LIPITOR 20 MG

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor's instructions!

The dosage and treatment regimen will be determined by the

doctor only.

This medicine is not intended for children below 10 years

of age.

Complete the treatment regimen recommended by the doctor.

Even if there is an improvement in your health, do not discontinue

treatment with the medicine without consulting a doctor.

Reduction of the dosage should generally be done gradually.

Attention:

Wait at least two hours between taking this medicine and taking

antacids.

Do not exceed the recommended dose!

The tablet must not be crushed/halved/chewed, since it is

film-coated.

If you took an overdose or if a child has accidentally swallowed

the medicine, immediately proceed to a hospital emergency room

and bring the package of the medicine with you.

If you forget to take the medicine at the required time, take a

dose as soon as you remember, but never take a double dose!

Adhere to the treatment regimen as recommended by the

doctor.

Do not take medicines in the dark! Check the label and the dose

each time you take medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine,

consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Lipitor

may cause side effects

in some users. Do not be alarmed when reading the list of side

effects. You may not suffer from any of them.

Discontinue use of the medicine and refer to a doctor

immediately if:

you develop a severe allergic reaction which causes swelling

of the face, tongue and throat and you suffer from breathing

difficulties (rare).

you develop a severe skin reaction, including peeling and swelling

of the skin, blisters on the skin, mouth, eyes, or genitals and

fever (rare).

you develop a rash with pink-red spots on the palms of the hands

and soles of the feet (rare).

you develop muscle weakness, muscle tenderness or pain, and if

you simultaneously feel bad and have a high fever. This may result

from muscle tissue breakdown which can be life-threatening and

cause kidney problems (rare).

you suffer from sudden bleeding or bruises – this may indicate

liver problems. Refer to the doctor immediately for advise (very

rare).

Additional side effects:

Common side effects – inflammation of the nasal passages, sore

throat, nose bleed, allergic reaction, increased blood sugar levels

(if you have diabetes, continue to strictly monitor blood sugar

levels), increase in blood creatine kinase, headache, nausea,

constipation, flatulence, indigestion, diarrhea, joint and muscle

pains, back pain, blood test results that indicate impaired liver

function.

Uncommon side effects – loss of appetite, weight gain, decreased

blood sugar levels (if you have diabetes, continue to strictly monitor

blood sugar levels), nightmares, insomnia, dizziness, numbness

or tingling in the fingers and toes, decreased sensation of pain or

touch, altered sense of taste, memory loss, blurred vision, ringing

in the ears/head, vomiting, hiccups, abdominal pain, pancreatitis

(which may cause severe abdominal pain), liver inflammation, rash,

itching, urticaria, hair loss, neck pain, muscle fatigue, fatigue,

feeling unwell, weakness, chest pain, swelling of the ankles

(edema), fever, white blood cells in the urine.

Rare side effects – visual disturbances, unexpected bleeding

and bruising, yellowing of the skin and whites of the eyes, tendon

injury.

Very rare side effects – hearing loss, enlargement of the breasts

in men and women.

Side effects reported with use of other statins – sexual function

difficulties, depression, shortness of breath, persistent cough,

fever, diabetes.

- If one of the side effects worsens, or if you suffer from a side

effect not mentioned in the leaflet, consult with the doctor.

5. HOW SHOULD THE MEDICINE BE STORED?

Store the medicine in a dry place, below 25°C.

Avoid poisoning! This medicine and any other medicine must be

kept in a safe place out of the reach of children and/or infants

to avoid poisoning. Do not induce vomiting without explicit

instruction from the doctor.

Do not use the medicine after the expiry date (exp. date) that

appears on the package. The expiry date refers to the last day

of that month.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains:

Calcium carbonate, Microcrystalline cellulose, Lactose

monohydrate, Croscarmellose sodium, Polysorbate 80,

Hydroxypropyl cellulose, Magnesium stearate, Opadry white,

Simethicone emulsion.

The preparation contains lactose:

Lipitor

10 mg: 27.25 mg lactose monohydrate.

Lipitor

20 mg: 54.5 mg lactose monohydrate.

Lipitor

40 mg: 109 mg lactose monohydrate.

Lipitor

80 mg: 218 mg lactose monohydrate.

What does the medicine look like and what are the contents

of the package:

Lipitor

10 mg: a round, white, film-coated tablet, with "ATV"

imprinted on one side and "10" on the other side.

Lipitor

20 mg: a round, white, film-coated tablet, with "ATV"

imprinted on one side and "20" on the other side.

Lipitor

40 mg: a round, white, film-coated tablet, with "ATV"

imprinted on one side and "40" on the other side.

Lipitor

80 mg: a round, white, film-coated tablet, with "ATV"

imprinted on one side and "80" on the other side.

License

holder:

Pfizer

Pharmaceuticals

Israel

Ltd.,

9 Shenkar St., Herzliya Pituach 46725.

Manufacturer: Pfizer GmbH, Germany.

This leaflet was checked and approved by the Ministry of Health

in October 2013.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health:

Lipitor

10 mg: 126.04.30587.00/01

Lipitor

20 mg: 126.05.30588.00/01

Lipitor

40 mg: 125.43.30440.05/06

Lipitor

80 mg: 125.44.30446.11/12

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

Name, form and strength of the preparation

Lipitor

®

10 mg

Lipitor

®

20 mg

Lipitor

®

40 mg

Lipitor

®

80 mg

Film-coated tablets

Atorvastatin (as calcium) 10 mg, 20 mg, 40 mg, 80 mg

A list of inactive and allergenic ingredients in the preparation can

be found in section 6.

Read this leaflet carefully in its entirety before using the

medicine. This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor or

pharmacist.

This medicine has been prescribed to treat you. Do not pass

it on to others. It may harm them even if it seems to you that

their medical condition is similar to yours. This medicine is not

intended for children below 10 years of age.

WHAT DO I HAVE TO KNOW ABOUT THE MEDICINE?

This medicine contains lactose and therefore should not be

used in patients suffering from a sensitivity to lactose and/or

impaired ability to break down lactose and/or impaired ability

to absorb glucose or galactose.

Be sure to maintain a low-cholesterol diet and to perform

physical activity in addition to use of this medicine.

For information on side effects, please see section 4.

1. WHAT IS THE MEDICINE INTENDED FOR?

To reduce elevated blood lipid levels (cholesterol and

triglycerides) and increase HDL.

To prevent cardiovascular diseases (such as: myocardial

infarction and/or stroke) in patients at high risk for a primary

event.

In patients with a coronary heart disease, Lipitor

reduces the

risk of myocardial infarction, stroke, hospitalization due to heart

failure, angina pectoris and/or need for catheterization.

Therapeutic group:

Statins – HMG-CoA reductase enzyme inhibitors.

2. BEFORE USING THE MEDICINE

Do not use the medicine if:

you are sensitive (allergic) to the active ingredient or to any

of the other ingredients contained in the medicine or to other

medicines from this family.

you are suffering from an active liver disease or if you have

persistent elevation of blood transaminase levels.

you are pregnant or breastfeeding, planning to become

pregnant or to breastfeed.

you are a woman of child-bearing age and you do not use

reliable contraception.

do not use the medicine in children below 10 years of age

and in girls who have not yet started menstruating.

you are taking cyclosporine, telaprevir (for the treatment of

hepatitis C), or combination of tipranavir and ritonavir (for the

treatment of the AIDS virus).

you are suffering from a disease of the skeletal muscles.

