A comparison of the content and primary literature support for online medication information provided by Lexicomp and Wikipedia

Objectives The research compared the comprehensiveness and accuracy of two online resources that provide drug information: Lexicomp and Wikipedia. Methods Medication information on five commonly prescribed medications was identified and comparisons were made between resources and the relevant literature. An initial content comparison of the following three categories of medication information was performed: dose and instructions, uses, and adverse effects or warnings. The content comparison included sixteen points of comparison for each of the five investigated medications, totaling eighty content comparisons. For each of the medications, adverse reactions that appeared in only one of the resources were identified. When primary, peer-reviewed literature was not referenced supporting the discrepant adverse reactions, a literature search was performed to determine whether or not evidence existed to support the listed claims. Results Lexicomp consistently provided more medication information, with information provided in 95.0% (76/80) of the content, compared to Wikipedia’s 42.5% (34/80). Lexicomp and Wikipedia had information present in 91.4% (32/35) and 20.0% (7/35) of dosing and instructions content, respectively. Adverse effects or warning content was provided in 97.5% (39/40) of Lexicomp content and 55.0% (22/40) of Wikipedia content. The “uses” category was present in both Lexicomp and Wikipedia for the 5 medications considered. Of adverse reactions listed solely in Lexicomp, 191/302 (63.2%) were supported by primary, peer-reviewed literature in contrast to 7/7 (100.0%) of adverse reactions listed only in Wikipedia. A review of US Food and Drug Administration Prescribing Information and the Adverse Event Reporting System dashboard found support for a respective 17/102 (16.7%) and 92/102 (90.2%) of Lexicomp’s adverse reactions that were not supported in the literature. Conclusion Lexicomp is a comprehensive medication information tool that contains lists of adverse reactions that are not entirely supported by primary-peer reviewed literature.


Interacting Agents
Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with LIPITOR (7). Digoxin: Patients should be monitored appropriately (7.8).
Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased (7.9). Rifampin should be simultaneously co-administered with LIPITOR (7.7).

INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been Sections or subsections omitted from the full prescribing information are not listed.
inadequate. In patients with CHD or multiple risk factors for CHD, LIPITOR can be started simultaneously with diet.

Prevention of Cardiovas cular Dis eas e
In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, LIPITOR is indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke Reduce the risk for revascularization procedures and angina In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, LIPITOR is indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke 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

LIPITOR is indicated:
As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb); As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV); For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet; To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable; 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

Limitations of Us e
LIPITOR has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

Types IIa and IIb)
The recommended starting dose of LIPITOR is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of LIPITOR is 10 to 80 mg once daily. LIPITOR can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of LIPITOR should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines). After initiation and/or upon titration of LIPITOR, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

Heterozygous Familial Hypercholes terolemia in Pediatric Patients (10-17 years of age)
The recommended starting dose of LIPITOR is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines,Clinical Pharmacology (12), and Indications and Usage (1. 2)]. Adjustments should be made at intervals of 4 weeks or more.

Homozygous Familial Hypercholes terolemia
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 treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Concomitant Lipid-Lowering Therapy
LIPITOR may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7)].

Dos age in Patients With Renal Impairment
Renal disease does not affect the plasma concentrations nor LDL-C reduction of LIPITOR; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions,Skeletal Muscle (5.1),Clinical Pharmacology,Pharmacokinetics (12.3)].

Dos age in Patients Taking Cyclos porine, Clarithromycin, Itraconazole, or Certain Proteas e 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 Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7)].

Nurs ing mothers
It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require LIPITOR treatment should not breastfeed their infants [see Use in Specific Populations (8.3)].

Skeletal Mus cle
Rare cas es of rhabdomyolys is with acute renal failure s econdary to myoglobinuria have been reported with LIPITOR and with other drugs in this clas s . 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 CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
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; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
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 cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with LIPITOR and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin 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 Interactions (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 1 [see also Dosage and Administration (2.6), Drug Interactions (7), Clinical Pharmacology (12.3)]. LIPITOR therapy s hould be temporarily withheld or dis continued in any patient with an acute, s erious condition s ugges tive of a myopathy or having a ris k factor predis pos ing to the development of renal failure s econdary to rhabdomyolys is (e.g., s evere acute infection, hypotens ion, major s urgery, trauma, s evere metabolic, endocrine and electrolyte dis orders , and uncontrolled s eizures ).

