METABOLISM MATTERS

LIVALO may have a reduced potential for CYP-mediated drug interactions2,3,5,6

Metabolism matters for patients on multiple medications:

  • The CYP450 (cytochrome P450) system is involved in approximately 75% of all drugs metabolized8
  • The principal route of LIVALO metabolism is conjugation with glucuronic acid via liver UGTs with subsequent formation of pitavastatin lactone and is only minimally metabolized through the CYP450 system4
  • LIVALO may have a reduced potential for clinically significant drug interactions mediated by the CYP450 system2,3,5,6

HOW IS LIVALO METABOLIZED?

ZOOM PLAY CYP450 Pathway
*CYP450=cytochrome P450=CYP.
UGT=uridine 5'-diphosphate (UDP) glucuronosyltransferase.
Drug Interactions
  • Cyclosporine. Co-administration is contraindicated
  • Erythromycin. Do not exceed a 1-mg dose of LIVALO once daily
  • Rifampin. Do not exceed a 2-mg dose of LIVALO once daily
  • Use with gemfibrozil should be avoided
  • Other fibrates. Co-administration with fenofibrate did not result in a significant increase in AUC or Cmax of LIVALO, however, HMG-CoA reductase inhibitors like LIVALO should be used with caution with fibrates due to the increased risk of myopathy
  • Niacin (≥1 g/day). A reduction in LIVALO dosage should be considered due to potential risk of skeletal muscle effects
  • Colchicine. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing LIVALO with colchicine
METABOLISM MATTERS↑

PATIENTS HAVE CONCERNS

Three reasons why patients don't fill statin prescriptions

53.4% 53.4% of patients report fear of side effects as a reason for not filling their initial statin prescription.1 —Harrison

According to a survey studying usage of statins*9 (the largest known cholesterol survey conducted in the US, involving 10,138 respondents):

  • Stopped statins due to side effects:
    62%
    • Of former statin users*, more than 6 in 10 (62%) stopped their statin due to side effects, such as muscle pain and/or weakness.
    • Muscle-related side effects were reported by 60% of former statin users and 25% of current users.
    *Of the 10,138 respondents 1,220 were former statin users. 8,918 were current users.
  • 84% used one or more products with drug-drug interaction (DDI) potential
    Drug interaction potential 8 out of 109

    Some statin prescriptions go unfilled due to patient fear of DDIs. Patients cite multiple medications as a reason for not filling their initial statin prescription.1 A better understanding of the characteristics of current and former statin users may be helpful for formulating strategies to improve long-term therapy adherence.9

    • 84% (> 8 in 10) of all respondents used at least one prescription, OTC, or herbal/ vitamin product, which may have the potential for drug-drug interaction.
    • Of those respondents, patients used on average 3 products with statin interaction potential.
    • Only 26% proactively spoke to their doctor about the possibility of their medications interfering with each other.
PATIENTS HAVE CONCERNS↑

LIVALO EFFICACY

As an adjunctive therapy to diet for patients with primary hyperlipidemia or mixed dyslipidemia7:Try LIVALO for the efficacy your patients need

LIVALO MAY OFFER PATIENTS:

  • Mean LDL-C reduction up to 45% with the maximum dose of 4 mg7,10,11.
  • Improvements in other lipid parameters, including HDL-C, TG, Non-HDL-C, and Apo B4.
  • Comparable efficacy to the most commonly prescribed strengths of atorvastatin (10-20 mg) and simvastatin (20-40 mg)‡,4,10,11.
LIVALO was not studied against atorvastatin 40-mg and 80-mg doses, or simvastatin 80-mg dose.

CONTRAINDICATIONS

LIVALO is contraindicated in patients with a known hypersensitivity to product components, in patients with active liver disease (which may include unexplained persistent elevations in hepatic transaminase levels), in women who are pregnant or may become pregnant, in nursing mothers, or in co-administration with cyclosporine.

