be used for therapeutic effect to be achieved and patients should be adequately monitored (see section 4.4).

Ezetimibe

Use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased when ezetimibe is co-administered with atorvastatin. Appropriate clinical monitoring is recommended for these patients.

Colestipol

Plasma concentrations of atorvastatin and its active metabolites were reduced (approximately 25%) when colestipol was co-administered with TOTALIP. However, the effects on lipids were greater when TOTALIP and colestipol were administered simultaneously than when administered alone.

Fusidic acid

Interaction studies between atorvastatin and fusidic acid have not been conducted. As with other statins, muscle related events, including rhabdomyolysis, have been reported with this association in the post-marketing setting. The mechanism of this interaction is not known. Patients should be closely monitored and temporarily withholding treatment with atorvastatin may be appropriate.

Colchicine

Although interaction studies between atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine. Caution should be exercised when prescribing atorvastatin with colchicine.

Effects of atorvastatin on other medicinal products

Digoxin

Co-administration of repeated doses of digoxin and atorvastatin 10 mg slightly altered steady-state plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately.

Oral contraceptives

Co-administration of TOTALIP and an oral contraceptive resulted in increased plasma concentrations of norethindrone and ethinylestradiol.

Warfarin

In a clinical study in patients on chronic warfarin treatment, concomitant administration of atorvastatin 80 mg daily caused a small decrease of approximately 1.7 seconds in prothrombin time during the first 4 days of dosing, which returned to normal within 15 days. days of treatment with atorvastatin. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting atorvastatin therapy in patients on coumarin anticoagulants and often enough during therapy to ensure that there is no significant changes in prothrombin time. Once a stable prothrombin time has been documented, prothrombin times can be monitored at intervals usually recommended in patients on coumarin anticoagulants. If doses of atrovastatin are changed or discontinued, the same procedure should be repeated. Atorvastatin therapy has not been associated with bleeding or other changes in prothrombin time in patients not receiving anticoagulants.

Pediatric population

Interaction studies with other medicinal products have only been conducted in adults. The extent of interactions in the pediatric population is unknown. The interactions described above for adults and the warnings given in section 4.4 should be considered for the pediatric population.

Table 1: Effects of concomitantly administered medicinal products on the pharmacokinetics of atorvastatin

Co-administration of medicines and dosage Atorvastatin Dose (mg) AUC & Variations Clinical recommendations # Tipranavir 500 mg BID / Ritonavir 200 mg BID, 8 days (14 - 21 days) 40 mg day 1, 10 mg day 20 ↑ 9.4 fold In cases where co-administration with atorvastatin is necessary, do not exceed 10 mg of atorvastatin per day. Clinical monitoring of these patients is recommended Telaprevir 750 mg every 8 hours, 10 days 20 mg, SD ↑ 7.9 fold Ciclosporin 5.2 mg / kg / day, stable dose 10 mg OD for 28 days ↑ 8.7 fold Lopinavir 400 mg BID / Ritonavir 100 mg BID, 14 days 20 mg OD for 4 days ↑ 5.9 fold In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. With doses of atorvastatin exceeding 20 mg, clinical monitoring of these patients is recommended Clarithromycin 500 mg BID, 9 days 80 mg OD for 8 days ↑ 4.4 fold (Saquinavir 400 mg BID / Ritonavir 300 mg BID from 5-7 days, increases to 400 mg BID on day 8), 4-18 days, 30 min post atorvastatin dose 40 mg OD for 4 days ↑ 3.9 fold In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. With atorvastatin doses exceeding 40 mg, clinical monitoring of these patients is recommended. Darunavir 300 mg BID / Ritonavir 100 mg BID, 9 days 10 mg OD for 4 days ↑ 3.3 fold Itraconazole 200 mg OD, 4 days 40 mg SD ↑ 3.3 fold Fosamprenavir 700 mg BID / Ritonavir 100 mg BID, 14 days 10 mg OD for 4 days ↑ 2.5 fold Fosamprenavir 1400 mg BID, 14 days 10 mg OD for 4 days ↑ 2.3 fold Nelfinavir 1250 mg BID, 14 days 10 mg OD for 28 days ↑ 1.7 fold ^ No specific recommendations Grapefruit juice, 240 ml OD * 40 mg, SD ↑ 37% Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended. Diltiazem 240 mg OD, 28 days 40 mg, SD ↑ 51% After initiation or following a "dose adjustment of diltiazem, clinical monitoring of these patients is recommended. Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33%^ The lowest maximum dose and clinical monitoring of these patients is recommended Amlodipine 10 mg, single dose 80 mg, SD ↑ 18% No specific recommendations Cimetidine 300 mg QID, 2 weeks 10 mg OD for 2 weeks ↓ less than 1% ^ No specific recommendations Antacid suspensions of magnesium and aluminum hydroxide, 30ml QID, 2 weeks 10 mg OD for 4 weeks ↓ 35%^ No specific recommendations Efavirenz 600 mg OD, 14 days 10 mg for 3 days ↓ 41% No specific recommendations Rifampicin 600 mg OD, 7 days (co-administered) 40 mg SD ↑ 30% If co-administration cannot be avoided, concomitant administration of atorvastatin with rifampicin and clinical monitoring is recommended. Rifampicin 600 mg OD, 5 days (divided doses) 40 mg SD ↓ 80% Gemfibrozil 600 mg BID, 7 days 40mg SD ↑ 35% A lower starting dose and clinical monitoring of these patients is recommended Fenofibrate 160 mg OD, 7 days 40mg SD ↑ 3% A lower starting dose and clinical monitoring of these patients is recommended Boceprevir 800 mg TID, 7 days 40mg SD ↑ 2.3 fold A lower starting dose and clinical monitoring of these patients is recommended. The dose of atorvastatin should not exceed a daily dose of 20 mg during co-administration with boceprevir.

