Drug Safety-related Labeling Changes (SrLC)

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LIPITOR (NDA-020702)

(ATORVASTATIN CALCIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/02/2024 (SUPPL-81)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Missed Doses

If a dose is missed, advise patients not to take the missed dose and resume with the next scheduled dose.

12/07/2022 (SUPPL-79)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

• Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)]

• Hypersensitivity to atorvastatin or any excipients in LIPITOR. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6.2)].

5 Warnings and Precautions

5.2 Immune-Mediated Necrotizing Myopathy

Additions and/or revisions underlined:

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue LIPITOR if IMNM is suspected.

5.3 Hepatic Dysfunction

Additions and/or revisions underlined:

Increases in serum transaminases have been reported with use of LIPITOR [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving LIPITOR in clinical trials.

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

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7)].

Consider liver enzyme testing before LIPITOR initiation and when clinically indicated thereafter. LIPITOR is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LIPITOR.

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

Additions and or revisions underlined:

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including LIPITOR. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

5.5 Increased Risk of Hemorrhagic Stroke in Patients on LIPITOR 80 mg with Recent Hemorrhagic Stroke

Additions and or revisions underlined:

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or TIA within the preceding 6 months, were treated with LIPITOR 80 mg, a higher incidence of hemorrhagic stroke was seen in the LIPITOR 80 mg group compared to placebo (55, 2.3% LIPITOR 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 non-fatal hemorrhagic stroke was significantly higher in the LIPITOR 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 LIPITOR group [see Adverse Reactions (6.1)]. Consider the risk/benefit of use of LIPITOR 80 mg in patients with recent hemorrhagic stroke.

6 Adverse Reactions

Addition and/or revisions underlined:

The following important adverse reactions are described below and elsewhere in the labeling:

• Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]

• Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]

• Hepatic Dysfunction [see Warnings and Precautions (5.3)]

• Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)]

  6.1 Clinical Trials Experience

  Extensive additions and/or revisions; please refer to label for complete information

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of LIPITOR as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of LIPITOR for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls.

The safety and effectiveness of LIPITOR as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of LIPITOR for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14)].

The safety and effectiveness of LIPITOR have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH).

8.5 Geriatric Use

Additions and/or revisions underlined:

…

Advanced age (greater than or equal to 65 years) is a risk factor for LIPITOR-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving LIPITOR for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Newly added subsection:

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of LIPITOR, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Additions and/or revisions underlined:

In patients with chronic alcoholic liver disease, plasma concentrations of LIPITOR are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. LIPITOR is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)].

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Discontinue LIPITOR when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. LIPITOR decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LIPITOR may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.

Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with LIPITOR use in pregnant women are insufficient to determine if there is a drug- associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses greater than or equal to 6 times the MRHD (see Data).

…

Data

Human Data

A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

…

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Statins, including LIPITOR, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with LIPITOR [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

Data

Following a single oral administration of 10 mg/kg of radioactive atorvastatin to lactating rats, the concentration of total radioactivity was determined. Atorvastatin and/or its metabolites were measured in the breast milk and pup plasma at a 2:1 ratio (milk:plasma).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

…

Myopathy and Rhabdomyolysis

Advise patients that LIPITOR may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Hepatic Dysfunction

Inform patients that LIPITOR may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].

Increases in HbA1c and Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with LIPITOR. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].

Pregnancy

Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if LIPITOR should be discontinued [see Use in Specific Populations (8.1)].

…

PATIENT INFORMATION

Extensive additions and revisions; please refer to label for complete information.

11/16/2020 (SUPPL-77)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Myopathy and Rhabdomyolysis

LIPITOR may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including LIPITOR.

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher LIPITOR dosage [see Drug Interactions (7.1)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

LIPITOR exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with LIPITOR is not recommended. LIPITOR dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2.6)]. Cases of myopathy/rhabdomyolysis have been reported with atorvastatin coadministered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].

Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking LIPITOR [see Drug Interactions (7.1)].Discontinue LIPITOR if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if LIPITOR is discontinued. Temporarily discontinue LIPITOR in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the LIPITOR dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR

LIPITOR is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). LIPITOR plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to Lipitor and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Table 3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR (newly added; please refer to label for complete table information)

7.2 Drug Interactions the may Decrease Exposure to LIPITOR

Table 4 presents drug interactions that may decrease exposure to LIPITOR and instructions for preventing or managing them.

Table 4: Drug Interactions that may Decrease Exposure to LIPITOR (newly added; please refer to label for complete table information)

7.3 LIPITOR Effects on Other Drugs

Table 5 presents LIPITOR’s effect on other drugs and instructions for preventing or managing them.