Range of Changes in Lipid Parameters at Week 12 in 3 12-Week Trials Studying LIVALO*
  • 10
  • 5
  • -10
  • -20
  • -30
  • -40
  • -50
LDL-C
2 mg
-38%
-39%
4 mg
-44%
-45%
HDL-C
2%
6%
2 mg
4%
6%
4 mg
TG
2 mg
-14%
-16%
4 mg
-17%
-22%
*Based on the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria and the 2004 ATP III Guidelines update.
STUDY DESIGN↓

Three 12-week, randomized, multicenter, double-blind, double-dummy, Phase 3 studies in patients with primary hyperlipidemia or mixed dyslipidemia: Study 301: LIVALO (pitavastatin) 2 mg (n=315) and 4 mg (n=298); Study 302: LIVALO 2 mg (n=307) and 4 mg (n=319); Study 306: in patients ≥65 years, LIVALO 1 mg (n=207), 2 mg (n=224), and 4 mg (n=210).

Range of Changes in Non-HDL-C and Apo B at Week 12 in 3 12-Week Trials Studying LIVALO*4,7,10,11
  • 10
  • 5
  • -10
  • -20
  • -30
  • -40
  • -50
Non-HDL-C
2 mg
-35%
-36%
4 mg
-41%
Apo B
2 mg
-30%
-31%
4 mg
-35%
-37%

*Mean % change from baseline.

STUDY DESIGN↓

Three 12-week, randomized, multicenter, double-blind, double-dummy, Phase 3 studies in patients with primary hyperlipidemia or mixed dyslipidemia: Study 301: LIVALO (pitavastatin) 2 mg (n=315) and 4 mg (n=298); Study 302: LIVALO 2 mg (n=307) and 4 mg (n=319); Study 306: in patients ≥65 years, LIVALO 1 mg (n=207), 2 mg (n=224), and 4 mg (n=210).

LIVER ENZYME ABNORMALITIES

  • Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including LIVALO (pitavastatin).
  • It is recommended that liver enzyme tests be performed before the initiation of LIVALO and if signs or symptoms of liver injury occur.
  • There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIVALO, promptly interrupt therapy. If an alternate etiology is not found do not restart LIVALO.
  • Advise patients to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
  • LIVALO should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.
LIVALO EFFICACY↑

Use in specific patient populations, dosing, & safety

Use in Specific Patient Populations, Dosing, & Safety

Specific Patient Populations

LDL-C improvements in specific patient populations

Consider prescribing LIVALO for patients with primary hyperlipidemia or mixed dyslipidemia including:

  • Patients with moderate or high risk of coronary heart disease (CHD)*12
    • Patients experienced a mean % change of -44% in LDL-C with LIVALO 4 mg.
    • However, the effects of LIVALO on cardiovascular morbidity or mortality have not been determined.
  • Patients with type 2 diabetes mellitus and combined dyslipidemia
    • Patients experienced a mean % change of -41% in LDL-C with LIVALO 4 mg.
  • Elderly patients (≥65 years)
    • Mean % change in LDL-C at 1 mg, 2 mg, and 4 mg doses of LIVALO were -31%, -39%, and -44%, respectively.
    • Of the 2800 patients randomized to LIVALO 1 mg to 4 mg in controlled clinical studies, 1209 (43%) were 65 years and older. No significant differences in efficacy or safety were observed between elderly patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.
    • LIVALO should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (≥65 years), renal impairment, and inadequately treated hypothyroidism.
*Based on the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria and the 2004 ATP III Guidelines update.
STUDY DESIGN↓

Three 12-week, randomized, multicenter, double-blind, double-dummy, Phase 3 studies:
Study 304: in patients with primary hyperlipidemia or mixed dyslipidemia and ≥2 additional risk factors for CHD, LIVALO 4 mg (n=233); Study 305: in patients with type 2 diabetes mellitus and combined dyslipidemia, LIVALO 4 mg (n=274); Study 306: in elderly patients (≥65 years) with primary hyperlipidemia or mixed dyslipidemia, LIVALO 1 mg (n=207), 2 mg (n=224), and 4 mg (n=210).

Drug Interaction Studies

Based on drug interactions/pharmacokinetic (pk) studies in healthy volunteers, no dosage adjustment recommended in combination with4:

Atazanavir, lopinavir/ritonavir, or darunavir/ritonavir (HIV protease inhibitors)

  • Co-administration with the following drugs did not result in clinically significant changes in the AUC or Cmax of LIVALO: atazanavir, lopinavir/ritonavir, or darunavir/ritonavir.

Diltiazem LA

  • Co-administration with diltiazem LA did not result in clinically significant changes in the AUC or Cmax for either drug.

Itraconazole

  • Co-administration with itraconazole, an antifungal, did not result in clinically significant changes in the AUC or Cmax for LIVALO.

