General Information

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 for:

• 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. 
• use in pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH) to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B).

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.

Mechanism of Action

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.

Side Effects

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

Clinical Trial Results

The FDA approval of Livalo in adults 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

The FDA Approval of Livalo in pediatrics with heterozygous familial hypercholesterolemia (HeFH) was based on a double-blind, placebo-controlled, 12-week trial, 82 pediatric patients (36 boys and 46 girls), 8 to 16 years of age with genetically confirmed HeFH, fasting low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL or LDL-C ≥160 mg/dL with an additional cardiovascular risk factor (male gender, a family history of premature CV disease, presence of low HDL (<45 mg/dL) or high TG (>150 mg/dL), presence of high lipoprotein (a) (>75 nmol/L), presence of type 2 diabetes mellitus or presence of hypertension) were randomized to Livalo 1 mg, 2 mg, and 4 mg. Mean LDL-C at baseline was 235 mg/dL (range 160.5 mg/dL to 441mg/dL). Approximately 39% of patients were Tanner Stage 1 at baseline. Livalo significantly reduced plasma LDL-C, non-HDL-C, TC, and Apo-B compared to placebo. The reductions in LDL-C, Apo-B, TC, and non-HDL-C were dose dependent. There was no statistically significant improvement in HDL-C or TG at any Livalo dose.