Table 5: LIPITOR Effects on Other Drugs (newly added; please refer to label for complete table information)

09/25/2020 (SUPPL-78)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Immune-Mediated Necrotizing Myopathy

(New subsection added)

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

11/27/2019 (SUPPL-74)

Approved Drug Label (PDF)

7 Drug Interactions

7.4 Letermovir

(newly added subsection)

Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29). Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg LIPITOR daily.

The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. Use of LIPITOR is not recommended in patients taking letermovir co-administered with cyclosporine.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(additions underlined)

...

 

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:

…

• anti-virals

…

04/12/2019 (SUPPL-73)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Skeletal Muscle

(Additions and/or revisions are underlined)

Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., clarithromycin, itraconazole, and HIV and HCV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.

The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of the drugs listed in Table 2. Physicians considering combined therapy of LIPITOR with any of these drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug…

(Please refer to label for changes in)

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

7 Drug Interactions

(Additions and/or revisions are underlined)

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole).

7.1 Strong Inhibitors of CYP 3A4

(Additions and/or revisions are underlined)

Combination of Protease Inhibitors

Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR with several combinations of protease inhibitors. In patients taking tipranavir plus ritonavir or glecaprevir plus pibrentasvir, concomitant use of LIPITOR should be avoided. In patients taking lopinavir plus ritonavir, or simeprevir, use the lowest necessary LIPITOR dose. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or elbasvir plus grazoprevir, the dose of LIPITOR should not exceed 20 mg. In patients taking nelfinavir the dose of LIPITOR should not exceed 40  mg and close clinical monitoring is recommended.

7.3 Cyclosporine

(Additions and/or revisions are underlined)

Atorvastatin is a substrate of the hepatic transporters. Atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 10 mg and cyclosporine 5.2 mg/kg/day compared to that of LIPITOR alone.

The co-administration of LIPITOR with cyclosporine should be avoided.

7.4 Glecaprevir and Pibrentasvir; Elbasvir and Grazoprevir

(Newly Added Subsection)

Concomitant administration of glecaprevir and pibrentasvir or elbasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy.

Coadministration of glecaprevir and pibrentasvir with atorvastatin increase plasma concentrations of atorvastatin by 8.3-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, coadministrationof LIPITOR in patients receiving concomitant medications with products containing glecaprevir and pibrentasvir is not recommended.

Coadministration of elbasvir and grazoprevir with atorvastatin increase plasma concentrations of atorvastatin by 1.9-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the dose of LIPITOR should not exceed 20 mg daily in patients receiving concomitant medications with products containing elbasvir and grazoprevir.

08/10/2018 (SUPPL-71)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Additions and/or revisions are underlined)

 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.

06/23/2017 (SUPPL-67)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following:

• Lactation

6 Adverse Reactions

6.1 Clinical Trials Experience

Addition of the following:

Adverse Reactions from Clinical Studies of LIPITOR in Pediatric Patients

In a 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to 17 years) (n equals140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; revised as below:

Risk Summary

LIPITOR is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, LIPITOR may cause fetal harm when administered to a pregnant woman. LIPITOR should be discontinued as soon as pregnancy is recognized. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ? 6 times the MRHD.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.

Data

Human Data

Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a greater than or equal to 3 to

4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Animal Data

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively.

Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.

In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.

8.2 Lactation

PLLR conversion; revised as below:

Risk Summary

LIPITOR use is contraindicated during breastfeeding. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended during treatment with LIPITOR.

8.3 Females and Males of Reproductive Potential

PLLR conversion; revised as below:

Contraception

LIPITOR may cause fetal harmwhen administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LIPITOR.

8.4 Pediatric Use

Addition of the following:

Heterozygous Familial Hypercholesterolemia (HeFH)

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

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

1. LDL-C ? 190 mg/dL, or

2. LDL-C ? 160 mg/dLand

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

4. two or more other CVD risk factors are present.

Use of LIPITOR for this indication is supported by evidence from

• A placebo-controlled clinical trial of 6 months duration in 187 boys and postmenarchal girls, 10 years to 17 years of age. atients treated with 10 mg or 20 mg daily LIPITOR had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.

• A three year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve a target LDL-C < 130 mg/dL. The safety and efficacy of LIPITOR in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.

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

The long-termefficacy of LIPITOR therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

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

Homozygous Familial Hypercholesterolemia (HoFH)

Clinical efficacy of LIPITOR with dosages up to 80 mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Addition of the following:

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Additions and/or revisions underlined:

17.3 Embryofetal Toxicity

Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment and to inform their healthcare provider of a known or suspected pregnancy.

 17.4 Lactation

Advise women not to breastfeed during treatment with LIPITOR.

This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com.

06/23/2017 (SUPPL-69)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined

Adverse reactions associated with LIPITOR therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.