Grapefruit juice

  • Co-administration with grapefruit juice did not result in clinically significant changes in the AUC or Cmax of LIVALO.

Warfarin

  • LIVALO 4 mg daily had no significant effect on PT/INR. Co-administration of LIVALO did not result in clinically significant changes in the AUC* or Cmax of warfarin. Patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to their therapy.

Enalapril

  • Co-administration with enalapril, an ACE inhibitor, did not result in clinically significant changes in the AUC or Cmax for either drug.

Fibrates

  • Use with gemfibrozil should be avoided.
  • Co-administration with fenofibrate did not result in clinically significant changes in the AUC or Cmax of LIVALO, however, HMG-CoA reductase inhibitors like LIVALO should be used with caution with fibrates due to the increased risk of myopathy.

Digoxin

  • Co-administration with digoxin did not result in clinically significant changes in the AUC or Cmax for either drug.
*AUC=area under the curve.
Cmax=maximum concentration observed.
Dosing

LIVALO general dosing recommendations:

  • LIVALO is available in once-daily doses of 1 mg, 2 mg, or 4 mg
  • Recommended starting dose is 2 mg once daily. The dose may be increased to a maximum of 4 mg once daily if necessary, based on patient response and goal of therapy
  • Doses of LIVALO greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4 mg once-daily dosing of LIVALO
  • After initiation or upon titration of LIVALO, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly
  • LIVALO can be taken with or without food, at any time of day
  • The consumption of grapefruit juice has no clinically significant effect on LIVALO exposure

Special dosing considerations:

  • Patients with moderate or severe renal impairment not on hemodialysis (GFR 30-59 mL/min/1.73 m2 and 15-29 mL/min/1.73 m2, respectively) and patients with end-stage renal disease on hemodialysis should receive a starting dose of LIVALO 1 mg once daily and a maximum dose of LIVALO 2 mg once daily
  • In patients taking erythromycin, a dose of LIVALO 1 mg once daily should not be exceeded
  • In patients taking rifampin, a dose of LIVALO 2 mg once daily should not be exceeded
  • A reduction in LIVALO dosage should be considered when used in combination with niacin (≥1 g/day)
Clinical Safety & Tolerability

LIVALO clinical safety and tolerability4

Adverse Reactions Reported by ≥2% of Patients Treated with LIVALO and ≥ Placebo in Short-term Controlled Studies Lasting Up to 12 Weeks
Adverse reaction Placebo
N=208
LIVALO 1 mg
N=309
LIVALO 2 mg
N=951
LIVALO 4 mg
N=1540
Back pain 2.9% 3.9% 1.8% 1.4%
Constipation 1.9% 3.6% 1.5% 2.2%
Diarrhea 1.9% 2.6% 1.5% 1.9%
Myalgia 1.4% 1.9% 2.8% 3.1%
Pain in extremity 1.9% 2.3% 0.6% 0.9%
Use in specific patient populations, dosing, & safety↑

Eligible patients may pay as little as $18 PER MONTH*

Helping your patients save…

COPAY CARD

Eligible patients may pay as little as $18 a month*

Unlike many others, the LIVALO $18 Co-pay card:

  • Covers up to $75 monthly on out-of-pocket costs on each 30-day supply.
  • Can be used with mail-order prescriptions.
  • Can be used with all strengths (1 mg, 2 mg, and 4 mg).

SEE FULL DETAILS AND ELIGIBILITY ON THE LIVALO PATIENT SITE. VISIT LIVALO patient site

*Certain rules and restrictions apply.
According to a recent survey studying usage of statins:*9 (the largest known cholesterol survey conducted in the US, involving 10,138 participants) Nearly half of all respondents switched statins at least once.9
32%
  • 32% of statin users switched due to cost.
*Of the 10,138 respondents 1,220 were former statin users. 8,918 were current users.
Eligible patients may pay as little as $18 PER MONTH↑

LIVALO INFORMATIONAL EVENTS

Participate in peer-to-peer programs


LIVALO INFORMATIONAL EVENTS↑

COMPARE YOUR KNOWLEDGE

ENGAGE IN SOME QUESTIONS AND GET RELEVANT INSIGHTS!

  • 1. What mean percent reduction in LDL-C does LIVALO offer?