Do not use the medicine without consulting a doctor before

commencing treatment:

if you are suffering, or have suffered in the past, from impaired

function of the liver or kidneys or from a brain hemorrhage.

if you regularly consume large quantities of alcoholic

beverages.

Special warnings regarding use of the medicine

! If you are sensitive to any food or medicine, inform the doctor

before taking the medicine.

! Before commencing treatment with the medicine, a liver function

test should be performed.

! During treatment with the medicine, liver function and cholesterol

level tests should be performed.

! Inform the doctor that you are taking this medicine before

undergoing any kind of surgery (including dental surgery).

! Statins may increase the risk of diabetes in patients who

are in a risk group; these patients require blood sugar level

monitoring.

If you are taking, or have recently taken, other medicines,

including non-prescription medicines and nutritional

supplements, tell the doctor or pharmacist. It is particularly

important to inform the doctor or pharmacist if you are taking:

medicines that in combination with atorvastatin increase its

blood concentration and may increase the risk of muscle

pain:

Antibiotics, such as: erythromycin, clarithromycin, fusidic

acid, other cholesterol-lowering preparations (e.g., fibric acid

derivatives, nicotinic acid), antifungal preparations from the

azole group (e.g., itraconazole), boceprevir (for treatment

of hepatitis C), colchicine (for gout), anti-HIV medicines

(protease inhibitors) such as: saquinavir, ritonavir, darunavir,

fosamprenavir, lopinavir and nelfinavir.

medicines that in combination with atorvastatin increase its

blood concentration:

diltiazem (for the heart and blood vessels), rifampin (antibiotic)

(when taken simultaneously with atorvastatin), amlodipine (for

treatment of high blood pressure).

medicines that in combination with atorvastatin lower its blood

concentration:

efavirenz (e.g., Stocrin), rifampin (antibiotic) when not

administered in proximity to atorvastatin, antacids (containing

magnesium or aluminum).

medicines whose blood concentration rises when administered

in combination with atorvastatin:

oral contraceptives containing norethindrone or ethinylestradiol,

digoxin (for the heart) – you should be monitored.

If you are taking anticoagulants (warfarin) – coagulation factors

should be monitored.

Do not eat grapefruit or drink grapefruit juice during the course

of treatment with the preparation.

Do not take Lipitor

together with the following medicines:

Cyclosporine, telaprevir (for treatment of hepatitis C) or a

combination of tipranavir and ritonavir (for treatment of the

AIDS virus).

Use of the medicine and food

Swallow the tablet whole with a small amount of water. The

medicine can be taken with or without a meal.

Maintain a low-cholesterol diet during the course of treatment

with this medicine.

Do not eat grapefruit or drink grapefruit juice during the course

of treatment with the preparation.

Use of the medicine and alcohol

During the course of treatment with the medicine, do not drink

excessive amounts of alcohol (see section 2, subsection "Do not

use the medicine without consulting a doctor before commencing

treatment").

Pregnancy and breastfeeding

Do not use the medicine if you are pregnant or breastfeeding,

planning to become pregnant or breastfeed.

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lipitor 10 mg

Lipitor 20 mg

Lipitor 40 mg

Lipitor 80 mg

2 THERAPEUTIC INDICATION

Hypercholesterolaemia

LIPITOR is indicated as an adjunct to diet for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B,

and triglycerides and to increase HDL-cholesterol in patients 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.

LIPITOR is also indicated to reduce total-C and LDL-C in patients with homozygous familial hypercholesterolaemia as an

adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Pediatric Patients (10-17 years of age)

LIPITOR is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to

17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following

findings are present:

a. LDL-C remains

190 mg/dL or

b. LDL-C remains

160 mg/dL and:

there is a positive family history of premature cardiovascular disease or

two or more other CVD risk factors are present in the pediatric patient

Prevention of cardiovascular disease

Prevention of cardiovascular and/or cerebrovascular events such as MI or stroke: as an adjunct to correction of other risk

factors such as hypertension in patients with three or more additional risk factors or diabetes with one additional risk factor.

In patients with clinically evident coronary heart disease, LIPITOR is indicated to:

Reduce the risk of non-fatal myocardial infarction

Reduce the risk of fatal and non-fatal stroke

Reduce the risk for revascularization procedures

Reduce the risk of hospitalization for CHF

Reduce the risk of angina

3 DOSAGE AND ADMINISTRATION

General

Before instituting therapy with LIPITOR, an attempt should be made to control hypercholesterolemia with

appropriate diet, exercise and weight reduction in obese patients, and to treat underlying medical problems. The patient

should continue on a standard cholesterol lowering diet during treatment with LIPITOR. (see National Cholesterol

Education Program (NCEP) Guidelines, summarized in Table 1).

The usual starting dose is 10 mg or 20 mg once daily. The dosage range of LIPITOR is 10 to 80 mg once daily. Starting and

maintenance doses should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response.

Adjustment of dosage should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.

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Doses may be given at any time of day with or without food.

After initiation and/or upon titration of LIPITOR, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted

accordingly.

Therapy with lipid-altering agents should be a component of multiple-risk-factor intervention in individuals at increased risk

for atherosclerotic vascular disease due to hypercholesterolemia.

TABLE 1. NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes

and Drug Therapy in Different Risk Categories

Risk Category

LDL Goal

(mg/dL)

LDL Level at Which to

Initiate Therapeutic

Lifestyle Changes (mg/dL)

LDL Level at Which to Consider

Drug

Therapy (mg/dL)

or CHD risk

equivalents

(10-year risk >20%)

<100

(100-129: drug optional)

2+ Risk Factors

(10-year risk

20%)

<130

10-year risk 10%-20%:

10-year risk <10%:

0-1 Risk factor

<160

(160-189: LDL-lowering

drug optional)

CHD, coronary heart disease

Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of < 100 mg/dL

cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify

triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may call for deferring drug

therapy in this subcategory.

Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1

risk factor is not necessary.

After the LDL-C goal has been achieved, if the TG is still

200 mg/dL, non HDL-C (total-C minus HDL-C) becomes a

secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

Prior to initiating therapy with LIPITOR, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes

mellitus,

hypothyroidism,

nephrotic

syndrome,

dysproteinemias,

obstructive

liver

disease,

other

drug

therapy,

alcoholism) should be excluded, and a lipid profile performed to measure total-C, LDL-C, HDL-C, and TG. For patients

with TG <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation: LDL-C = total-C - (0.20 x

[TG] + HDL-C). For TG levels >400 mg/dL (<4.5 mmol/L) this equation is less accurate and LDL-C concentrations should

be determined by ultracentrifugation.

LIPITOR has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons

(Fredrickson Types I and V).

NCEP (National Cholesterol Education Program) Pediatric Panel Guidelines

Classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature

cardiovascular disease is summarized below:

Category

Total-C (mg/dL)

LDL-C (mg/dL)

Acceptable

Borderline

High

<170

170-199

<110

110-129

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Primary Hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed)

hyperlipidaemia (Fredrickson Types IIa and IIb)

Patients should be started with LIPITOR 10 mg daily. A therapeutic response is evident within two weeks, and the

maximum response is usually achieved within four weeks. The response is maintained during chronic therapy.Doses should

be individualized 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 LIPITOR.

