Lipitor

Lipitor is generally well-tolerated. Minor side effects include:

• Constipation
• Diarrhea
• Fatigue
• Gas
• Heartburn
• Headache

Other commonly reported side effects include:

• Common cold (nasopharyngitis)
• Joint pain (arthralgia)
• Pain in the extremities
• Urinary tract infection

Lipitor may cause liver and muscle damage. Serious liver damage caused by statins is rare. Liver tests should be performed at the beginning of treatment then as needed thereafter.

Inflammation of the muscles caused by statins can lead to serious breakdown of muscle cells called rhabdomyolysis. Rhabdomyolysis causes the release of muscle protein (myoglobin) into the blood, and myoglobin can cause kidney failure and even death. When used alone, statins cause rhabdomyolysis in less than one percent of patients. To prevent the development of serious rhabdomyolysis, patients taking atorvastatin should contact their health-care professional immediately if they develop unexplained muscle pain, weakness, or muscle tenderness.

Statins have been associated with increases in HbA1c and fasting serum glucose levels as seen in diabetes.

There are also post-marketing reports of:

• memory loss,
• forgetfulness,
• amnesia,
• confusion, and
• memory impairment.

Symptoms may start one day to years after starting treatment and resolve within a median of three weeks after stopping the statin.

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

Rhabdomyolysis and myopathy [see WARNINGS AND PRECAUTIONS]

Liver enzyme abnormalities [see WARNINGS AND PRECAUTIONS]

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 16,066patients (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 patient streated 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 clinicaladverse 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).

Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint 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.

In ASCOT [see Clinical Studies] 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.

In CARDS [see Clinical Studies] 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.

In TNT [see Clinical Studies] 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 LIPITOR10mg daily (n=5006) orLIPITOR80 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 ( ≥ 3x ULN twice within 4-10days) occurred in 62 (1.3%) individuals with atorvastatin80mg andinnine(0.2%)individualswithatorvastatin10mg.ElevationsofCK( ≥ 10x 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%).

In IDEAL [see Clinical Studies] 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 LIPITOR80 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.

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 ( ≥ 3xULN twice within 4-10days) 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].

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 (17LIPITOR vs. 18placebo). 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].

There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the LIPITOR 80mg/day group vs. 211(8.9%)in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the LIPITOR80 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 LIPITOR80 mg group (5.0%) than in the placebo group(4.0%).

Adverse Reactions From Clinical Studies Of LIPITOR In Pediatric Patients

In a 26-weekcontrolled study in boys and postmenarchal girls with HeFH (ages 10years to17 years)(n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR10 to 20mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apoB levels, was generally similar to that of placebo [see Use in Special Populations and Clinical Studies].

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 notlisted 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 stat in use [see WARNINGS AND PRECAUTIONS].

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 aregenerally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) andsymptom resolution (median of 3 weeks).

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Joint pain.
• Upset stomach.
• Nose and throat irritation.
• Not able to sleep.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Lipitor or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Lipitor. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

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 (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.

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

Atorvastatin AUC was significantly increased with concomitant administration of Lipitor with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of Lipitor alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking the HIV protease inhibitor tipranavir 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. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of Lipitor should not exceed 20 mg and should be used with caution [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)]. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of Lipitor should not exceed 40 mg and close clinical monitoring is recommended.

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 (2.6) and Warnings and Precautions (5.1)].

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).

Cyclosporine

Atorvastatin and 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 (5.1)].

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 (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 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.

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.

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 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.

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.

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 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.

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 HbA1c 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.

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

Figure 3: Effect of Lipitor 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)

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.

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.)

In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and 75th 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), 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).

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.

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).

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).

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%.

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).

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®
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 Cholesterol?

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 dosing has not been established in children under 10 years of age.

Before You Start Lipitor

Tell your doctor if you:

• have muscle aches or weakness
• drink more than 2 glasses of alcohol daily
• have diabetes
• have a thyroid problem
• have kidney problems

Some medicines should not be taken with Lipitor. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Lipitor and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for:

• your immune system
• cholesterol
• infections
• birth control
• heart failure
• HIV or AIDS

Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist.

How Should I Take Lipitor?

• Take Lipitor exactly as prescribed by your doctor. Do not change your dose or stop Lipitor without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during your treatment with Lipitor. Your dose of Lipitor may be changed based on these blood test results.
• Take Lipitor each day at any time of day at about the same time each day. Lipitor can be taken with or without food.
  Don't break Lipitor tablets before taking.
• 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. 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.

What Should I Avoid While Taking Lipitor?

• Talk to your doctor before you start any new medicines. This includes prescription and non-prescription medicines, vitamins, and herbal supplements. Lipitor and certain other medicines can interact causing serious side effects.
• Do not get pregnant. If you get pregnant, stop taking Lipitor right away and call your doctor.