& Data of change in x-fold represent a simple proportion between co-administration and atorvastatin alone (e.g. 1-time = no change). Change data as% represent the% difference relative to atorvastatin alone (e.g. 0% = no change).

# See sections 4.4 and 4.5 for clinical evidence.

* contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of the medicinal product metabolised by CYP3A4. Intake of a 240 mL glass of grapefruit juice decreased AUC values by 20.4% for the active orthohydroxide metabolite. Large quantities of grapefruit juice (over 1.2 L per day for 5 days) increased the amount of grapefruit juice. Atorvastatin AUC of 2.5 times and the active AUC (atorvastatin and metabolites).

^ equivalent activity of total atorvastatin

Increase is indicated with "↑", decrease with "↓"

OD = once a day; SD = single dose; BID = twice a day; TID = three times a day; QID = four times a day

Table 2: Effects of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products

Atorvastatin and posology Co-administered medicinal products Medicinal product / Dose (mg) AUC & Variations Clinical recommendations 80 mg OD for 10 days Digoxin 0.25 mg OD, 20 days ↑ 15% Patients taking digoxin should be adequately monitored. 40 mg OD for 22 days Oral contraceptives OD, 2 months No specific recommendations - norethindrone 1 mg ↑ 28% - ethinyl estradiol 35 mcg ↑ 19% 80 mg OD for 15 days * Phenazone, 600 mg SD ↑ 3% No specific recommendations 10 mg, SD Tipranavir 500 mg BID / ritonavir 200 mg BID, 7 days No variations No specific recommendations 10 mg, OD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓ 27% No specific recommendations 10 mg OD for 4 days Fosamprenavir 700 mg BID / ritonavir 100 mg BID, 14 days No variations No specific recommendations

& Data% change represent the% difference relative to atorvastatin alone (e.g. 0% = no change)

* Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone

Increase is indicated with "↑", decrease with "↓"

OD = once a day; SD = single dose

04.6 Pregnancy and breastfeeding

Patients of childbearing age

During treatment, women of childbearing potential must use an adequate method of contraception (see section 4.3).

Pregnancy

TOTALIP is contraindicated in pregnancy (see section 4.3). Safety in pregnant women has not been established. No controlled clinical studies have been conducted with atorvastatin in pregnant women. Rare cases of congenital anomalies have been reported following intrauterine exposure to HMG-CoA reductase inhibitors. Animal studies have shown reproductive toxicity (see section 5.3).