Homozygous Familial Hypercholesterolaemia

The dosage of LIPITOR in patients with homozygous FH is 10 to 80 mg daily. LIPITOR should be used as an adjunct to

other lipid-lowering treatment (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

In a compassionate-use study of patients with homozygous familial hyper-cholesterolaemia, most patients responded to

80mg of atorvastatin with a greater than 15% reduction in LDL-C (18%-45%).

Severe dyslipidemias in Pediatric Patients

Experience in pediatrics is limited to a small number of patients (age 4-17 years) with severe dyslipidemias, such as familial

hypercholesterolemia. The recommended starting dose in this population is 10 mg of LIPITOR per day. The dose may be

increased to 80 mg daily, according to the response and tolerability. Doses should be individualized according to the

recommended goal of therapy (see

section 2 Therapeutic indications, and section 9.4 Pediatric Use

Adjustments should be made at intervals of 4 weeks or more.

Prevention of cardiovascular or cerebrovascular events

In the primary prevention trials the dose was 10 mg/day. Higher dosages may be necessary in order to attain (LDL-)

cholesterol levels according to current guidelines.

Use in Patients with Hepatic Insufficiency

(See sections

Contraindications and

6 Warnings and Precautions

)

Dosage in Patients with Renal Insufficiency

Renal disease has no influence on the plasma concentrations or on the LDL-C reduction with LIPITOR ; thus, no adjustment

of dose is required

section

6 Warnings and Precautions

Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors

In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor

(telaprevir), therapy with LIPITOR should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should

be used when prescribing LIPITOR and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole,

or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or

fosamprenavir plus ritonavir, therapy with LIPITOR should be limited to 20 mg, and appropriate clinical assessment is

recommended to ensure that the lowest dose necessary of LIPITOR is employed.In patients taking the HIV protease

inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with LIPITOR should be limited to 40 mg, and

appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPITOR is employed (see

section

6.1 Warnings and Precaution -Skeletal Muscle and section 8 Drug Interactions).

Use in Elderly

Efficacy and safety in patients older than 70 using recommended doses is similar to that seen in the

general population. (see

section

9.5 Use in Specific Populations- Geriatric Use

).

4 DOSAGE FORMS AND STRENGTHS

LIPITOR tablets are white round, film-coated, and are available in four strengths (see Table 1).

Table 1: LIPITOR Tablet Strengths and Identifying Features

Tablet Strength

Identifying Features

10 mg of atorvastatin

“10” on one side and “ATV” on the other

20 mg of atorvastatin

“20” on one side and “ATV” on the other.

40 mg of atorvastatin

“40” on one side and “ATV” on the other

80 mg of atorvastatin

“80” on one side and “ATV” on the other

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5

CONTRAINDICATIONS

Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase

Levels

Hypersensitivity to Any Component of This Medication [listed in section 11 (Description)]

Pregnancy

[see Use in Specific Population

(9.1)]

Lactation

[see Use in Specific Populations (9.2)]

6

WARNINGS AND PRECAUTIONS

6.1 Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with

LIPITOR and with other drugs in this class.

A history of renal impairment may be a risk factor for the development of

rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.

Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction

with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin

with certain drugs such as cyclosporine and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., clarithromycin,

itraconazole, and HIV and HCV protease inhibitors) increases the risk of myopathy/ rhabdomyolysis.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked

elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness,

particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing LIPITOR.

LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of the drugs listed

in Table 2. Physicians considering combined therapy of LIPITOR with any of these drugs should carefully weigh the

potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or

weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug.

Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the

aforementioned drugs

[see Drug Interaction

(7)]

. Periodic creatine phosphokinase (CPK) determinations may be

considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.

Prescribing recommendations for interacting agents are summarized in Table 2

[see Dosage and Administration

(3

, Drug

Interactions (8), and Clinical Pharmacology (12.3)]

Table 2. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents

Prescribing Recommendations

Cyclosporine, tipranavir plus ritonavir, glecaprevir plus

pibrentasvir, letermovir when co-administered with

cyclosporine

Avoid atorvastatin

Clarithromycin, itraconazole, saquinavir plus ritonavir*,

darunavir plus ritonavir, fosamprenavir, fosamprenavir plus

ritonavir, elbasvir plus grazoprevir, letermovir

Do not exceed 20 mg atorvastatin daily

Nelfinavir

Do not exceed 40 mg atorvastatin daily

Lopinavir plus ritonavir, simeprevir, fibric acid derivatives,

erythromycin, azole antifungals, lipid-modifying doses of

niacin, colchicine

Use with caution and lowest dose necessary

*Use the lowest dose necessary (12.3)

LIPITOR therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition

suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to

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rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and

electrolyte disorders, and uncontrolled seizures).

6.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated

with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist

despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing

myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be

necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation

of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

6.3 Liver Dysfunction

Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function.

Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum

transaminases occurred in 0.7% of patients who received LIPITOR in clinical trials. The incidence of these

abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.

One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated

with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase

levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations

continued treatment with a reduced dose of LIPITOR.

It is recommended that liver enzyme tests be obtained prior to initiating therapy with LIPITOR and repeated as clinically

indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins,

including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during

treatment with LIPITOR, promptly interrupt therapy. If an alternate etiology is not found, do not restart LIPITOR.

LIPITOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of

liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of

LIPITOR

[see Contraindications (5)]

6.4 Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including

LIPITOR.

Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical

studies have shown that LIPITOR does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects

of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-

gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly

with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone,

and cimetidine.

6.5 CNS Toxicity

Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve

vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up

to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-

under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in

each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been

observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100

mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum

recommended human dose of 80 mg/day.

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular

spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class

produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-

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dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans

taking the highest recommended dose.

6.6

Use in Patients with Recent Stroke or TIA

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where

LIPITOR 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding

6 months, a higher incidence of hemorrhagic stroke was seen in the LIPITOR 80 mg group compared to placebo (55, 2.3%

atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was

similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal

hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16,

0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a

higher incidence of hemorrhagic stroke in the atorvastatin group

[see Adverse Reactions (7.1)]

7

ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

Rhabdomyolysis and myopathy

[see Warnings and Precautions (6.1)]

Liver enzyme abnormalities

[see Warnings and Precautions (6.3)]

7.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical

trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates

observed in clinical practice.

In the LIPITOR placebo-controlled clinical trial database of 16,066 patients (8755 LIPITOR vs. 7311 placebo; age range

10–93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53

weeks, 9.7% of patients on LIPITOR and 9.5% of the patients on placebo discontinued due to adverse reactions regardless

of causality. The five most common adverse reactions in patients treated with LIPITOR that led to treatment discontinuation

and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase

increase (0.4%), and hepatic enzyme increase (0.4%).

The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients

treated with LIPITOR in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea

(6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).

Table 3 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater

than placebo in patients treated with LIPITOR (n=8755), from seventeen placebo-controlled trials.

Table 3.

Clinical adverse reactions occurring in > 2% in patients treated with any dose of

LIPITOR and at an incidence greater than placebo regardless of causality (% of patients).

