Livalo (pitavastatin)

Company
Kowa Company

Approval Status
Approved August 2009

Treatment for
primary hyperlipidemia and mixed dyslipidemia

Areas
Cardiovascular / Cardiology

Livalo is a HMG-CoA reductase inhibitor. It differs from other statins in that it has a unique cyclopropyl group on the base structure. This cyclopropyl group contributes to a more effective inhibition of the HMG-CoA reductase enzyme to inhibit cholesterol production, and potentially affords greater low-density lipoprotein cholesterol (LDL-C) clearance and reduction of plasma cholesterol.

Livalo is specifically 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 HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia.

Livalo is supplied as a tablet (1, 2 and 4 mg) for oral administration. The recommended initial dose of the drug is 2 mg and the maximum dose is 4 mg. After initiation or upon titration of Livalo, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.
Considerations:
Renal Impairment: Patients with moderate renal impairment and end stage renal disease receiving hemodialysis should receive a starting dose of Livalo 1 mg once daily and a maximum dose of Livalo 2 mg once daily. Those with severe renal impairment should not use Livalo.
Use with Erythromycin: a dose of Livalo 1 mg once daily should not be exceeded.
Use with Rifampin: a dose of Livalo 2 mg once daily should not be exceeded.

FDA Approval
The FDA approval of Livalo was based on the following trials:

Dose-ranging Study
This multicenter, randomized, double-blind, placebo-controlled, dose-ranging study enrolled 251 subjects with primary hyperlipidemia. The subjects received Livalo 1, 2 or 4 mg or placebo for 12 weeks. Livalo significantly reduced plasma LDL-C, TC, TG, and Apo-B compared to placebo and was associated with variable increases in HDL-C across the dose range.

Active-controlled study with atorvastatin (NK-104-301):
This randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study enrolled 817 subjects with primary hyperlipidemia or mixed dyslipidemia. The subjects entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either Livalo or atorvastatin. For the percent change from baseline to endpoint in LDL-C, Livalo was non-inferior to atorvastatin for the two pairwise comparisons: Livalo 2 mg vs. atorvastatin 10 mg and Livalo 4 mg vs. atorvastatin 20 mg. Mean treatment differences were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.

Active-controlled study with simvastatin (NK-104-302)
This randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study enrolled 843 subjects with primary hyperlipidemia or mixed dyslipidemia. The subjects entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12 week treatment with either Livalo or simvastatin. For the percent change from baseline to endpoint in LDL-C, Livalo was non-inferior to simvastatin for the two pairwise comparisons: Livalo 2 mg vs. simvastatin 20 mg and Livalo 4 mg vs. simvastatin 40 mg. Mean treatment differences were 4% (1%, 7%) and 1% (-2%, 4%), respectively.

Active-controlled study with pravastatin in elderly (NK-104-306)
This randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority study enrolled 942 elderly patients (older than 65 years) with primary hyperlipidemia or mixed dyslipidemia. The subjects entered a 6- to 8-week washout/dietary lead-in period, and then were randomized to a once daily dose of Livalo or pravastatin for 12 weeks. Livalo significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: Livalo 1 mg vs. pravastatin 10 mg, Livalo 2 mg vs. pravastatin 20 mg and Livalo 4 mg vs. pravastatin 40 mg. Mean treatment differences were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.

Active-controlled study with simvastatin in patients with greater then 2 risk factors for coronary heart disease (NK-104-304)
This randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study enrolled 351 subjects with primary hyperlipidemia or mixed dyslipidemia. Following a 6- to 8-week wash-out/dietary lead-in period, subjects were randomized to a 12-week treatment with either Livalo or simvastatin. Livalo 4 mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference was 0% (-2%, 3%).

Active- controlled study with atorvastatin in patients with type II diabetes mellitus (NK-104-305)
This randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority study enrolled 410 subjects with type II diabetes mellitus and combined dyslipidemia. The subjects entered a 6- to 8-week washout/dietary lead-in period and were randomized to a once daily dose of Livalo or atorvastatin for 12 weeks. The treatment difference for LDL-C percent change from baseline was -2% (-6.2%, 1.5%). The two treatment groups were not statistically different on LDL-C. However, the lower limit of the CI was -6.2%, slightly exceeding the -6% non-inferiority limit so that the non-inferiority objective was not achieved.

Ongoing Study Commitments

  • Kowa has agreed to conduct a clinical trial to assess the effect of severe renal impairment on pitavastatin pharmacokinetics.
    Final Protocol Submission: October 30, 2009
    Study Completion Date: October 30, 2010
    Final Report Submission: December 31, 2010
  • Kowa has agreed to conduct a drug-drug interaction clinical trial to examine the effect of the combination of lopinavir/ritonavir on pitavastatin Cmax and AUC.
    Final Protocol Submission: October 30, 2009
    Study Completion Date: October 30, 2010
    Final Report Submission: December 31, 2010

Adverse events associated with the use of Livalo may include, but are not limited to, the following:

  • Back Pain
  • Constipation
  • Diarrhea
  • Myalgia
  • Pain in extremity

Livalo is a HMG-CoA reductase inhibitor. It differs from other statins in that it has a unique cyclopropyl group on the base structure. This cyclopropyl group contributes to a more effective inhibition of the HMG-CoA reductase enzyme to inhibit cholesterol production, and potentially affords greater low-density lipoprotein cholesterol (LDL-C) clearance and reduction of plasma cholesterol.

For additional information regarding Livalo or primary hyperlipidemia and mixed dyslipidemia, please visit the Livalo web page.

Livalo (pitavastatin) Drug Information

The Livalo (pitavastatin) drug information shown above is licensed from Thomson CenterWatch. The information provided here is for general educational purposes only and does not constitute medical or pharmaceutical advice which should be sought from qualified medical and pharmaceutical advisers.

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