LIPITOR®

atorvastatin calcium

Lipitor is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-b, d-dihydroxy-5- (1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C₃₃H₃₄ FN₂O₅)₂Ca·3H₂O and its molecular weight is 1209.42. Its structural formula is:

Indications

LIPITOR (atorvastatin calcium) is indicated as an adjunct to lifestyle changes, including diet, (at least equivalent to the Adult Treatment Panel III (ATP III) TLC diet), for the reduction of elevated total cholesterol (total-C), LDL-C, TG and apolipoprotein B (apo B) in hyperlipidemic and dyslipidemic conditions, when response to diet and other nonpharmacological measures alone has been inadequate, including:

• Primary hypercholesterolemia (Type IIa);

  
  

• Combined (mixed) hyperlipidemia (Type IIb), including familial combined hyperlipidemia, regardless of whether cholesterol or triglycerides are the lipid abnormality of concern;

  
  

• Dysbetalipoproteinemia (Type III);

  
  

• Hypertriglyceridemia (Type IV);

  
  

• Familial hypercholesterolemia (homozygous and heterozygous). For homozygous familial hypercholesterolemia, LIPITOR should be used as an adjunct to treatments such as LDL apheresis, or as monotherapy if such treatments are not available.

  
  

• An adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia, if after an adequate trial of diet therapy the following findings are still present:

  1. LDL-C remains ≥4.9 mmol/L (190 mg/dL) or

     
     

  2. LDL-C remains ≥4.1 mmol/L (160 mg/dL) and:

     • there is a positive family history of premature cardiovascular disease or

       
       

     • two or more other CVD risk factors are present in the pediatric patient

       LIPITOR also raises HDL-cholesterol and therefore lowers the LDL-C/HDL-C and total-C/HDL-C ratios in patients with primary hypercholesterolemia and combined (mixed) hyperlipidemia (Fredrickson Type IIa and IIb dyslipidemia). In pooled data from 24 controlled clinical trials, LIPITOR raised HDL-C levels 5%-7% in primary hypercholesterolemic (type IIa) patients and 10%-15% in mixed (type IIb) dyslipidemic patients.

In clinical trials, LIPITOR (10 to 80 mg/day) significantly improved lipid profiles in patients with a wide variety of hyperlipidemic and dyslipidemic conditions. In 2 dose-response studies in mildly to moderately hyperlipidemic patients (Fredrickson Types IIa and IIb), LIPITOR reduced the levels of total cholesterol (29-45%), LDL-C (39-60%), apo B (32-50%), TG (19-37%), and increased high density lipoprotein cholesterol (HDL-C) levels (5-9%). Comparable responses were achieved in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, combined hyperlipidemia, including familial combined hyperlipidemia and patients with non-insulin dependent diabetes mellitus. In patients with hypertriglyceridemia (Type IV), LIPITOR (10 to 80 mg daily) reduced TG (25-56%) and LDL-C levels (23-40%). LIPITOR has not been studied in conditions where the major abnormality is elevation of chylomicrons (TG levels >11 mmol/L), i.e. types I and V. Lipitor Canada

In an open-label study in patients with dysbetalipoproteinemia (Type III), LIPITOR (10 to 80 mg daily) reduced total-C (40-57%), TG (40-56%) and IDL-C+ VLDL-C levels (34-58%).

In an open label study in patients with homozygous familial hypercholesterolemia (FH) LIPITOR (10 to 80 mg daily) reduced mean LDL-C levels (22%). In a pilot study, LIPITOR 80 mg/day showed a mean LDL-C lowering of 30% for patients not on plasmapheresis and of 31% for patients who continued plasmapheresis. A mean LDL-C lowering of 35% was observed in receptor defective patients and of 19% in receptor negative patients.

Prior to initiating therapy with LIPITOR, secondary causes should be excluded for elevations in plasma lipid levels (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, and alcoholism), and a lipid profile performed to measure total cholesterol, LDL-C, HDL-C, and TG. For patients with TG <4.52 mmol/L (<400 mg/dL), LDL-C can be estimated using the following equation: Lipitor Canada

LDL-C (mmol/L)=total-C- [(0.37×(TG)+HDL-C)]

LDL-C (mg/dL)=total-C- [(0.2×(TG)+HDL-C)]{*Friedewald, W.T. et al. Clin. Chem. 1972;18(6):489-502.}

For patients with TG levels >4.52 mmol/L (>400 mg/dL), this equation is less accurate and LDL C concentrations should be measured directly or by ultracentrifugation.

Patients with high or very high triglyceride levels, i.e. >2.2 mmol/L (200 mg/dL) or >5.6 mmol/L (500 mg/dL), respectively, may require triglyceride-lowering therapy (fenofibrate, bezafibrate or nicotinic acid) alone or in combination with LIPITOR.

In general, combination therapy with fibrates must be undertaken cautiously and only after risk-benefit analysis (see Warnings and Precautions, Muscle Effects, Pharmacokinetic Interactions and Drug Interactions).

Elevated serum triglycerides are most often observed in patients with the metabolic syndrome (abdominal obesity, atherogenic dyslipidemia [elevated triglycerides, small dense LDL particles and low HDL-cholesterol], insulin resistance with or without glucose intolerance, raised blood pressure and prothrombic and proinflammatory states).

(For the treatment of specific dyslipidemias refer to the Report of the Canadian Working Group on Hypercholesterolemia and Other Dyslipidemias or to the US NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III].)

When drugs are prescribed attention to therapeutic lifestyle changes (reduced intake of saturated fats and cholesterol, weight reduction, increased physical activity, ingestion of soluble fibers) should always be maintained and reinforced.

Warnings and Precautions