Adverse Reaction*

Any dose

N=8755

10 mg

N=3908

20 mg

N=188

40 mg

N=604

80 mg

N=4055

Placebo

N=7311

Nasopharyngitis

12.9

Arthralgia

11.7

10.6

Diarrhea

14.1

Pain in extremity

Urinary tract

infection

Dyspepsia

Nausea

Musculoskeletal

pain

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Muscle Spasms

Myalgia

Insomnia

Pharyngolaryngeal

pain

* Adverse Reaction > 2% in any dose greater than placebo

Other adverse reactions reported in placebo-controlled studies include:

Body as a whole

: malaise, pyrexia;

Digestive system:

abdominal discomfort, eructation, flatulence, hepatitis, cholestasis;

Musculoskeletal system

: musculoskeletal pain, muscle fatigue, neck pain, joint swelling, lupus like syndrom;

Metabolic and

nutritional system

: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine

phosphokinase increase, hyperglycemia;

Nervous system

: nightmare;

Respiratory system:

epistaxis;

Skin and appendages

urticaria;

Special senses

: vision blurred, tinnitus;

Urogenital system:

white blood cells urine positive.

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT

[see Clinical Studies (14.1)]

involving 10,305 participants (age range 40–80 years, 19% women; 94.6%

Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with LIPITOR 10 mg daily (n=5,168) or placebo

(n=5,137), the safety and tolerability profile of the group treated with LIPITOR was comparable to that of the group treated

with placebo during a median of 3.3 years of follow-up.

Collaborative Atorvastatin Diabetes Study (CARDS)

In CARDS

[see Clinical Studies (14.1)]

involving 2,838 subjects (age range 39–77 years, 32% women; 94.3% Caucasians,

2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with LIPITOR 10 mg daily (n=1,428) or

placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions

between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.

Treating to New Targets Study (TNT)

In TNT

[see Clinical Studies (14.1)]

involving 10,001 subjects (age range 29–78 years, 19% women; 94.1% Caucasians,

2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with LIPITOR 10 mg daily (n=5006) or

LIPITOR 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in

the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404,

8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4–10

days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg.

Elevations of CK (≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%)

compared to the low-dose atorvastatin group (6, 0.1%).

Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL)

In IDEAL

[see Clinical Studies

(14.1)]

involving 8,888 subjects (age range 26–80 years, 19% women; 99.3% Caucasians,

0.4% Asians, 0.3% Blacks, 0.04% other) treated with LIPITOR 80 mg/day (n=4439) or simvastatin 20–40 mg daily

(n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the

treatment groups during a median follow-up of 4.8 years.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL involving 4731 subjects (age range 21–92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians,

3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6

months treated with LIPITOR 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher

incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4–10 days) in the atorvastatin group (0.9%)

compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%)

compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group

and 89 subjects (3.8%) in the placebo group

[see

Warnings and Precautions (6)]

In a post-hoc analysis, LIPITOR 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and

increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of

fatal hemorrhagic stroke was similar between groups (17 LIPITOR vs. 18 placebo). The incidence of non-fatal hemorrhagic

strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo

group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at

increased risk for hemorrhagic stroke [7 (16%) LIPITOR vs. 2 (4%) placebo].

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There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the LIPITOR 80

mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were

numerically smaller in the LIPITOR 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who

experienced non-cardiovascular death were numerically larger in the LIPITOR 80 mg group (5.0%) than in the placebo

group (4.0%).

Adverse Reactions from Clinical Studies of LIPITOR in Pediatric Patients

In a 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to 17 years) (n=140, 31% female;

92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR 10 to 20 mg daily,

as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo

[see Use

in Special Populations (9.4) and Clinical Studies (14.6)]

7.2

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of LIPITOR. Because these reactions are

reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or

establish a causal relationship to drug exposure.

Adverse reactions associated with LIPITOR therapy reported since market introduction, that are not listed above, regardless

of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema

multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture,

fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use

[see Warnings and

Precautions (6.1)]

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory

impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are

generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and

symptom resolution (median of 3 weeks).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an

online form

https://sideeffects.health.gov.il

8

DRUG INTERACTIONS

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives,

lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease

inhibitors, and itraconazole)

[see Warnings and Precautions (6.1) and

Clinical Pharmacology (12.3)]

8.1 Strong Inhibitors of CYP 3A4

LIPITOR is metabolized by cytochrome P450 3A4. Concomitant administration of LIPITOR with strong inhibitors of CYP

3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects

depend on the variability of effect on CYP 3A4.

Clarithromycin

Atorvastatin AUC was significantly increased with

concomitant administration of LIPITOR 80 mg with clarithromycin (500

mg twice daily) compared to that of LIPITOR alone

[see

Clinical Pharmacology (12.3)]

. Therefore, in patients taking

clarithromycin, caution should be used when the LIPITOR dose exceeds 20 mg

[see Dosage and Administration (2.6)

and

Warnings and Precautions (5.1)]

Combination of Protease Inhibitors

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Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR with several combinations of

protease inhibitors

[see

Clinical Pharmacology (12.3)]

. In patients taking tipranavir plus ritonavir or glecaprevir plus

pibrentasvir, concomitant use of LIPITOR should be avoided. In patients taking lopinavir plus ritonavir, or simeprevir, use

the lowest necessary LIPITOR dose. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir,

fosamprenavir plus ritonavir, or elbasvir plus grazoprevir, the dose of LIPITOR should not exceed 20 mg. In patients taking

nelfinavir the dose of LIPITOR should not exceed 40 mg and close clinical monitoring is recommended

[see Dosage and

Administration (3) and Warnings and Precautions (6.1)]

Itraconazole

Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 40 mg and itraconazole 200 mg

[see

Clinical Pharmacology (12.3)]

. Therefore, in patients taking itraconazole, caution should be used when the LIPITOR

dose exceeds 20 mg

[see

Dosage and Administration (3)

and

Warnings and Precautions (6.1)]

8.2 Grapefruit Juice

Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially

with excessive grapefruit juice consumption (>1.2 liters per day).

8.3 Cyclosporine

Atorvastatin is a substrate of the hepatic transporters. Atorvastatin-metabolites are substrates of the OATP1B1 transporter.

Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was

significantly increased with concomitant administration of LIPITOR 10 mg and cyclosporine 5.2 mg/kg/day compared to

that of LIPITOR alone

[see

Clinical Pharmacology (12.3)]

The co-administration of LIPITOR with cyclosporine should be avoided

[see Warnings and Precautions (6.1)]

8.4 Letermovir

Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to

atorvastatin (ratio of AUC: 3.29)

[see Clinical Pharmacology (12.3)]

. Letermovir inhibits efflux transporters P-gp, BCRP,

MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg

LIPITOR daily

[see Dosage and Administration (3)]

The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when

letermovir is co-administered with cyclosporine. Use of LIPITOR is not recommended in patients taking letermovir co-

administered with cyclosporine.

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.5 Glecaprevir and Pibrentasvir; Elbasvir and Grazoprevir

Concomitant administration of glecaprevir and pibrentasvir or elbasvir and grazoprevir may lead to increased plasma

concentrations of atorvastatin and an increased risk of myopathy.

Coadministration of glecaprevir and pibrentasvir with atorvastatin increase plasma concentrations of atorvastatin by 8.3-fold

due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, coadministration of LIPITOR in patients receiving

concomitant medications with products containing glecaprevir and pibrentasvir is not recommended.