Treatment of mothers with atorvastatin can reduce fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process and usually the discontinuation of lipid-lowering drugs during pregnancy has little impact on the long-term risk associated with primary hypercholesterolemia.

For these reasons, TOTALIP should not be used in women who are pregnant or trying to get pregnant or who suspect they are pregnant. Treatment with TOTALIP should be suspended for the duration of pregnancy or until it has been assessed whether the patient is pregnant (see section 4.3.)

Feeding time

It is unknown 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). Due to its potential serious side effects in women. taking TOTALIP should not breastfeed 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 and female fertility (see section 5.3).

04.7 Effects on ability to drive and use machines

TOTALIP has negligible influence on the ability to drive or use machines.

04.8 Undesirable effects

In controlled clinical trials conducted with atorvastatin versus placebo, in 16,066 patients treated (8755 with atorvastatin vs 7311 with placebo) for a mean period of 53 weeks, 5.2% of patients treated with atorvastatin discontinued treatment due to adverse reactions compared with 4% of patients treated with placebo.

The table below shows the safety profile of TOTALIP, based on data from clinical studies and considerable post-marketing experience.

Estimated frequencies of events are based on the following convention: common (≥ 1/100,

Infections and infestations:

Common: nasopharyngitis

Disorders of the blood and lymphatic system

Rare: thrombocytopenia

Disorders of the immune system

Common: allergic reactions.

Very rare: anaphylaxis

Metabolism and nutrition disorders

Common: hyperglycemia.

Uncommon: hypoglycaemia, weight gain, anorexia

Psychiatric disorders

Uncommon: nightmares, insomnia

Nervous system disorders

Common: headache.

Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia

Rare: peripheral neuropathy

Eye disorders:

Uncommon: blurred vision

Rare: visual disturbances

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, diarrhea.

Uncommon: vomiting, upper and lower abdominal pain, belching, pancreatitis

Hepatobiliary disorders

Uncommon: hepatitis

Rare: cholestasis

Very rare: hepatic failure

Skin and subcutaneous tissue disorders

Uncommon: urticaria, rash, pruritus, alopecia.

Rare: angioneurotic edema, bullous eruptions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal system disorders

Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain

Uncommon: neck pain, muscle fatigue

Rare: myopathy, myositis, rhabdomyolysis, tendinopathy sometimes complicated by rupture

Not known: immune-mediated necrotizing myopathy (see section 4.4)

Diseases of the reproductive system and breast

Very rare: gynaecomastia

General disorders and administration site conditions

Uncommon: malaise, asthenia, chest pain, peripheral edema, fatigue, pyrexia

Diagnostic tests

Common: liver function test abnormal, creatine phosphokinase increased

Uncommon: leukocyte positive urine test

As with other HMG-CoA reductase inhibitors, elevations in serum transaminases have been reported in patients treated with TOTALIP. These changes were usually mild and transient and did not require treatment discontinuation. Clinically significant (> 3 times ULN) increases in serum transaminases were observed in 0.8% of patients treated with TOTALIP. These increases were dose-dependent and reversible in all patients.

In clinical studies, elevated creatine phosphokinase (CPK) levels above 3 times the upper limit of normal were observed in 2.5% of patients treated with TOTALIP, similar to other HMG-CoA reductase inhibitors. Levels above 10 times the upper limit of normal were observed in 0.4% of patients treated with TOTALIP (see section 4.4).

Pediatric population

The clinical safety database includes safety data from 249 pediatric patients treated with atorvastatin, including 7 patients aged less than 6 years, 14 patients aged 6-9 years, and 228 patients aged 10-17 years.

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Common: Abdominal pain

Diagnostic tests

Common: Alanine aminotransferase increased, serum phosphokinase increased

Based on the available data, the frequency, type and severity of adverse reactions in children are expected to be the same as in adults. Long-term safety experience in the pediatric population is currently limited.

