Rx
ROSUCOL 5mg/10mg/20mg
|
COMPOSITION;
Each tablet of Rosucol contains;
Rosuvastatin
calcium; 5mg/10mg/20mg
DESCRIPTION;
Rosuvastatin was developed by Shionogi & marketed by AstraZeneca as Crestor. Crestor is the fifth-highest selling
drug in the United States, accounting for approx. $2.6 billion in sales in
2013.Approval in United States by the FDA came on August 12,2003.
ROSUCOL is an
antilipemic agent that competitively inhibits hydroxymethylglutaryl-coenzyme A
(HMG-CoA) reductase. HMG-CoA reducuase catalyzes the conversion of HMG-CoA to
mevalonic acid, the rate-limiting step in cholesterol biosynthesis. ROSUCOL
belongs to a class of medications called statins and is used to reduce plasma
cholesterol levels and prevent cardiovascular disease
PHARMACODYNAMICS:
Rosucol is a
synthetic, enantiomerically pure antilipemic agent. It is used to lower total
cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B
(apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride
(TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C,
low HDL-C and high TG concentrations in the plasma are associated with
increased risk of atherosclerosis and cardiovascular disease. The total
cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and
high ratios are associated with higher risk of disease. Increased levels of
HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG
and increasing HDL-C, Rosucol reduces the risk of cardiovascular morbidity and
mortality.
MECHANISM OF
ACTION;
Rosucol is a
competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the
conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol
biosynthesis. ROSUCOL acts primarily in the liver. Decreased hepatic
cholesterol concentrations stimulate the upregulation of hepatic low density
lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosucol also
inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall
effect is a decrease in plasma LDL and VLDL. In vitro and in vivo animal
studies also demonstrate that ROSUCOL exerts vasculoprotective effects
independent of its lipid-lowering properties. ROSUCOL exerts an
anti-inflammatory effect on rat mesenteric microvascular endothelium by
attenuating leukocyte rolling, adherence and transmigration (PMID: 11375257).
The drug also modulates nitric oxide synthase (NOS) expression and reduces
ischemic-reperfusion injuries in rat hearts (PMID: 15914111). ROSUCOL increases
the bioavailability of nitric oxide (PMID: 11375257, 12031849, 15914111) by
upregulating NOS (PMID: 12354446) and by increasing the stability of NOS
through post-transcriptional polyadenylation (PMID: 17916773). It is unclear as
to how ROSUCOL brings about these effects though they may be due to decreased
concentrations of mevalonic acid.
PHARMACOKINETIC
Absorption
Absolute bioavailability is about 20%. C max
is reached in 3 to 5 h. Administration with food did not affect the AUC.
Distribution
The mean steady-state Vd is about 134 L.
ROSUCOL is 88% protein bound, mainly to albumin.
Metabolism
ROSUCOL's major metabolite is formed by
CYP2C9.
Not extensively metabolized; approximately
10% is recovered as metabolite.
Elimination
Primarily excreted in the feces (90%). The
elimination half-life is approximately 19 h.
Special Populations
Renal
Function Impairment
Plasma concentrations increase about 3-fold in patients with severe
renal impairment (CrCl less than 30 mL/min). Mild to moderate renal impairment
did not affect plasma levels.
Hepatic
Function Impairment
C max and AUC are increased.
Elderly
No differences in plasma concentrations
between patients 65 yr of age and older compared with younger patients.
Gender
No differences in plasma concentrations
between men and women.
Race
An approximate 2-fold increase in median exposure has been demonstrated
in Asian subjects. No clinically important differences in pharmacokinetics have
been found among Afro-Caribbean, black, white, or Hispanic patients.
Asian
patients
Median exposure in Asian subjects was
approximately 2-fold more compared with a white control group.
Hemodialysis
Steady-state plasma concentrations in patients on chronic hemodialysis
are approximately 50% higher compared with subjects with healthy renal function.
INDICATION
Ø As an adjunct to diet to reduce elevated total
cholesterol (TC), LDL-C, non–HDL-C, apolipoprotein B (Apo B), and triglyceride
(TG) levels, andto increase HDL-C in patients with primary hyperlipidemia or
mixed dyslipidemia;
Ø As an adjunct to diet for the treatment of patients with
hypertriglyceridemia;
Ø As an adjunct to other lipid-lowering treatments, or
alone if such treatments are not available;
Ø To reduce LDL-C, TC, and Apo B in patients with
homozygous familial hypercholesterolemia;
Ø As an adjunct to diet to slow the progression of
atherosclerosis in adults as part of a treatment strategy to lower TC and LDL-C
to target levels;
Ø As an adjunct to diet for the treatment of patients with
primary dysbetalipoproteinemia (type III hyperlipoproteinemia);
Ø As an adjunct to diet to reduce TC, LDL-C, and Apo-B in
children 10 to 17 yr of age (girls must be at least 1 yr postmenarche) with
heterozygous familial hypercholesterolemia;
Ø To reduce the risk of stroke, MI, and arterial revascularization
procedures in individuals without clinically evident coronary heart disease,
but with an increased risk of CV disease based on age and other risk factors.