Coadministration of elbasvir and grazoprevir with atorvastatin increase plasma concentrations of atorvastatin by 1.9-fold due

in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the dose of LIPITOR should not exceed 20 mg daily in

patients receiving concomitant medications with products containing elbasvir and grazoprevir

[see Dosage and

Administration (3), Warnings and Precautions (6.1), and Clinical Pharmacology (12.3)]

.6

Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with

gemfibrozil, concomitant administration of LIPITOR with gemfibrozil should be avoided

[see Warnings and Precautions

(6.1)]

.7

Other Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with

concurrent administration of other fibrates, LIPITOR should be administered with caution when used concomitantly with

other fibrates

[see Warnings and Precautions (6.1)]

.8

Niacin

The risk of skeletal muscle effects may be enhanced when LIPITOR is used in combination with niacin; a reduction in

LIPITOR dosage should be considered in this setting

[see

Warnings and Precautions (6.1)]

.9

Rifampin or other Inducers of Cytochrome P450 3A4

Concomitant administration of LIPITOR with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to

variable reductions in plasma concentrations of atorvastatin.

Due to the dual interaction mechanism of rifampin,

simultaneous co-administration of LIPITOR with rifampin is recommended, as delayed administration of LIPITOR after

administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

.10 Digoxin

When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased

[see Clinical Pharmacology (12.3)].

Patients taking digoxin should be monitored appropriately.

.11 Oral Contraceptives

Co-administration of LIPITOR and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol

[see

Clinical Pharmacology (12.3)]

. These increases should be considered when selecting an oral contraceptive for a woman

taking LIPITOR.

.12 Warfarin

LIPITOR had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin

treatment.

.13 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and

caution should be exercised when prescribing atorvastatin with colchicine.

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9

USE IN SPECIFIC POPULATIONS

9.1 Pregnancy

Risk Summary

LIPITOR is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is

no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol

synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, LIPITOR may cause

fetal harm when administered to a pregnant woman. LIPITOR should be discontinued as soon as pregnancy is recognized

[see Contraindications (5)]

. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated

risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no

evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human

exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m

). In rats

administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses

≥ 6 times the MRHD

(see Data)

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized

pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown

an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received

following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively

followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous

abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases

is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the

prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in

the first trimester when pregnancy was identified.

Animal Data

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was

administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day,

respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to

100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the

MRHD based on surface area (mg/m

). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-

implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there

was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.

In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20

(weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with

225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at

100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at

100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses

correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.

9.2 Lactation

Risk Summary

LIPITOR use is contraindicated during breastfeeding

[see Contraindications (5)]

. There is no available information on the

effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin

is present in human milk, but it has been shown that another drug in this class

passes into human milk and atorvastatin is

present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that

breastfeeding is not recommended during treatment with LIPITOR.

9.3 Females and Males of Reproductive Potential

Contraception

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LIPITOR may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use

effective contraception during treatment with LIPITOR

[see Use in Specific Populations (9.1)]

9.4 Pediatric Use

Heterozygous Familial Hypercholesterolemia (HeFH)

The safety and effectiveness of LIPITOR have been established in pediatric patients, 10 years to 17 years of age, with HeFH

as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels when, after an adequate trial of diet therapy, the

following are present:

LDL-C ≥ 190 mg/dL, or

LDL-C ≥ 160 mg/dL and

a positive family history of FH, or premature CVD in a first, or second-degree relative, or

two or more other CVD risk factors are present.

Use of LIPITOR for this indication is supported by evidence from

[see

Dosage and Administration (3), Adverse Reactions

(7.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]

A placebo-controlled clinical trial of 6 months duration in 187 boys and postmenarchal girls, 10 years to 17 years of

age. Patients treated with 10 mg or 20 mg daily LIPITOR had an adverse reaction profile generally similar to that

of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual

maturation in boys or on menstrual cycle length in girls.

A three year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who

were titrated to achieve a target LDL-C < 130 mg/dL. The safety and efficacy of LIPITOR in lowering LDL-C

appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study

design

Advise postmenarchal girls of contraception recommendations, if appropriate for the patient

[see Use in Specific

Populations (9.1), (9.3)]

The long-term efficacy of LIPITOR therapy initiated in childhood to reduce morbidity and mortality in adulthood has not

been established.

The safety and efficacy of LIPITOR have not been established in pediatric patients younger than 10 years of age with HeFH.

Homozygous Familial Hypercholesterolemia (HoFH)

Clinical efficacy of LIPITOR with dosages up to 80 mg/day for 1 year was evaluated in an uncontrolled study of patients

with HoFH including 8 pediatric patients

[see

Clinical Studies (14.5)]

9.5 Geriatric Use

Of the 39,828 patients who received LIPITOR in clinical studies, 15,813 (40%) were

65 years old and 2,800 (7%) were

75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects,

and other reported clinical experience has not identified differences in responses between the elderly and younger patients,

but greater sensitivity of some older adults cannot be ruled out. Since advanced age (

65 years) is a predisposing factor for

myopathy, LIPITOR should be prescribed with caution in the elderly.

9.6 Hepatic Impairment

Lipitor is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic

transaminase levels

[see Contraindications (5) and

Clinical Pharmacology (12.3)]

10

OVERDOSAGE

There is no specific treatment for LIPITOR overdosage. In the event of an overdose, the patient should be treated

symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins,

hemodialysis is not expected to significantly enhance LIPITOR clearance.

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11

DESCRIPTION

LIPITOR is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A

(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step

in cholesterol biosynthesis.

Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß,

-dihydroxy-5-(1-methylethyl)-3-phenyl-4-

[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin

calcium is (C

Ca3H

O and its molecular weight is 1209.42. Its structural formula is:

Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below.

Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in

ethanol; and freely soluble in methanol.

LIPITOR Tablets for oral administration contain 10, 20, 40, or 80 mg of atorvastatin and the following inactive ingredients:

calcium carbonate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose,

magnesium stearate, polysorbate 80Opadry White YS-1-7040 (hydroxypropyl methylcellulose, polyethylene glycol,

titanium dioxide, talc);simethicone emulsion.

12

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

LIPITOR is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-

methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, LIPITOR lowers

plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by

increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; LIPITOR also

reduces LDL production and the number of LDL particles.

12.2

Pharmacodynamics

LIPITOR, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action

and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration,

correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response

[see

Dosage and Administration (3)]

12.3

Pharmacokinetics

Absorption:

LIPITOR is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2

hours. Extent of absorption increases in proportion to LIPITOR dose. The absolute bioavailability of atorvastatin (parent

drug) is approximately 14% 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. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as

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assessed by Cmax and AUC, LDL-C reduction is similar whether LIPITOR is given with or without food. Plasma LIPITOR

concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with

morning. However, LDL-C reduction is the same regardless of the time of day of drug administration

[see Dosage and

Administration (3)]

Distribution:

Mean volume of distribution of LIPITOR is approximately 381 liters. LIPITOR is ≥98% bound to plasma

proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on

observations in rats, LIPITOR is likely to be secreted in human milk

[see

Contraindications (5) and

Use in Specific

Populations (9.2)]

Metabolism:

LIPITOR is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation

products.