Liver Dys function
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Pers is tent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occas ions ) in s erum trans aminas es occurred in 0.7% of patients who received LIPITOR in clinical trials . The incidence of thes e abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, res pectively.
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 Use with caution and with the lowest dose necessary (12.3) * 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 (4.1)].

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.

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-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.

Us e 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 (6.1)].

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

Clinical Trial Advers e Experiences
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies 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%).

Advers e Reaction
Any 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 * Adverse Reaction ≥ 2% in any dose greater than placebo swelling; 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  (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.
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 nonfatal 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].
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%).

Pos tmarketing Experience
The following adverse reactions have been identified during postapproval 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, and pancreatitis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].
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).

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 protease inhibitors, and itraconazole) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3)].

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.

Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of LIPITOR with gemfibrozil should be avoided [see Warnings and Precautions (5.1)].

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 (5.1)].

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 (5.1)].

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.

Digoxin
When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of LIPITOR should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing LIPITOR and the lowest dose necessary should be used. appropriately.

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.

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

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.

Pregnancy
Pregnancy Category X LIPITOR is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development.
Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. 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 based on surface area (mg/m ) [see Contraindications,Pregnancy (4.3)].
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 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 AUC at 80 mg/day.
Statins may cause fetal harm when administered to a pregnant woman. LIPITOR should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking LIPITOR, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.

Nurs ing Mothers
It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother's milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring LIPITOR treatment should be advised not to nurse their infants [see Contraindications (4)].

Pediatric Us e
Safety and effectiveness in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months' duration in adolescent boys and postmenarchal girls. Patients treated with LIPITOR had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Dos es greater than 20 mg have not been s tudied in this patient population.

Geriatric Us e
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.

Hepatic Impairment
Lipitor is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Pharmacokinetics (12.3)].

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.

DESCRIPTION
LIPITOR is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

Mechanis m 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. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.
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. LIPITOR reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C.
LIPITOR reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. LIPITOR also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. LIPITOR reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. LIPITOR reduces intermediate density lipoprotein cholesterol (IDL-C) in 33 34 2 5 2 2 hypertriglyceridemia. LIPITOR reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

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 (2)].

Pharmacokinetics
Abs orption: 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 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 (2)].
Dis tribution: 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, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3)].
Metabolis m: 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 (7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: LIPITOR and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic 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, Geriatric Use (8.5)].
Pediatric: Pharmacokinetic data in the pediatric population are not available.
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, Dosage in Patients with Renal Impairment (2.5), Warnings and Precautions, Skeletal Muscle (5.1)].
Hemodialys is : 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.

Carcinogenes is , Mutagenes is , 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 Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). See Sections 5.1 and 7 for clinical significance. 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. Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71% ) have been reported with excessive grapefruit consumption (≥ 750 mL -1.2 liters per day). 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. † † See Section 7 for clinical significance. * activation: the Ames test with Salmonella typhimurium and 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.
Studies in 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

Prevention of Cardiovas cular Dis eas e
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of LIPITOR on fatal and nonfatal 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 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 Dis eas e Death (in ASCOT-LLA)
LIPITOR also significantly decreased the relative risk for revascularization procedures by 42%.
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.
The effect of LIPITOR 10 mg/day on lipid levels was similar to that seen in previous clinical trials.
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). 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 5). The overall risk reduction was consistent regardless of age (<65, ≥65) or gender.  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 5). 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 5). 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 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.

Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dys lipidemia (Fredrickson Types IIa and IIb)
LIPITOR reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia. 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 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 7).  -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4 The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 7 is not known. Table 7 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.