The following adverse events have been reported with statin use:

- Sexual dysfunction

- Depression

- Exceptional cases of interstitial lung disease, especially in long-term therapy (see section 4.4)

- Diabetes mellitus: frequency depends on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol / l, BMI> 30kg / m2, elevated triglyceride levels, history of hypertension).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. Website: www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

There is no specific treatment available for TOTALIP overdose. In case of overdose, treat symptomatically and institute supportive measures as needed. Liver function tests should be performed and serum CPK levels monitored. Due to the high plasma protein binding of atorvastatin, hemodialysis is not expected to significantly increase the clearance of atorvastatin.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: lipid modifying substances, HMG-CoA reductase inhibitors.

ATC code: C10AA05.

Atorvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme of conversion of 3-hydroxy-3-methyl-glutaryl Coenzyme A to mevalonic acid, a precursor of sterols, including cholesterol. Liver triglycerides and cholesterol are incorporated into very low density lipoproteins (VLDL) and released into the plasma for distribution to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL and are mainly catabolized by the high-affinity LDL receptor (LDL receptor).

Atorvastatin lowers plasma cholesterol and serum concentrations of lipoproteins, inhibiting HMG-CoA reductase, and consequently the biosynthesis of hepatic cholesterol, and increases the number of liver LDL receptors present on the cell surface, with consequent increased uptake and catabolism of LDL.

Atorvastatin reduces the production of LDL and the number of LDL particles. Atorvastatin causes a conspicuous and prolonged increase in LDL receptor activity, together with a useful modification of the quality of circulating LDL particles. Atorvastatin is effective in lowering LDL cholesterol in patients with homozygous familial hypercholesterolaemia, a population that has usually failed to respond to lipid-lowering medicinal products.

In a dose-response study, atorvastatin was shown to reduce concentrations of total cholesterol (30% - 46%), LDL cholesterol (41% - 61%), apolipoprotein B (34% - 50%) and triglycerides (14 % - 33%) causing simultaneously variable increases in HDL cholesterol and apolipoprotein A1.These results are consistent in patients with heterozygous familial hypercholesterolaemia, non-familial hypercholesterolemia and mixed hyperlipemia, including patients with non-insulin-dependent diabetes mellitus.

Reductions in total cholesterol, LDL-C and apolipoprotein B have been shown to reduce the risk of cardiovascular events and cardiovascular mortality.

Homozygous familial hypercholesterolaemia

In an 8-week multi-center compassionate use study with an optional extension phase of variable length, 335 patients were enrolled including 89 with homozygous familial hypercholesterolaemia. Of these 89 patients, the mean percentage reduction in LDL cholesterol was approximately 20%. Atorvastatin was administered in doses up to 80mg / day.

Atherosclerosis

In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL) the effect of an intensive lipid-lowering treatment with atorvastatin 80 mg and a standard lipid-lowering treatment with pravastatin 40 mg on coronary atherosclerosis by intravascular ultrasound (IVUS) was evaluated, during angiography, in patients with coronary artery disease. In this randomized, double-blind, multicenter, controlled clinical trial, IVUS was performed in 502 patients at baseline and at 18 months. No progression of atherosclerosis was observed in the atorvastatin group (n = 253).

Median percent changes in total atheroma volume (main study objective) from baseline were -0.4% (p = 0.98) for the atorvastatin group and + 2.7% (p = 0.001) for the pravastatin group (n = 249). Comparison of the effects of atorvastatin versus pravastatin was statistically significant (p = 0.02). The effect of aggressive lipid-lowering treatment on cardiovascular endpoints (eg, need for revascularization, non-fatal myocardial infarction, coronary death) was not evaluated in this study.

In the atorvastatin group, LDL cholesterol decreased to a mean of 2.04 mmol ± 0.8 (78.9 mg / dL ± 30) from a baseline of 3.89 mmol / L ± 0.7 (150 mg / dl ± 28) and in the pravastatin group, LDL cholesterol decreased to a mean value of 2.85 mmol / l ± 0.7 (110 mg / dl ± 26) from a baseline of 3.89 mmol / L ± 0.7 (150 mg / dL ± 26) (pPCR of 36.4% in the atorvastatin group compared to the 5.2% reduction observed in the pravastatin group (p

The results of the study were obtained with the 80 mg dose and therefore cannot be extrapolated to the lower dosages.

