2. INTRODUCTION
11.5 years of life are lost- consequence of MI.
Hyperlipidemia -atherosclerosis & associated
condition like CAD CerebroVD PAD.
Dyslipidemia -endothelial damage – HT.
Fatal & nonfatel CHD events & strokes – reduced by
30-40%- statin.
Higher cholesterol – higher CHD risk.
NCEP-ATP3 – new target LDL-C <70mg/dl-high risk
patient.
3. INTRODUCTION
NCMH- GOI- 62 million by 2015
an inhibitor of HMG-CoA reductase.
synthetic lipid-lowering agent for oral
administration.
Hygroscopic and slightly unstable in light.
comparative safety profile, fewer drug interactions.
Effective in elderly, diabetic & those at high risk of
developing CHD.
4. Classification of Plasma Lipid Levels
Total cholesterol
<200 mg/dl Desirable
200-239 mg/dl Borderline high
≥240 mg/dl High
HDL-C
<40 mg/dl Low (consider <50 mg/dl as low for women)
>60 mg/dl High
LDL-C
<70 mg/dl Optimal for very high risk (minimal goal for CHD
equivalent patients)
<100 mg/dl Optimal
100-129 mg/dl Near optimal
130-159 mg/dl Borderline high
160-189 mg/dl High
≥190 mg/dl Very high
Triglycerides
<150 mg/dl Normal
150-199 mg/dl Borderline high
200-499 mg/dl High
≥500 mg/dl Very high
5.
6. CHEMISTRY
Chemical name:
(3R,5S,6E)-7-[2-cyclopropyl-4- (4-
fluorophenyl) quinolin-3-yl]-3,5-dihydroxyhept
-6-enoic acid
Chemical structure:
Molecular formula: C25H24FNO4
Molecular weight: 421.461
7. PHARMACOKINETIC
Bioavailability : 60%
TMAX : 1 hour
Volume of distribution : 148 L
Half life : 11 hours
Plasma protein binding : 96%
Metabolism : hepatic (substrate of CYP2C9)
Excretion : biliary
8. MECHANISM OF ACTION
Competitive inhibitor of HMG-CoA reductase, which
is rate limiting enzyme in cholesterol synthesis in
liver.
INDICATION & USES
Primary hyperlipidemia and mixed dyslipidemia as
an adjuvant therapy to diet to reduce elevated
TC, LDL-C,TG and to increase HDL-C.
9. DOSAGE AND ADMINISTRATION
Can be taken with or without food, at any time of day
Dose Range: 1 mg to 4 mg OD.
Primary hyperlipidemia and mixed dyslipidemia:
Starting dose 2 mg, maximum of 4 mg/day
Moderate renal impairment and ESRD on haemodialysis:
Starting dose 1mg OD max. dose of 2mg/day
Dosage Forms And Strengths:
tab. 1 mg , 2 mg and 4 mg.
10. CONTRAINDICATIONS
1) Known hypersensitivity
2) Active liver disease
3) Pregnancy and nursing mother
4) Co-administration with cyclosporine
ADVERSE DRUG REACTIONS
Most common:
myalgia, back pain, diarrhea, constipation and
pain in extrimity .
Most serious:
rhabdomyolysis , myopathy , myoglobinuria and
ARF.
11. DRUG INTERACTIONS
Cyclosporine : C/I
Lopinavir/Ritonavir: combination
should not be used
Erythromycin : limit dose to 1 mg
Rifampin : limit dose to 2 mg
Fibrates : increased risk of skeletal
muscles effects
Niacin : increased risk of skeletal
muscles effects
12. WARNING PRECAUTIONS
Skeletal muscle effects ( e.g., myopathy and
rhabdomyolysis) : risk increases in dose dependent
manner, with advance age, renal impairment and
combination use with fibrates.
Liver enzymes abnormalities and monitoring:
persistent elevation in AST/ALT can occur. (>3
times upper limit of normal-decrease dose/
withdraws
13. USE IN SPECIFIC POPULATIONS
Pregnancy :
Teratogenic effects: Pregnancy Category X
Nursing Mothers :
Rat study-excreted into breast milk.
Pediatric Use:
Safety and have not been established.
Geriatric Use:
No significant differences in efficacy or safety
were observed between elderly & younger patients.
