Corestin-10 Tablet

CORESTIN

Corestin

TM

(Rosuvastatin)

Presentation

Corestinill 5 mg film-coated tablets. Each tablet contains Rosuvastatin calcium INN corresponding

to 5mg rosuvastatin.

Corestinill 10 mg film-coated tablets. Each tablet contains Rosuvastatin calcium INN corresponding

to 10mg rosuvastatin.

Indications

Corestin is indicated for patients with primary hypercholesterolaemia (type lla including

heterozygous familial hypercholesterolaemia) or mixed dyslipidaemia (type llb) as an adjunct to

diet when response to diet and exercise is inadequate.

Corestin reduces elevated LDL-cholesterol, total cholesterol, triglycerides and ApoB, and increases

HDL-cholesterol.

Corestin is also indicated in patients with homozygous familial hypercholesterolaemia, either alone

or as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis).

Method of administration

Before initiating treatment with Corestin, the patient should be placed on a standard cholesterol-

lowering diet that should continue during treatment. The dose of Corestin should be individualised

according to the goal of therapy and patient response, using current consensus guidelines.

The usual start dose is Corestin 10 mg once daily and the majority of patients are controlled at this

dose. A dose adjustment to 20 mg can be made after 4 weeks, if necessary Corestin at a dose of 40

mg should only be used in patients with severe hypercholesterolaemia (including those with familial

hypercholesterolaemia) who do not achieve their treatment goal on 20 mg. Corestin may be given at

any time of day, with or without food.

Use in children

Paediatric experience is limited to a small number of children (aged 8 years or above) with

homozygous familial hypercholesterolaemia. Use in children should be super\/ised by specialists.

Use in the elderly

No dose adjustment is necessary.

Dosage in patients with renal insufficiency

No dose adjustment is necessary in patients with mild to moderate renal impairment. For patients

with severe renal impairment (CrCI <30 ml/min) the dose of Corestin should not exceed 10 mg

once daily. Dosage in patients with hepatic impairment No dose adjustment is necessary in patients

with mild to moderate hepatic impairment. Increased systemic exposure to rosuvastatin has been

observed in patients with severe hepatic impairment therefore the dose of Corestin should not

exceed 20 mg once daily.

Interactions requiring dose adjustments

Gemzibrozil: Increased systemic exposure to rosuvastatin has been obser\/ed in subjects taking

concomitant Corestin and gemfibrozil. Patients taking this combination should not exceed a dose of

Corestin 10 mg once daily.

Contraindications

Rosuvastatin is contraindicated in patients:

- with hypersensitivity to any component of this product.

- with active liver disease including unexplained, persistent elevations of serum transaminases and

any serum transaminase elevation exceeding 3 x the upper limit of normal.

- with myopathy.

- receiving concomitant cyclosporin.

Special warnings and special precautions for use

As with other HI\/IG-CoA reductase inhibitors, Corestin should be used with caution in patients

who consume excessive quantities of alcohol and/or have a history of liver disease. It is

recommended that liver function tests be carried out prior to, and 3 months following, the initiation

of treatment with Rosuvastatin. Rosuvastatin should be discontinued or the dose reduced if the level

of serum transaminases is greater than 3 times the upper limit of normal.

Patients should be asked to report inexplicable muscle pain or weakness immediately, particularly if

associated with malaise orfever. CK levels should be measured in these patients. Rosuvastatin

therapy should be discontinued if CK levels are mark edly elevated (>10xULN) or, if on clinical

grounds, myopathy is diagnosed or suspected.

In Rosuvastatin trials there was no evidence of increased skeletal muscle effects in the small

number of patients dosed with Corestin and concomitant therapy.

Corestin should not be used in any patient with an acute, serious condition suggestive of myopathy

or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis,

hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or

uncontrolled seizures).

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been ObS€l’\/Gd in

patients treated with higher doses of Corestin, in particular 40 mg. This is usually transient, and not

predictive of acute or progressive renal disease.

Interaction with other medicinal products and other forms of interaction

Vitamin K antagonists: As with other HIVIG-CoA reductase inhibitors, the initiation of treatment or

dosage up-titration of Corestin in patients treated concomitantly with vitamin K antagonists (e.g.

warfarin) may result in an increase in INR. Discontinuation or down-titration of Corestin may result

in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Gemlibrozil: Concomitant use of Rosuvastatin and gemfibrozil resulted in a 2-fold increase in

rosuvastatin Cmax and AUC.

Cyclosporin: During concomitant treatment with Rosuvastatin and cyclosporin, rosuvastatin plasma

levels were on average 7 times higher than those obser\/ed in healthy volunteers.

Concomitant administration of Corestin and cyclosporine did not affect plasma concentrations of

cyclosporin.

Antacid: The simultaneous dosing of Corestin with an antacid suspension containing aluminium and

magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately

50%. This effect was mitigated when the antacid was dosed 2 hours after Corestin.

Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is

neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. No interactions have been

observed between rosuvastatin and either fluconazole or ketoconazole.

Erythromycin: Concomitant use of Rosuvastatin and erythromycin resulted in a 20% decrease in

AUC (0-t) and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the

increase in gut motility caused by erythromycin.

Ora/ Contraceptive: Concomitant use of Rosuvastatin and an oral contraceptive resulted in an

increase in ethinyl oestradiol and norgestrel AUC of 26% and 34%, respectively. These increased

plasma levels should be considered when selecting oral contraceptive doses.

Other medications: There were no clinically relevant interactions with digoxin, fenofibrate,

antihypertensive agents, antidiabetic agents and hormone replacement therapy.

Use during pregnancy and lactation

Rosuvastatin should not be used during pregnancy or lactation as the safety of Rosuvastatin during

pregnancy and whilst breast-feeding has not been established.

Undesirable effects

The adverse events seen with Rosuvastatin are generally mild and transient. ln controlled clinical

trials less than 4% of Rosuvastatin treated patients were withdrawn due to adverse events.

Headache, dizziness, constipation, nausea, abdominal pain, myalgia, asthenia.

Overdose

There is no specific treatment in the event of overdose. ln the event of overdose, the patient should

be treated symptomatically and supportive measures instituted as required. Liver function and CK

levels should be monitored. Ha emodialysis is unlikely to be of benefit.

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting

enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for

cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol

lowering.

Corestin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and

catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number

of VLDL and LDL particles.

A therapeutic response to Corestin is evident within 1 week of commencing therapy and 90% of

maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4

weeks and is maintained after that.

Pharmacokinetic properties

Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after

oral administration. The absolute bioavailability is approximately 20%.

Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of

cholesterol synthesis and LDL-C clearance. Approximately 90% of rosuvastatin is bound to plasma

proteins, mainly to albumin.

Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%), mainly to the N-

desmethyl metabolite and the lactone metabolite. The N-desmethyl metabolite is approximately

50% less active than rosuvastatin whereas the lactone form is considered clinically inactive.

Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor

activity.

Excretion: Approximately 90% of rosuvastatin is excreted as unchanged drug in the faeces and the

remaining part is excreted in urine. The plasma elimination half- life is approximately 19 hours. The

elimination half-life does not increase at higher doses.

How supplied

Supplied in blister pack Corestin 5mg is supplied in 28s pack. Corestin 10mg is supplied in 14s

pack.

Special precautions for storage

Blister packs: Do not store above 30°C.