Lipitor

Contraindications, Pregnancy and Lactation (

Warnings and Precautions, CNS Toxicity (

LIPITOR is indicated:

• •To reduce the risk of:
  • oMyocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD
  • oMI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD
  • oNon-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD
• •As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in:
  • oAdults with primary hyperlipidemia.
  • oAdults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).
• •As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH).
• •As an adjunct to diet for the treatment of adults with:
  • oPrimary dysbetalipoproteinemia
  • oHypertriglyceridemia

• •Take orally once daily with or without food (
  2.1 Important Dosage Information

  • •Take Lipitor orally once daily at any time of the day, with or without food.
  • •Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating LIPITOR, and adjust the dosage if necessary.
  ).
• •Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating LIPITOR, and adjust dosage if necessary (
  2.1 Important Dosage Information

  • •Take Lipitor orally once daily at any time of the day, with or without food.
  • •Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating LIPITOR, and adjust the dosage if necessary.
  ).
• •
  Adults
  (
  2.2 Recommended Dosage in Adult Patients

  The recommended starting dosage of LIPITOR is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily.
  ):
  • oRecommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily.
  • oPatients requiring LDL-C reduction >45% may start at 40 mg once daily.
• •
  Pediatric Patients Aged 10 Years of Age and Older with HeFH:
  Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily (
  2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH

  The recommended starting dosage of LIPITOR is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily.
  ).
• •
  Pediatric Patients Aged 10 Years of Age and Older with HoFH:
  Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily (
  2.4 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH

  The recommended starting dosage of LIPITOR is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily.
  ).
• •See full prescribing information for LIPITOR dosage modifications due to drug interactions (
  2.5 Dosage Modifications Due to Drug Interactions

  Concomitant use of LIPITOR with the following drugs requires dosage modification of LIPITOR

  [see Warnings and Precautions (5.1)and Drug Interactions (7.1)]

  .

  Anti-Viral Medications

  • •In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed LIPITOR 20 mg once daily.
  • •In patients taking nelfinavir, do not exceed LIPITOR 40 mg once daily.

  Select Azole Antifungals or Macrolide Antibiotics

  • •In patients taking clarithromycin or itraconazole, do not exceed LIPITOR 20 mg once daily.

  For additional recommendations regarding concomitant use of LIPITOR with other anti-viral medications, azole antifungals or macrolide antibiotics,

  see Drug Interactions (7.1)

  .
  ).

LIPITOR tablets:

• •10 mg of atorvastatin: white elliptical, film-coated tablets with “PD 155” on one side and “10” on the other
• •20 mg of atorvastatin: white elliptical, film-coated tablets with “PD 156” on one side and “20” on the other
• •40 mg of atorvastatin: white elliptical, film-coated tablets with “PD 157” on one side and “40” on the other
• •80 mg of atorvastatin: white elliptical, film-coated tablets with “PD 158” on one side and “80” on the other

• •
  Pregnancy:
  May cause fetal harm. (
  8.1 Pregnancy

  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 ≥ 6 times the MRHD

  (see Data)

  .

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

  Data

  Human Data

  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.

  Animal Data

  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.

  Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma.
  ).
• •
  Lactation:
  Breastfeeding not recommended during treatment with LIPITOR (
  8.2 Lactation

  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).
  ).