PITAVASTATIN

Fda.gov 08/03/2009

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.

INTRODUCTIONNCMH- 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.

Classification of Plasma Lipid LevelsTotal 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

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

PHARMACOKINETICBioavailability : 60%

TMAX : 1 hour

Volume of distribution : 148 L

Half life : 11 hours

Plasma protein binding : 96%

Metabolism : hepatic (substrate of CYP2C9)

Excretion : biliary

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.

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.

CONTRAINDICATIONS1) Known hypersensitivity2) Active liver disease3) Pregnancy and nursing mother4) Co-administration with cyclosporine

ADVERSE DRUG REACTIONSMost common:

myalgia, back pain, diarrhea, constipation and pain in extrimity . Most serious:

rhabdomyolysis , myopathy , myoglobinuria and ARF.

DRUG INTERACTIONSCyclosporine : 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

WARNING PRECAUTIONSSkeletal 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

USE IN SPECIFIC POPULATIONSPregnancy :

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.

CLINICAL STUDIESActive 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)

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-nt

N LDL-C TC TG Apo -B HDL-C

PLACEBO

53 -3 -2 1 -2 0

Livalo 1 mg

52 -32 -23 -15 -25 8

Livalo 2 mg

49 -36 -26 -19 -30 7

Livalo 4 mg

51 -43 -31 -18 -35 5

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