Atorvaliq

ATORVALIQ 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, only on an empty stomach (
  2.1 Important Dosage and Administration Information

  • •Measure the ATORVALIQ dose using a calibrated oral syringe or other oral dosing device scored using metric units of measurements (i.e., mL).
  • •Take ATORVALIQ orally once daily at any time of day, only on an empty stomach (1 hour before or 2 hours after a meal).
  • •Advise patients to take a missed dose as soon as possible. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose.
  • •Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ATORVALIQ, and adjust the dosage if necessary.
  ).
• •Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ATORVALIQ, and adjust dosage if necessary (
  2.1 Important Dosage and Administration Information

  • •Measure the ATORVALIQ dose using a calibrated oral syringe or other oral dosing device scored using metric units of measurements (i.e., mL).
  • •Take ATORVALIQ orally once daily at any time of day, only on an empty stomach (1 hour before or 2 hours after a meal).
  • •Advise patients to take a missed dose as soon as possible. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose.
  • •Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ATORVALIQ, and adjust the dosage if necessary.
  ).
• •
  Adults
  (
  2.2 Recommended Dosage in Adult Patients

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

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

  [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 ATORVALIQ 20 mg once daily.
  • •In patients taking nelfinavir, do not exceed ATORVALIQ 40 mg once daily.

  Select Azole Antifungals or Macrolide Antibiotics

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

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

  [see Drug Interactions (7.1)]

  .
  ).

Oral Suspension: 20 mg/5mL white to off-white suspension with an orange flavor.

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

  Risk Summary

  Discontinue ATORVALIQ when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ATORVALIQ 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 atorvastatin 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 ATORVALIQ (
  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 ATORVALIQ, 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 ATORVALIQ

  [see Use in Specific Populations (8.1), and 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).
  ).

• •
  Myopathy and Rhabdomyolysis:
  Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ATORVALIQ dosage. Discontinue ATORVALIQ if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ATORVALIQ in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing ATORVALIQ dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever (
  2.5 Dosage Modifications Due to Drug Interactions

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

  [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 ATORVALIQ 20 mg once daily.
  • •In patients taking nelfinavir, do not exceed ATORVALIQ 40 mg once daily.

  Select Azole Antifungals or Macrolide Antibiotics

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

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

  [see Drug Interactions (7.1)]

  .
  ,
  5.1 Myopathy and Rhabdomyolysis

  ATORVALIQ may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including ATORVALIQ.

  Risk Factors for Myopathy

  Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher ATORVALIQ dosage

  [see Drug Interactions (7.1)and Use in Specific Populations (8.5, 8.6)]

  .

  Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

  ATORVALIQ 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 ATORVALIQ is not recommended. ATORVALIQ dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications

  [see Dosage and Administration (2.5)]

  . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir

  [see Adverse Reactions (6.1)]

  . 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 ATORVALIQ

  [see Drug Interactions (7.1)]

  .

  Discontinue ATORVALIQ if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if ATORVALIQ is discontinued. Temporarily discontinue ATORVALIQ 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 ATORVALIQ dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
  ,
  7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with ATORVALIQ

  Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin 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)]

  .

  Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with ATORVALIQ is not recommended.

  In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with ATORVALIQ.

  In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed ATORVALIQ 20 mg.

  In patients taking nelfinavir, do not exceed ATORVALIQ 40 mg

  [see Dosage and Administration (2.5)].

  Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with ATORVALIQ.

  Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

  Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with ATORVALIQ

  •

  •

  •

  •

  •

  •

  Cyclosporine or Gemfibrozil
  Clinical Impact:	Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3)] . Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with ATORVALIQ.
  Intervention:	Concomitant use of cyclosporine or gemfibrozil with ATORVALIQ is not recommended.
  Anti-Viral Medications
  Clinical Impact:	Atorvastatin plasma levels were significantly increased with concomitant administration of ATORVALIQ with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3)] . Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin.
  Intervention:
  Examples:	Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.
  Select Azole Antifungals or Macrolide Antibiotics
  Clinical Impact:	Atorvastatin plasma levels were significantly increased with concomitant administration of ATORVALIQ with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3)] .
  Intervention:	In patients taking clarithromycin or itraconazole, do not exceed ATORVALIQ 20 mg [see Dosage and Administration (2.5)] . Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with ATORVALIQ. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
  Examples:	Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
  Niacin
  Clinical Impact:	Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin [see Warnings and Precaustions (5.1)] .
  Intervention:	Consider if the benefit of using lipid modifying dosages of niacin concomitantly with ATORVALIQ outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
  Fibrates (other than Gemfibrozil)
  Clinical Impact:	Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with ATORVALIQ.
  Intervention:	Consider if the benefit of using fibrates concomitantly with ATORVALIQ outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
  Colchicine
  Clinical Impact:	Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin.
  Intervention:	Consider the risk/benefit of concomitant use of colchicine with ATORVALIQ. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
  Grapefruit Juice
  Clinical Impact:	Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
  Intervention:	Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking ATORVALIQ.
  ,
  8.5 Geriatric Use

  Of the total number of atorvastatin-treated patients in clinical trials, 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 patients and younger patients.

  Advanced age (≥65 years) is a risk factor for atorvastatin-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 ATORVALIQ for the increased risk of myopathy

  [see Warnings and Precautions (5.1)and Clinical Pharmacology (12.3)]

  .
  ,
  8.6 Renal Impairment

  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 ATORVALIQ, therefore there is no dosage adjustment in patients with renal impairment

  [see Warnings and Precautions (5.1)and Clinical Pharmacology (12.3)]

  .
  ).
• •
  Immune-Mediated Necrotizing Myopathy (IMNM):
  Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue ATORVALIQ if IMNM is suspected (
  5.2 Immune-Mediated Necrotizing Myopathy

  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 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 ATORVALIQ if IMNM is suspected.
  ).
• •
  Hepatic Dysfunction:
  Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ATORVALIQ (
  5.3 Hepatic Dysfunction

  Increases in serum transaminases have been reported with use of atorvastatin

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

  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 ATORVALIQ initiation and when clinically indicated thereafter. ATORVALIQ 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 ATORVALIQ.
  ).