Hypertriglyceridemia (Fredrickson Type IV)
The response to LIPITOR in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 8). For the LIPITOR-treated patients, median (min, max) baseline TG level was 565 (267-1502). 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 9).

Homozygous Familial Hypercholes terolemia
In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH 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%.

Heterozygous Familial Hypercholes terolemia in Pediatric Patients
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) 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 seconddegree 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 10). long-term efficacy of LIPITOR therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

REFERENCES
[1] 16 HOW SUPPLIED/STORAGE AND HANDLING 10 mg tablets : coded "PD 155" on one side and "10" on the other.

PATIENT COUNSELING INFORMATION
Patients taking LIPITOR should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment. (5.1)]. Patients s hould als o be advis ed to inform other healthcare profes s ionals pres cribing a new medication that they are taking LIPITOR.

Mus cle Pain
All patients starting therapy with LIPITOR should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing LIPITOR. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.

Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of LIPITOR and if signs or symptoms of liver injury occur. All patients treated with LIPITOR should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using LIPITOR. Discuss future pregnancy plans with your patients, and discuss when to stop LIPITOR if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking LIPITOR and call their healthcare professional.

Breas t-feeding
Women who are breastfeeding should be advised to not use LIPITOR. Patients who have a lipid disorder and are breast-feeding, should be advised to discuss the options with their healthcare professional. LAB-0021-31.0

LIPITOR atorvastatin calcium tablets
(LIP-ih-tore) Read the Patient Information that comes with LIPITOR before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment.
If you have any questions about LIPITOR, ask your doctor or pharmacist.

What is LIPITOR?
LIPITOR is a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C ("bad" cholesterol) and triglycerides in your blood. It can raise your HDL-C ("good" cholesterol) as well. LIPITOR is for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.
LIPITOR can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as: age, smoking, high blood pressure, low HDL-C, heart disease in the family.
LIPITOR can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as: eye problems, kidney problems, smoking, or high blood pressure.
® LIPITOR starts to work in about 2 weeks.

What is Choles terol?
Cholesterol and triglycerides are fats that are made in your body. They are also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol and triglycerides can clog your blood vessels. It is especially important to lower your cholesterol if you have heart disease, smoke, have diabetes or high blood pressure, are older, or if heart disease starts early in your family.

Who Should Not Take LIPITOR?
Do not take LIPITOR if you: are pregnant or think you may be pregnant, or are planning to become pregnant. Lipitor may harm your unborn baby. If you get pregnant, stop taking LIPITOR and call your doctor right away. are breast feeding. LIPITOR can pass into your breast milk and may harm your baby. have liver problems. are allergic to LIPITOR or any of its ingredients. The active ingredient is atorvastatin. See the end of this leaflet for a complete list of ingredients in LIPITOR.
LIPITOR has not been studied in children under 10 years of age. Your doctor should start you on a low-fat diet before giving you LIPITOR. Stay on this low-fat diet when you take LIPITOR. If you miss a dose of LIPITOR, take it as soon as you remember. Do not take LIPITOR if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time.

Before You Start LIPITOR
Do not take 2 doses of LIPITOR at the same time.
If you take too much LIPITOR or overdose, call your doctor or Poison Control Center right away. Or go to the nearest emergency room. Call your doctor right away if you have: muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if you also have a fever or feel more tired than usual. This may be an early sign of a rare muscle problem. muscle problems that do not go away even after your doctor has advised you to stop taking LIPITOR. Your doctor may do further tests to diagnose the cause of your muscle problems. allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right away. nausea and vomiting. passing brown or dark-colored urine. you feel more tired than usual your skin and whites of your eyes get yellow. stomach pain. allergic skin reactions.
In clinical studies, patients reported the following common side effects while taking LIPITOR: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests.
The following additional side effects have been reported with LIPITOR: tiredness, tendon problems, memory loss, and confusion.
Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.
These are not all the side effects of LIPITOR. Ask your doctor or pharmacist for a complete list.
How do I s tore LIPITOR Store LIPITOR at room temperature, 68 to 77°F (20 to 25°C).