The safety and tolerability profiles were comparable between the two treatment groups.

The effect of lipid reduction on primary cardiovascular endpoints was not investigated in this study. Therefore, the clinical significance of these findings with respect to the prevention of primary and secondary cardiovascular events is unknown.

Acute coronary syndrome

In the MIRACL study, atorvastatin 80 mg was evaluated in 3,086 patients (atorvastatin n = 1,538; placebo n = 1,548) with acute coronary syndrome (non-Q myocardial infarction or unstable angina). Treatment was initiated during phase acute after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg / day increased the time to onset of the combined primary endpoint, defined as death from any cause, non-fatal myocardial infarction, cardiac arrest with resuscitation or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a 16% risk reduction (p = 0.048). This was mainly due to a 26% reduction in the risk of re-hospitalization for angina pectoris with evidence of myocardial ischaemia (p = 0.018). The other secondary endpoints did not individually reach statistical significance (overall: Placebo: 22.2%; Atorvastatin: 22.4%)

The safety profile of atorvastatin in the MIRACL study was in line with that described in section 4.8.

Prevention of cardiovascular disease

The effect of atorvastatin on fatal and non-fatal coronary artery disease was evaluated in a randomized double-blind placebo-controlled Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOTT-LLA). Patients were hypertensive, aged 40 to 79 years, with no previous myocardial infarction or treatment for angina, and with total cholesterol (CT) 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 coronary heart disease in first degree relative, CT: HDL-C> 6, peripheral vascular disease, left ventricular hypertrophy, previous cerebrovascular events, specific ECG changes, proteinuria / albuminuria. Not all patients included were at high risk for a first cardiovascular event.

Patients were treated with antihypertensive therapy (amlodipine or atenolol-based regimen) and atorvastatin 10 mg / day (n = 5,168) or placebo (n = 5,137).

The effect of atorvastatin on absolute and relative risk reduction was as follows:

Event Relative Risk Reduction (%) No. of Events (Atorvastatin vs. placebo) Absolute Risk Reduction1 (%) p-value (Fatal CHD and 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 event rates that occurred over the median follow-up period of 3.3 years.

CDH = coronary heart disease; MI = myocardial infarction

Total mortality and cardiovascular mortality did not significantly reduce (185 vs. 212 events, p = 0.17 and 74 vs. 82 events, p = 0.51). In subgroup analyzes based on gender (81% men, 19% women), a beneficial effect of atorvastatin was found in men, but could not be established in women, possibly due to the low event rates in the subgroup of women. Total and cardiovascular mortality were numerically higher in women (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was a significant treatment interaction due to antihypertensive therapy at baseline. The primary endpoint (fatal CHD and 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 heart disease was also evaluated in a multicentre, randomized, double-blind, placebo-controlled study, the Collaborative Atorvastatin Diabetes Study (CARDS) conducted in patients with type 2 diabetes of age. 40 - 75 years, with no previous 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, ongoing smoking, retinopathy, microalbuminuria or macroalbuminuria.

Patients were treated with atorvastatin 10 mg / day (n = 1,428) or placebo (n = 1,410) for a median follow-up period of 3.9 years.

The effect of atorvastatin on absolute and relative risk reduction 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, death from acute CHD, unstable angina, CABG, PTCA, revascularization, stroke] 37% 83 vs. 127 3,2% 0,0010 MI (fatal and non-fatal AMI, silent MI) 42% 38 vs. 64 1,9% 0,0070 Icuts (fatal and non-fatal) 48% 21 vs. 39 1,3% 0,0163

1Based on difference in crude event rates that occurred over the median follow-up period of 3.9 years.

AMI = acute myocardial infarction, CHD = coronary artery disease, CABG = coronary artery bypass surgery, MI = myocardial infarction, PTCA = percutaneous transluminal coronary angioplasty

No differences in treatment effect were observed in relation to gender, age or baseline LDL-C level. A positive trend in mortality rate was observed (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group, p = 0.0592).