    View Results

    Did you know that your colleagues choose the following:

    • A) 9.5% 0.0%
    • B) 38% 0.0%
    • C) 45% 0.0%
    • D) 81% 0.0%
    • 0%
    • 50%
    • 100%

    LIVALO offers a 45% mean LDL -C reduction at the maximum dose of 4 mg.*4

    Learn more
  • 2. For the majority of statin patients, is managing Non-HDL-C and Apo B still an important priority?

    View Results

    Did you know that your colleagues choose the following:

    • A) Yes 0.0%
    • B) No 0.0%
    • 0%
    • 50%
    • 100%

    You may not be aware that LIVALO offers significant mean LDL-C reductions, as well as improvements in other atherogenic lipid parameters*4,7,10,11

    Learn more
  • 3. Do your patients ever express concern about drug-drug interactions (DDIs) when prescribed a statin?

    View Results

    Did you know that your colleagues choose the following:

    • A) Yes 0.0%
    • B) No 0.0%
    • 0%
    • 50%
    • 100%

    According to the largest known cholesterol survey conducted in the US, involving 10,138 respondents, some statin prescriptions go unfilled due to patient fear of DDIs.1,9

    Learn more
  • 4. Do you consider drug metabolism when selecting a statin for your patients?

    View Results

    Did you know that your colleagues choose the following:

    • A) Yes 0.0%
    • B) No 0.0%
    • 0%
    • 50%
    • 100%

    Did you know the CYP450 (cytochrome P450) system is involved in approximately 75% of all drugs metabolized?8 LIVALO may have a reduced potential for clinically significant drug interactions mediated by the CYP450 system2,3,5,6

    Learn more
  • 5. Approximately what percentage of your patients take multiple medications?

    View Results

    Did you know that your colleagues choose the following:

    • A) 25% 0.0%
    • B) 50% 0.0%
    • C) 75% 0.0%
    • D) 100% 0.0%
    • 0%
    • 50%
    • 100%

    Did you know patients cite multiple medications as a reason for not filling their initial statin prescription?1 According to a survey studying usage of statins (the largest known cholesterol survey conducted in the US, involving 10,138 participants), 84% (> 8 in 10) of all respondents used at least one prescription, OTC, or herbal/ vitamin product, which may have the potential for drug-drug interaction. Of those respondents, patients used on average 3 products with statin interaction potential.9†

    Learn more
*Based on the mean % change from baseline in LDL-C observed in 3 12-week, double-blind, non-inferiority phase 3 studies in patients with primary hyperlipidemia or mixed dyslipidemia taking LIVALO 2 mg (-38, -39, -39) and 4 mg (-45, -44, -44).
Of the 10,138 respondents 1,220 were former statin users. 8,918 were current users.
COMPARE YOUR KNOWLEDGE↑
INDICATIONS AND USAGE

Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.

PRIMARY HYPERLIPIDEMIA AND MIXED DYSLIPIDEMIA

LIVALO (pitavastatin) is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hyperlipidemia or mixed dyslipidemia.

LIMITATIONS OF USE

IMPORTANT SAFETY INFORMATION FOR LIVALO® (pitavastatin) tablets

CONTRAINDICATIONS

LIVALO (pitavastatin) is contraindicated in patients with a known hypersensitivity to product components, in patients with active liver disease (which may include unexplained persistent elevations in hepatic transaminase levels), in women who are pregnant or may become pregnant, in nursing mothers, or in co-administration with cyclosporine.

WARNINGS AND PRECAUTIONS
Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.

Liver Enzyme Abnormalities

Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including LIVALO.

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIVALO.

ADVERSE REACTIONS

In short-term controlled studies, the most frequent adverse reactions reported by ≥2% of patients treated with LIVALO 1 mg, 2 mg, and 4 mg, respectively, and at a rate ≥ placebo were back pain (3.9%, 1.8%, 1.4% vs 2.9%), constipation (3.6%, 1.5%, 2.2% vs 1.9%), diarrhea (2.6%, 1.5%, 1.9% vs 1.9%), myalgia (1.9%, 2.8%, 3.1% vs 1.4%), and pain in extremity (2.3%, 0.6%, 0.9% vs 1.9%). This is not a complete listing of all reported adverse events.

For additional information please see the full Prescribing Information.


REFERENCES:

Kowa LIVALO® is a registered trademark of the Kowa group of companies.
©Kowa Pharmaceuticals America, Inc. (2014)
All rights reserved. LIV-MT-1241 June 2014
US Healthcare Professionals only.