What are the Possible Side Effects of Lipitor?

Lipitor can cause serious side effects. These side effects have happened only to a small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or Lipitor is stopped. These serious side effects include:

• Muscle problems. Lipitor can cause serious muscle problems that can lead to kidney problems, including kidney failure. You have a higher chance for muscle problems if you are taking certain other medicines with Lipitor.
• Liver problems. Your doctor should do blood tests to check your liver before you start taking Lipitor and if you have symptoms of liver problems while you take Lipitor. Call your doctor right away if you have the following symptoms of liver problems:
  • feel tired or weak
  • loss of appetite
  • upper belly pain
  • dark amber colored urine
  • yellowing of your skin or the whites of your eyes

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 store Lipitor

• Store Lipitor at room temperature, 68 to 77°F (20 to 25°C).
• Do not keep medicine that is out of date or that you no longer need.
• Keep Lipitor and all medicines out of the reach of children. Be sure that if you throw medicine away, it is out of the reach of children.

General Information About Lipitor

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Lipitor for a condition for which it was not prescribed. Do not give Lipitor to other people, even if they have the same problem you have. It may harm them.

This leaflet summarizes the most important information about Lipitor. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Lipitor that is written for health professionals. Or you can go to the Lipitor website at www.Lipitor.com.

What are the Ingredients in Lipitor?

Active Ingredient: atorvastatin calcium

Inactive Ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.

LAB-0348-9.0
June 2017

PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Label

NDC 0071-0155-23

Pfizer

Lipitor®
(atorvastatin calcium)
tablets

10 mg*

90 Tablets
Rx only

PRINCIPAL DISPLAY PANEL - 10 mg Tablet Blister Pack

Lipitor®

(Atorvastatin Calcium)
Tablet

10 mg

DISTRIBUTED BY:
PARKE-DAVIS
DIV OF PFIZER INC, NY, NY 10017
MADE IN IRELAND

EXP & LOT AREA

PRINCIPAL DISPLAY PANEL - 10 mg Blister Pack Carton

Pfizer

Lipitor®
(atorvastatin calcium)

10 mg*

tablets

For in-institution use only

100 Tablets

NDC 0071-0157-23

Pfizer

Lipitor®
(atorvastatin calcium)

40 mg*

tablets

90 Tablets
Rx only

PRINCIPAL DISPLAY PANEL - 40 mg Tablet Blister Pack

Lipitor®

(Atorvastatin Calcium)
Tablet

40 mg

DISTRIBUTED BY:
PARKE-DAVIS
DIV OF PFIZER INC, NY, NY 10017
MADE IN IRELAND

EXP & LOT AREA

PRINCIPAL DISPLAY PANEL - 40 mg Blister Pack Carton

Pfizer

Lipitor®
(atorvastatin calcium)

40 mg*

tablets

For in-institution use only

100 Tablets

Lipitor (atorvastatin) belongs to a group of drugs called HMG CoA reductase inhibitors, or "statins." Atorvastatin reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).

Lipitor is used to treat high cholesterol, and to lower the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors.

Lipitor is for use in adults and children who are at least 10 years old.

You should not use Lipitor if you are allergic to atorvastatin, or if you have:

• liver disease; or

• if you are pregnant or breast-feeding.

Atorvastatin can harm an unborn baby or cause birth defects. Do not use if you are pregnant. Stop taking Lipitor and tell your doctor right away if you become pregnant. Use effective birth control to prevent pregnancy while you are taking this medicine.

Atorvastatin may pass into breast milk and could harm a nursing baby. Do not breast-feed while you are taking Lipitor.

To make sure this medicine is safe for you, tell your doctor if you have ever had:

• liver problems;

• muscle pain or weakness;

• kidney disease;

• diabetes;

• a thyroid disorder; or

• if you drink more than 2 alcoholic beverages daily.

Lipitor can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid).

Atorvastatin is not approved for use by anyone younger than 10 years old.

Take Lipitor exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Lipitor is usually taken once a day, with or without food. Take the medicine at the same time each day.

Do not break an Lipitor tablet before taking it.

You may need to stop using this medicine for a short time if you have:

• uncontrolled seizures;

• an electrolyte imbalance (such as high or low potassium levels in your blood);

• severely low blood pressure;

• a severe infection or illness; or

• surgery or a medical emergency.

It may take up to 2 weeks before your cholesterol levels improve, and you may need frequent blood test. You may not notice any change in your symptoms, but keep using the medication as directed. Your blood work will help your doctor determine how long to treat you with Lipitor.

Lipitor is only part of a complete treatment program that may also include diet, exercise, and weight control. Follow your doctor's instructions very closely.

Store at room temperature away from moisture, heat, and light.