Recurrent stroke

During the SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), the effects of atorvastatin 80 mg once daily or placebo on stroke were evaluated in 4,731 patients who had had stroke or transient ischemic attack (TIA) within the previous 6 months and who had no history of coronary heart disease (CHD) . 60% of patients were male between 21 and 92 years of age (mean age 63) with a mean baseline LDL of 133 mg / dL (3.4 mmol / L). LDL-C was 73 mg / dL (1.9 mmol / L) during treatment with atorvastatin and 129 mg / dL (3.3 mmol / L) during placebo treatment.The 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 adjusting for baseline factors) versus placebo. All cause mortality was 9.1% (216/2365) for atorvastatin versus 8, 9% (211/2366) of the placebo.

A post-hoc analysis found that atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% versus 274/2366, 11.6%, p = 0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% versus 33/2366, 1.4%, p = 0.02) compared to placebo.

• The risk of haemorrhagic stroke was increased in patients enrolled in the study with previous haemorrhagic stroke (7/45 atorvastatin versus 2/48 placebo; HR 4.06; 95% CI, 0.84 - 19.57) and the risk of ischemic stroke is similar for the two groups (3/45 atorvastatin versus 2/48 placebo; HR 1.64; 95% CI, 0.27 - 9.82).

• The risk of haemorrhagic stroke was increased in patients enrolled in the study and with previous lacunar infarction (20/708 atorvastatin versus 4/701 placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also reduced in these patients (79/708 atorvastatin versus 102/701 placebo; HR 0.76; 95% CI, 0.57-1.02). The net risk of stroke may be higher in patients with a previous lacunar infarction taking atorvastatin 80 mg once daily.

All cause mortality was 15.6% (7/45) in the atorvastatin group compared to 10.4% (5/48) in the subgroup of patients with prior haemorrhagic 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 infarction.

Pediatric population

Heterozygous Familial Hypercholesterolemia in Pediatric Patients aged 6-17 years

An 8-week open-label study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety and tolerability of atorvastatin in children and adolescents with genetically confirmed heterozygous familial hypercholesterolaemia and baseline LDL cholesterol ≥ 4 mmol / L. A total of 39 children and adolescents, aged 6-17 years, were enrolled. Group A included 15 children aged 6-12 years and Tanner Stage 1. Group B included 24 children aged 10-17 years and Tanner Stage ≥2.

The starting dose of atorvastatin was one 5 mg chewable tablet per day in group A and one 10 mg tablet per day in group B. If a subject did not reach the target LDL cholesterol level

The mean values of LDL cholesterol, total cholesterol, VLDL cholesterol and apolipoprotein B were reduced at the 2nd week in all subjects. In subjects in whom the dose was doubled, further reductions were observed as early as the beginning of the 2nd week, first evaluation after dose increase. The mean percent reduction in lipid parameters was similar for both groups, regardless of whether subjects remained on the starting dose or doubled the starting dose. At week 8, the percent change from baseline for LDL and total cholesterol averaged 40% and 30%, respectively, across the drug exposure range.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients aged 10-17 years

In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and girls (post-menarche phase), aged 10-17 years (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) o severe hypercholesterolaemia were randomized to treatment with atorvastatin (n = 140) or placebo (n = 47) for 26 weeks and subsequently all treated with atorvastatin for 26 weeks. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and then gradually increased to 20 mg if the LDL cholesterol level was> 3.36 mmol / L. Atorvastatin significantly reduced plasma levels of total cholesterol, LDL cholesterol, triglycerides and apolipoprotein B in the 26-week double-blind phase. The mean achieved LDL cholesterol was 3.38 mmol / l (range: 1, 81-6.26 mmol / L) in the atorvastatin group versus 5.91 mmol / L (range: 3.93-9.96 mmol / L) obtained in the placebo group in the 26-week double phase blind.

Another pediatric study with atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10-18 years showed that atorvastatin (N = 25) caused a significant reduction in LDL cholesterol at week 26 (p

A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia) included 46 patients treated with atorvastatin titrated based on response to treatment (some subjects were treated with 80 mg of atorvastatin daily). The study lasted. 3 years: LDL cholesterol was reduced by 36%.

The long-term efficacy of pediatric atorvastatin treatment in reducing adult morbidity and mortality has not been established.