14. CLINICAL STUDIES
Active controlled study with atorvastatin (NK -104-301)
For the percent change from baseline to endpoint in LDL-C, LIVALO was
Superior to atorvastatin. for the two pair wise comparisons: LIVALO 2 mg
vs. atorvastatin 10 mg and LIVALO 4 mg vs. atorvastatin 20 mg. Mean
treatment differences (95% CI) were 1% (-1%, 3%) and 1% (-
2%,4%), respectively.
Active-controlled study with simvastatin (NK-104-302):
Active-controlled study with pravastatin in elderly (NK-104-306):
Active-controlled study with simvastatin in patients with ≥ 2 risk
factors for coronary heart disease (NK-104-304)
Active-controlled study with atorvastatin in patients with type II
diabetes mellitus (NK-104-305)
15. CLINICAL STUDY
Dose-ranging study: to evaluate the efficacy of Livalo compared with placebo
Dose-Response in Patients with Primary Hypercholesterolemia (Adjusted
Mean % Change from Baseline at Week 12)
Treatme- N LDL-C TC TG Apo -B HDL-C
nt
PLACEBO 53 -3 -2 1 -2 0
Livalo 1 52 -32 -23 -15 -25 8
mg
Livalo 2 49 -36 -26 -19 -30 7
mg
Livalo 4 51 -43 -31 -18 -35 5
mg
Severe hypertriglyceridemia (i.e., triglyceride levels of >1000 mg/dl) requires therapy to prevent pancreatitis. Moderately elevated triglyceride levels (150 to 400 mg/dl) also are of concern because they often occur as part of the metabolic syndrome, which includes insulin resistance, obesity, hypertension, low HDL-C levels, and substantially increased CHD risk. The atherogenic dyslipidemia in patients with the metabolic syndrome is characterized by moderately elevated triglycerides, low HDL-C levels, and lipid-depleted LDL (sometimes referred to as "small, dense LDL") (Reaven, 2002; Reaven, 2003; Grundy et al., 2004a; Grundy et al., 2004c). The metabolic syndrome affects ~25% of adults and is common in CHD patients; hence, identification of moderate hypertriglyceridemia in a patient, even if the total cholesterol level is normal, should trigger an evaluation to identify this disorder
Table 35–1. National Cholesterol Education Program: Adult Treatment Guidelines (2001).Desirable Borderline to High1HighTotal cholesterol < 200 (5.2)2200–2392 (5.2–6.2)> 240 (6.2)2LDL cholesterol < 130 (3.4)3130–159 (3.4–4.1) > 160 (4.1)HDL cholesterol > 60 (1.55)Men > 40 (1.04)Women > 50 (1.30)Triglycerides < 150 (1.7) 150–199 (1.7–2.3) > 200 (2.3)1 Consider as high if coronary disease or more than 2 risk factors are present2 mg/dL (mmol/L)3 Optimal level is < 100 (2.6)
, When lowering of LDL-C is insufficient, the dosage may be increased to a (GFR 30 -60mL/min/1.73 m2)
, inadequately treated hypothyroidism
have shown that pitavastatin isOf the 2,800 patients randomized to LIVALO 1 mg to 4 mg in controlled clinical studies, 1,209 (43%) were 65 years and older.
Treatment Based on LDL-C Levels (2004 Revision of NCEP Adult Treatment Panel III Guidelines)RISK CATEGORY LDL-C GOAL THERAPEUTIC LIFESTYLE CHANGE DRUG THERAPY Very high risk <70 mg/dl* No threshold No threshold Atherosclerosis-induced CHD plus one of: (a) multiple risk factors,(b) diabetes mellitus, (c) a poorly controlled single factor,(d) acute coronary syndrome,(e) metabolic syndrome High risk <100 mg/dl* No threshold No threshold CHD or CHD equivalent Moderately high risk <130 mg/dl (Optional <100 mg/dl) ≥100 mg/dl ≥130 mg/dl (100-129 mg/dl)a 2+ risk factors 10-year risk: 10%-20% Moderate risk <130 mg/dl ≥130 mg/dl >160 mg/dl 2+ risk factors 10-year risk <10% 0-1 risk factor <160 mg/dl ≥160 mg/dl ≥190 mg/dl (Optional: 160-189 mg/dl)b