In vitro

inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of

LIPITOR. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.

In vitro

studies suggest the importance of LIPITOR metabolism by cytochrome P450 3A4, consistent with increased plasma

concentrations of LIPITOR in humans following co-administration with erythromycin, a known inhibitor of this isozyme

[see Drug Interactions (8.1)]

. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion:

LIPITOR and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism;

however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of LIPITOR in

humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to

the contribution of active metabolites. Less than 2% of a dose of LIPITOR is recovered in urine following oral

administration.

Specific Populations

Geriatric:

Plasma concentrations of LIPITOR are higher (approximately 40% for Cmax and 30% for AUC) in healthy

elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of

drug in the elderly patient population compared to younger adults

[see Use in Specific Populations (9.5)]

Pediatric:

Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled

allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model

with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.

Gender:

Plasma concentrations of LIPITOR in women differ from those in men (approximately 20% higher for Cmax and

10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with LIPITOR between men

and women.

Renal Impairment:

Renal disease has no influence on the plasma concentrations or LDL-C reduction of LIPITOR; thus,

dose adjustment in patients with renal dysfunction is not necessary

[see Dosage and Administration (3

and Warnings and

Precautions (6.1)]

Hemodialysis:

While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected

to significantly enhance clearance of LIPITOR since the drug is extensively bound to plasma proteins.

Hepatic Impairment:

In patients with chronic alcoholic liver disease, plasma concentrations of LIPITOR are markedly

increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are

approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease

[see Contraindications

(5)]

Drug Interaction Studies

Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are

substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the

intestinal absorption and biliary clearance of atorvastatin.

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TABLE 4. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

Co-administered drug and

dosing regimen

Atorvastatin

Dose (mg)

Ratio of AUC

&

Ratio of

Cmax

&

Cyclosporine 5.2 mg/kg/day, stable dose

10 mg QD

for 28 days

8.69

10.66

Tipranavir 500 mg BID

/ritonavir

200 mg BID

, 7 days

10 mg, SD

9.36

8.58

Glecaprevir 400 mg QD

/pibrentasvir

120 mg QD

, 7 days

10 mg QD

for 7 days

8.28

22.00

Telaprevir 750 mg q8h

, 10 days

20 mg, SD

7.88

10.60

#, ‡

Saquinavir 400 mg BID

/ ritonavir

400 mg BID

, 15 days

40 mg QD

for 4 days

3.93

4.31

Elbasvir 50 mg QD

/grazoprevir 200 mg

, 13 days

10 mg SD

1.94

4.34

Simeprevir 150 mg QD

, 10 days

40 mg SD

2.12

1.70

Clarithromycin 500 mg BID

, 9 days

80 mg QD

for 8 days

4.54

5.38

Darunavir 300 mg BID

/ritonavir

100 mg BID

, 9 days

10 mg QD

for 4 days

3.45

2.25

Itraconazole 200 mg QD

, 4 days

40 mg SD

3.32

1.20

Letermovir 480 mg QD

, 10 days

20 mg SD

3.29

2.17

Fosamprenavir 700 mg BID

/ritonavir

100 mg BID

, 14 days

10 mg QD

for 4 days

2.53

2.84

Fosamprenavir 1400 mg BID

, 14 days

10 mg QD

for 4 days

2.30

4.04

Nelfinavir 1250 mg BID

, 14 days

10 mg QD

for 28 days

1.74

2.22

Grapefruit Juice, 240 mL QD

40 mg, SD

1.37

1.16

Diltiazem 240 mg QD

, 28 days

40 mg, SD

1.51

1.00

Erythromycin 500 mg QID

, 7 days

10 mg, SD

1.33

1.38

Amlodipine 10 mg, single dose

80 mg, SD

1.18

0.91

Cimetidine 300 mg QID

, 2 weeks

10 mg QD

for 2 weeks

1.00

0.89

Colestipol 10 g BID

, 24 weeks

40 mg QD

for 8 weeks

0.74**

Maalox TC

30 mL QID

, 17 days

10 mg QD

for 15 days

0.66

0.67

Efavirenz 600 mg QD

, 14 days

10 mg for 3 days

0.59

1.01

Rifampin 600 mg QD

, 7 days

(co-administered)

40 mg SD

1.12

2.90

Rifampin 600 mg QD

, 5 days (doses

separated)

40 mg SD

0.20

0.60

Gemfibrozil 600 mg BID

, 7 days

40 mg SD

1.35

1.00

Fenofibrate 160 mg QD

, 7 days

40 mg SD

1.03

1.02

Boceprevir 800 mg TID

, 7 days

40 mg SD

2.32

2.66

&

Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).

See Sections 5.1 and 7 for clinical significance.

Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been

reported with excessive grapefruit consumption (≥ 750 mL - 1.2 liters per day).

Ratio based on a single sample taken 8-16 h post dose.

Due to the dual interaction mechanism of rifampin, 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 dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in

atorvastatin exposure when used clinically is likely to be higher than what was observed in this study.

Therefore, caution should be applied and the lowest dose necessary should be used.

Once daily

Twice daily

Single dose

Three times daily

Four times daily

Every 8 hours

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TABLE 5. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

Atorvastatin

Co-administered drug and dosing regimen

Drug/Dose (mg)

Ratio of AUC

Ratio of Cmax

80 mg QD

for 15 days

Antipyrine, 600 mg SD

1.03

0.89

80 mg QD

for 10 days

Digoxin 0.25 mg QD

, 20 days

1.15

1.20

40 mg QD

for 22 days

Oral contraceptive QD

, 2 months

- norethindrone 1 mg

- ethinyl estradiol 35

1.28

1.19

1.23

1.30

10 mg, SD

Tipranavir 500 mg BID

/ritonavir

200 mg BID

, 7 days

1.08

0.96

10 mg QD

for 4 days

Fosamprenavir 1400 mg BID

14 days

0.73

0.82

10 mg QD

for 4 days

Fosamprenavir 700 mg

/ritonavir 100 mg BID

, 14 days

0.99

0.94

See Section 7 for clinical significance.

Once daily

Twice daily

Single dose

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in

high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a

plasma AUC (0-24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.

A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas

in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0–24) values of

approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.

In vitro,

atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the

Ames test with

Salmonella typhimurium

Escherichia coli,

the HGPRT forward mutation assay in Chinese hamster lung

cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the

in vivo

mouse

micronucleus test.

In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on

fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in

fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3

months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and

epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased

sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on

semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.

14

CLINICAL STUDIES

14.1 Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of LIPITOR on fatal and non-fatal coronary heart

disease was assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years), without a previous myocardial

infarction and with TC levels ≤251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3 of the following

cardiovascular risk factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of

CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy

(14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this

double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP <140/90 mm Hg for

non-diabetic patients; <130/80 mm Hg for diabetic patients) and allocated to either LIPITOR 10 mg daily (n=5168) or

placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics

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of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed

for a median duration of 3.3 years.

The effect of 10 mg/day of LIPITOR on lipid levels was similar to that seen in previous clinical trials.