The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in children aged 0 and treatment of heterozygous hypercholesterolemia and in children aged 0 to

05.2 Pharmacokinetic properties

Absorption

Atorvastatin is rapidly absorbed following oral administration; maximum plasma concentrations (Cmax) are reached within 1 - 2 hours. The extent of absorption increases in proportion to the dose of atorvastatin. After oral administration, the bioavailability of the film-coated tablets is 95% - 99% of atorvastatin oral solution. Absolute bioavailability of atorvastatin is approximately 12% and systemic availability of HMG-CoA reductase inhibiting activity is approximately 30%. Low systemic availability is attributed to presystemic clearance in the gastrointestinal mucosa and / or hepatic first pass metabolism.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is 98% or more bound to plasma proteins.

Biotransformation

Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In addition to other metabolic pathways, these products are also metabolised via glucuronidation. In vitro inhibition of HMG-CoA reductase. by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of the circulating inhibitory activity of HMG-CoA reductase is attributed to active metabolites.

Elimination

Atorvastatin is eliminated primarily in the bile following hepatic and / or extrahepatic metabolism. However, the drug does not appear to undergo significant enterohepatic recirculation. In humans, the mean plasma elimination half-life of atorvastatin is approximately 14 hours. The half-life of HMG-CoA reductase inhibiting activity is approximately 20 - 30 hours due to the contribution of active metabolites.

Special populations

Elderly patients:

Plasma concentrations of atorvastatin and its active metabolites in the healthy elderly are higher than those in the young adult, while the effects on lipids are comparable to those seen in younger patient populations.

Pediatric patients:

In an 8-week open-label study, pediatric patients aged 6-17 years, Tanner Stage 1 (n = 15) and Tanner Stage ≥2 (n = 24), with heterozygous familial hypercholesterolaemia and baseline LDL cholesterol ≥ 4 mmol / l were treated with once daily atorvastatin 5 mg or 10 mg chewable tablets or atorvastatin 10 mg or 20 mg film-coated tablets, respectively. Body weight was the only significant covariant in the population pharmacokinetic model of atorvastatin. The apparent oral clearance of atorvastatin in pediatric subjects was similar to that in adults, using allometric equations based on body weight. Significant reductions in LDL cholesterol and total cholesterol were observed over the dose range of exposure to atorvastatin and o-hydroxyiatorvastatin.

Gender of belonging:

Concentrations of atorvastatin and its active metabolites in women differ from those in men (women: C about 20% higher and AUC about 10% lower). These differences were of no clinical significance, resulting in no clinically significant differences. significant effects on lipids between men and women.

Patients with renal impairment:

Renal disease does not affect the plasma concentration or lipid-lowering effects of atorvastatin and its active metabolites.

Patients with hepatic impairment:

Plasma concentrations of atorvastatin and its active metabolites are markedly increased (approximately 16 times the Cmax and approximately 11 times the AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).

SLOC1B1 polymorphism:

Hepatic uptake of all HMG-CoA reductase inhibitors, including atorvastatin, involve the OATP1B1 transporter. polymorphism in the gene encoded OATP1B1 (SLCO1B1 c.521CC) is associated with 2.4 times higher atorvastatin exposure (AUC) than in individuals without the genotype variant (c.521TT). Genetically insufficient absorption of atorvastatin is also possible in these patients. The possible consequences on efficacy are not known.

05.3 Preclinical safety data

Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and in one in vivo assay. Atorvastatin was not carcinogenic in rats, but high doses in mice (resulting in 6-11 times the AUC0-24h achieved in humans at the highest recommended doses) showed hepatocellular adenomas in males and hepatocellular carcinomas in females.

Experimental animal studies have shown that HMG-CoA reductase inhibitors may have effects on embryonic development or the fetus. In rats, rabbits and dogs, atorvastatin had no effect on fertility and was not teratogenic, however at doses believed to be maternally toxic, fetal toxicity was observed in rats and rabbits. The development of rat progeny is was delayed and postnatal survival reduced during exposure of mothers to high doses of atorvastatin. In rats, there is evidence of placental transmission. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether atorvastatin or its metabolites are excreted in milk.