DOSAGE & ADMINISTRATION
Heterozygous
Familial Hypercholesterolemia
Children 10 to 17 yr of age
Children 10 to 17 yr of age
PO Usual dosage is 5 to 20 mg once daily (max, 20 mg/day). Individualize
dosage according to the recommended goal of therapy; adjustments should be made
at intervals of 4 wk or more.
Homozygous
Familial Hypercholesterolemia
Adults
Adults
PO Start with 20 mg once daily (range, 5 to 40 mg/day). Estimate
response to therapy from preapheresis LDL-C levels.
Hyperlipidemia, Hypertriglyceridemia, Mixed
Dyslipidemia, Primary Dysbetalipoproteinemia, and Slowing of the Progression of
Atherosclerosis
Adults
PO Start with 10 to 20 mg once daily. After initiation or upon
titration, analyze lipid levels within 2 to 4 wk and adjust dosage accordingly
(range, 5 to 40 mg once daily).
Primary
Prevention of CV Disease
Adults
Adults
PO Start with 10 to 20 mg once daily (range,
5 to 40 mg once daily).
Asian
Patients
Adults
Adults
PO Start with 5 mg once daily.
Concurrent
Cyclosporine Therapy
Adults
Adults
PO Limit dosage of ROSUCOL to 5 mg/day.
Concurrent
Lipid-Lowering Therapy
Adults
Adults
PO Avoid concurrent therapy with gemfibrozil; however, if used in
combination with gemfibrozil, the dosage of ROSUCOL should be limited to 10 mg
once daily. The risk of skeletal muscle effects may be enhanced when ROSUCOL is
used in combination with fenofibrate or niacin; therefore, consider a reduction
in ROSUCOL.
Concurrent
Lopinavir/Ritonavir or Atazanavir/Ritonavir
Adults
Adults
PO Limit ROSUCOL dosage to 10 mg once daily.
Renal
Function Impairment
Adults
Adults
PO In patients with severe renal impairment
(CrCl less than 30 mL/min per 1.73 m 2 ) not on hemodialysis, start
with 5 mg once daily (max, 10 mg once daily).
General Advice
·
Administer as a
single dose at any time of day, with or without food.
·
Should be used in
addition to a diet restricted in saturated fat and cholesterol when response
to diet and nonpharmacologic interventions alone has been inadequate.
·
The 40 mg dose
should be reserved for adult patients that do not achieve their LDL-C goal with
the 20 mg dose.
|
DRUG INTERACTION;
Drug Interactions
|
|
CONTRAINDICATIONS;
Breast-feeding; active liver disease or
unexplained, persistent elevations of serum transaminases; hypersensitivity to
any component of the product; women who are or may become pregnant
PRECAUTIONS;
Monitor
It is
recommended that LFTs be performed before and at 12 wk following both the
initiation of therapy and any elevation in dose, and periodically (eg,
semiannually) thereafter.
|
Pregnancy
Category X.
Lactation
Contraindicated in breast-feeding women.
Children
Safety and efficacy not established in
children younger than 10 yr of age or for indications other than heterozygous
familial hypercholesterolemia.
Elderly
At higher risk for myopathy; use with
caution.
Renal
Function
Adjust the dose in patients with severe renal
impairment (CrCl less than 30 mL/min) not requiring hemodialysis.
Hepatic
Function
Contraindicated in patients with active liver
disease, which may include patients with unexplained, persistent elevations in
transaminase levels.
Endocrine
effects
Use caution when
administering with drugs that affect steroid levels or activity (eg,
ketoconazole, spironolactone). Increases in HbA 1c and fasting serum
glucose levels have been reported.
Liver
enzyme abnormalities
Increases in
transaminases have been reported. Use with caution in patients who consume
substantial quantities of alcohol and/or have a history of chronic liver
disease.
Proteinuria
and hematuria
Consider a dose
reduction in patients with unexplained, persistent proteinuria and/or hematuria
during routine urinalysis.
Skeletal
muscle effects
Myopathy and rhabdomyolysis with renal
dysfunction secondary to myoglobinuria have been reported with ROSUCOL.
Temporarily withhold therapy in any patient experiencing an acute or serious
condition suggestive of myopathy or predisposing to the development of renal
failure secondary to rhabdomyolysis (eg, dehydration, hypotension, sepsis). The
risk of myopathy with other drugs in this class is increased if cyclosporine,
gemfibrozil, lopinavir/ritonavir, or niacin is coadministered. Consider
myopathy in any patient with diffuse myalgia, muscle tenderness or weakness, or
marked elevation of CPK.
ADVERSE EFFECTS;
Generally
well-tolerated. Side effects may include myalgia, constipation, asthenia,
abdominal pain, and nausea. Other possible side effects include myotoxicity
(myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in
Asian patients, lower doses should be considered. Pharmacokinetic studies show
an approximately two-fold increase in peak plasma concentration and AUC in
Asian patients (Philippino, Chinese, Japanese, Korean, Vietnamese, or
Asian-Indian descent) compared to Caucasians patients.