LIPITOR significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo

group vs. 40 events in the LIPITOR group) or non-fatal MI (108 events in the placebo group vs. 60 events in the LIPITOR

group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for LIPITOR vs. 3.0% for placebo), p=0.0005

(see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal

dysfunction. The effect of LIPITOR was seen regardless of baseline LDL levels. Due to the small number of events, results

for women were inconclusive.

Figure 1: Effect of LIPITOR 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary

Heart Disease Death (in ASCOT-LLA)

LIPITOR also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for

LIPITOR and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined

significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for

LIPITOR and 2.3% for placebo). There was no significant difference between the treatment groups for death due to

cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of LIPITOR on cardiovascular disease (CVD)

endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40–75

with type 2 diabetes based on WHO criteria,

without prior history of cardiovascular disease and with LDL

160 mg/dL and TG

600 mg/dL. In addition to diabetes,

subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or

microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this

multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either LIPITOR 10 mg daily

(1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the

occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary

revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.

Baseline characteristics of subjects were: mean age of 62 years, mean HbA

7.7%; median LDL-C 120 mg/dL; median TC

207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.

The effect of LIPITOR 10 mg/day on lipid levels was similar to that seen in previous clinical trials.

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LIPITOR significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the LIPITOR

group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001)

(see Figure 2). An effect of LIPITOR was seen regardless of age, sex, or baseline lipid levels.

LIPITOR significantly reduced the risk of stroke by 48% (21 events in the LIPITOR group vs. 39 events in the placebo

group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the LIPITOR group vs. 64

events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the

treatment groups for angina, revascularization procedures, and acute CHD death.

There were 61 deaths in the LIPITOR group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).

Figure 2: Effect of LIPITOR 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial

infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS

In the Treating to New Targets Study (TNT), the effect of LIPITOR 80 mg/day vs. LIPITOR 10 mg/day on the reduction in

cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident

coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in

period with LIPITOR 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of LIPITOR and

followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following

major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and

fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128,

98, and 47 mg/dL during treatment with 80 mg of LIPITOR and 99, 177, 152, 129, and 48 mg/dL during treatment with 10

mg of LIPITOR.

Treatment with LIPITOR 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548

events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3

and Table 6). The overall risk reduction was consistent regardless of age (<65, ≥65) or gender.

Cumulative Hazard (%)

Placebo

Atorvastatin

HR 0.63 (0.48-0.83) p=0.001

Cumulative Hazard (%)

Time to First Primary Endpoint Through Four (4) Years of Follow-up (Years)

Placebo

Atorvastatin

Cumulative Hazard (%)

Placebo

Atorvastatin

HR 0.63 (0.48-0.83) p=0.001

Cumulative Hazard (%)

Time to First Primary Endpoint Through Four (4) Years of Follow-up (Years)

Placebo

Atorvastatin

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Figure 3: Effect of LIPITOR 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events

(TNT)

Atorvastatin 10 mg

Atorvastatin 80 mg

HR 0.78 (0.69-0.89) P=0.0002

Time to First Major Cardiovascular Endpoint (Years)

Subjects (%) Experiencing Event

Atorvastatin 10 mg

Atorvastatin 80 mg

HR 0.78 (0.69-0.89) P=0.0002

Time to First Major Cardiovascular Endpoint (Years)

Subjects (%) Experiencing Event

Atorvastatin 10 mg

Atorvastatin 80 mg

HR 0.78 (0.69-0.89) P=0.0002

Time to First Major Cardiovascular Endpoint (Years)

Subjects (%) Experiencing Event

Atorvastatin 10 mg

Atorvastatin 80 mg

HR 0.78 (0.69-0.89) P=0.0002

Time to First Major Cardiovascular Endpoint (Years)

Subjects (%) Experiencing Event

TABLE 6. Overview of Efficacy Results in TNT

Endpoint

Atorvastatin

10 mg

(N=5006)

Atorvastatin

80 mg

(N=4995)

HR

a

(95%CI)

PRIMARY ENDPOINT

First major cardiovascular endpoint

(10.9)

(8.7)

0.78 (0.69, 0.89)

Components of the Primary Endpoint

CHD death

(2.5)

(2.0)

0.80 (0.61, 1.03)

Non-fatal, non-procedure related MI

(6.2)

(4.9)

0.78 (0.66, 0.93)

Resuscitated cardiac arrest

(0.5)

(0.5)

0.96 (0.56, 1.67)

Stroke (fatal and non-fatal)

(3.1)

(2.3)

0.75 (0.59, 0.96)

SECONDARY ENDPOINTS*

First CHF with hospitalization

(3.3)

(2.4)

0.74 (0.59, 0.94)

First PVD endpoint

(5.6)

(5.5)

0.97 (0.83, 1.15)

First CABG or other coronary

revascularization procedure

(18.1)

(13.4)

0.72 (0.65, 0.80)

First documented angina endpoint

(12.3)

(10.9)

0.88 (0.79, 0.99)

All-cause mortality

(5.6)

(5.7)

1.01 (0.85, 1.19)

Components of All-Cause Mortality

Cardiovascular death

(3.1)

(2.5)

0.81 (0.64, 1.03)

Noncardiovascular death

(2.5)

(3.2)

1.25 (0.99, 1.57)

Cancer death

(1.5)

(1.7)

1.13 (0.83, 1.55)

Other non-CV death

(0.9)

(1.2)

1.35 (0.91, 2.00)

Suicide, homicide, and othertraumatic

non-CV death

(0.2)

(0.3)

1.67 (0.73, 3.82)

Atorvastatin 80 mg: atorvastatin 10 mg

Component of other secondary endpoints

* Secondary endpoints not included in primary endpoint

HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction;

CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery

bypass graft

Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons

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Of the events that comprised the primary efficacy endpoint, treatment with LIPITOR 80 mg/day significantly reduced the

rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest

(Table 6). Of the predefined secondary endpoints, treatment with LIPITOR 80 mg/day significantly reduced the rate of

coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in

the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.

There was no significant difference between the treatment groups for all-cause mortality (Table 6). The proportions of

subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically

smaller in the LIPITOR 80 mg group than in the LIPITOR 10 mg treatment group. The proportions of subjects who

experienced noncardiovascular death were numerically larger in the LIPITOR 80 mg group than in the LIPITOR 10 mg

treatment group.

In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with LIPITOR 80

mg/day was compared to treatment with simvastatin 20–40 mg/day in 8,888 subjects up to 80 years of age with a history of

CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an

average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this

prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a

median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145,

115, 45, and 100 mg/dL during treatment with 80 mg of LIPITOR and 105, 179, 142, 47, and 132 mg/dL during treatment

with 20–40 mg of simvastatin.

There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary

event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the LIPITOR 80 mg/day group vs. 463

(10.4%) in the simvastatin 20–40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01), p=0.07.

There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the LIPITOR 80

mg/day group vs. 374 (8.4%) in the simvastatin 20–40 mg/day group. The proportions of subjects who experienced CV or

non-CV death were similar for the LIPITOR 80 mg group and the simvastatin 20–40 mg group.

14.2 Hyperlipidemia and Mixed Dyslipidemia

LIPITOR reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia

(heterozygous familial and nonfamilial) and mixed dyslipidemia (

Fredrickson

Types IIa and IIb). Therapeutic response is

seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.

LIPITOR is effective in a wide variety of patient populations with hyperlipidemia, with and without hypertriglyceridemia, in

men and women, and in the elderly.

In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, LIPITOR given as a single

dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 7.)

TABLE 7. Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change From Baseline)

a

Dose

LDL-C

Apo B

HDL-C

Non-HDL-C/ HDL-C

Placebo

Results are pooled from 2 dose-response studies.

In patients with

Fredrickson

Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25

percentile) percent changes from baseline in HDL-C for LIPITOR 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17),

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7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant

decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.

In three multicenter, double-blind studies in patients with hyperlipidemia, LIPITOR was compared to other statins. After

randomization, patients were treated for 16 weeks with either LIPITOR 10 mg per day or a fixed dose of the comparative

agent (Table 8).

TABLE 8. Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled

Trials)

Treatment

(Daily Dose)

Total-C

LDL-C

Apo B

HDL-C

Non-HDL-C/

HDL-C

Study 1

LIPITOR 10 mg

Lovastatin 20 mg

95% CI for Diff

-9.2, -6.5

-10.7, -7.1

-10.0, -6.5

-15.2, -7.1

-1.7, 2.0

-11.1, -7.1

Study 2

LIPITOR 10 mg

Pravastatin 20 mg

95% CI for Diff

-10.8, -6.1

-14.5, -8.2

-13.4, -7.4

-14.1, -0.7

-4.9, 1.6

-11.5, -4.1

Study 3

LIPITOR 10 mg

Simvastatin 10 mg

95% CI for Diff

-8.7, -2.7

-10.1, -2.6

-8.0, -1.1

-15.1, -0.7

-4.3, 3.9

-9.6, -1.9

A negative value for the 95% CI for the difference between treatments favors LIPITOR for all except HDL-C,

for which a positive value favors LIPITOR. If the range does not include 0, this indicates a statistically significant

difference.

Significantly different from lovastatin, ANCOVA, p

0.05

Significantly different from pravastatin, ANCOVA, p

0.05

Significantly different from simvastatin, ANCOVA, p

0.05

The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 8 is not

known. Table 8 does not contain data comparing the effects of LIPITOR 10 mg and higher doses of lovastatin, pravastatin,

and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable.

14.3 Hypertriglyceridemia

The response to LIPITOR in 64 patients with isolated hypertriglyceridemia (

Fredrickson

Type IV) treated across several

clinical trials is shown in the table below (Table 9). For the LIPITOR-treated patients, median (min, max) baseline TG level

was 565 (267–1502).

TABLE 9. Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change From Baseline

Placebo

(N=12)

LIPITOR 10 mg

(N=37)

LIPITOR 20 mg

(N=13)

LIPITOR 80 mg

(N=14)

Triglycerides

-12.4 (-36.6, 82.7)

-41.0 (-76.2, 49.4)

-38.7 (-62.7, 29.5)

-51.8 (-82.8, 41.3)

Total-C

-2.3 (-15.5, 24.4)

-28.2 (-44.9, -6.8)

-34.9 (-49.6, -15.2)

-44.4 (-63.5, -3.8)

LDL-C

3.6 (-31.3, 31.6)

-26.5 (-57.7, 9.8)

-30.4 (-53.9, 0.3)

-40.5 (-60.6, -13.8)

HDL-C

3.8 (-18.6, 13.4)

13.8 (-9.7, 61.5)

11.0 (-3.2, 25.2)

7.5 (-10.8, 37.2)

VLDL-C

-1.0 (-31.9, 53.2)

-48.8 (-85.8, 57.3)

-44.6 (-62.2, -10.8)

-62.0 (-88.2, 37.6)

non-HDL-C

-2.8 (-17.6, 30.0)

-33.0 (-52.1, -13.3)

-42.7 (-53.7, -17.4)

-51.5 (-72.9, -4.3)

14.4 Dysbetalipoproteinemia

The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with

dysbetalipoproteinemia (

Fredrickson

Type III) are shown in the table below (Table 10).

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TABLE 10. Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia (Fredrickson Type III)

Median % Change (min, max)

Median (min, max) at

Baseline (mg/dL)

LIPITOR

10 mg

LIPITOR

80 mg

Total-C

442 (225, 1320)

-37 (-85, 17)

-58 (-90, -31)

Triglycerides

678 (273, 5990)

-39 (-92, -8)

-53 (-95, -30)

IDL-C + VLDL-C

215 (111, 613)

-32 (-76, 9)

-63 (-90, -8)

non-HDL-C

411 (218, 1272)

-43 (-87, -19)

-64 (-92, -36)

14.5 Homozygous Familial Hypercholesterolemia

In a study without a concurrent control group, 29 patients ages 6 years to 37 years with HoFH received maximum daily

doses of 20 to 80 mg of LIPITOR. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction

in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24%

increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval

shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction

of 22%.

14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients

In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and post-menarchal girls 10 years to

17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) or severe

hypercholesterolemia, were randomized to LIPITOR (n=140) or placebo (n=47) for 26 weeks and then all received

LIPITOR for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level

190 mg/dL or 2) a baseline LDL-C level

160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree

relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5–385.0 mg/dL) in the LIPITOR group compared to

230.0 mg/dL (range: 160.0–324.5 mg/dL) in the placebo group. The dosage of LIPITOR (once daily) was 10 mg for the first

4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of LIPITOR-treated patients who

required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).

LIPITOR significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week

double-blind phase (see Table 11).

TABLE 11. Lipid-altering Effects of LIPITOR in Adolescent Boys and Girls with Heterozygous Familial

Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in

Intention-to-Treat Population)

DOSAGE

Total-C

LDL-C

HDL-C

Apolipoprotein B

Placebo

-1.5

-0.4

-1.9

LIPITOR

-31.4

-39.6

-12.0

-34.0

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0–242.0 mg/dL) in the LIPITOR group compared to 228.5

mg/dL (range: 152.0–385.0 mg/dL) in the placebo group during the 26-week double-blind phase.

Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were

10 years to 15 years old (82 boys and 81 girls). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis

(if not already confirmed by family history). Approximately 98% were Caucasian, and less than 1% were Black or Asian.

Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to

achieve a target of < 130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age

groups within the trial as well as with previous clinical studies in both adult and pediatric placebo-controlled trials.

The long-term efficacy of LIPITOR therapy in childhood to reduce morbidity and mortality in adulthood has not been

established.

Lipitor LPD CC 011120

Pfleet 2020-0065343

16

HOW SUPPLIED/STORAGE AND HANDLING

10 mg tablets

(10 mg of atorvastatin):

coded “10” on one side and “ATV” on the other.

20 mg tablets

(20 mg of atorvastatin): coded “20” on one side and “ATV” on the other.

40 mg tablets

(40 mg of atorvastatin)

:

coded “40” on one side and “ATV” on the other.

80 mg tablets

(80 mg of atorvastatin)

:

coded “80” on one side and “ATV” on the other.

Blister packs containing 10, 30, 50, and 100 film-coated tablets.

Not all pack sizes may be marketed.

Storage

Store below 25°C

Shelf life

The expiry date of the product is indicated on the packaging materials

Manufacturer

Pfizer Manufacturing Deutschland GmbH, Freiburg, Germany

License Holder

Pfizer PFE Pharmaceuticals Israel Ltd 9 Shenkar St Herzliya Pituach

Revised in 11/2020