Leaflet

 

Crestomed

Coated Tablets

Composition:

   Each coated tablet contains:  5, 10,20 or 40mg of rosuvastatin as rosuvastatin calcium.

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 of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and inhibits hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Pharmacokinetic properties:

Absorption:  Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral Administration. The absolute bioavailability is approximately 20%.

Distribution:    The volume of distribution of rosuvastatin is approximately 134 L.  Approximately 90 % of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism:    Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. The main metabolite identified is the N-desmethyl and lactone metabolites. The N-desmethyl 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 the rosuvastatin dose is excreted unchanged in the feces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine .The plasma elimination half-life (t_1/2 )of rosuvastatin is approximately 19 hours.

Therapeutic Indications:

Crestomed is indicated:

• Primary hypercholesterolemia (Type IIa including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (Type IIb) as an adjunct to diet when response to diet and other non-pharmacological treatments (e.g exercise, weight reduction) is inadequate.

• Homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments or if such treatments are not appropriate. 

Contraindications

Crestomed is contraindicated

• In patients with a known hypersensitivity to any component of this product.

• In patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminases elevations exceeding 3x the upper limit of normal (ULN)

·         In patients with severe renal impairment (Cr CL < 30 mL/min).

• In patients with myopathy.

• In patients receiving concomitant cyclosporin.

• During pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.

The 40 mg dose is contraindicated in patients with pre-disposing factors for myopathy / rhabdomyolysis. Such factors include:

• Moderate renal impairment (Cr CL < 60 mL/min)

_        Hypothyroidism.

• Personal or family history of hereditary muscular disorders
• Previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate  
• Alcohol abuse
• Situations where an increase in plasma levels may occur
• Asian patients
• Concomitant use of fibrates

Side effects:

The adverse events seen with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse events.

Common: headache, dizziness, constipation, nausea, abdominal pain, mayalgia, asthenia.

Uncommon:   pruritus, rash and urticaria .

Rare: hypersensitivity reactions including angioedema, myopathy and rhabdomyolysis

As with other HMG-CoA reductase inhibitor, the incidence of adverse drug reactions tends to be dose dependent.

Renal effects: Proteinuria  has been observed in patients treated with rosuvastatin .  In most cases, proteinuria decreases or disappears spontaneously on continued therapy, and has not been shown to be predictive of acute or progressive renal disease.

Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy and rarely rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and in particular with doses > 20 mg .

A dose related increase in CK levels has been observed in patients taking rosuvastatin ; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated ( > 5x ULN ) , treatment should be discontinued .

Liver effects: As with other HMG-CoA reductase inhibitors, a dose related increase in transaminases has been observed in a small number of patients taking rosuvastatin ; the majority of cases were mild, asymptomatic and transient .

Pregnancy and Lactation

Crestomed is contraindicated in pregnancy and lactation.

Warnings and Precautions

• An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg.

• Rosuvastatin, as with other  HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for  myopathy / rhabdomyolysis .

In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (> 5x ULN) treatment should not be started

• Whilst on treatment, patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever.
• Therapy should be discontinued if CK levels are markedly elevated (> 5x ULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are <5x ULN). If symptoms resolve and  CK levels return to normal, then consideration should be given to re-introducing rosuvastatin or an alterative HMG-CoA reductase inhibitor
• Routine monitoring of CK levels in asymptomatic patients is not warranted.
• Rosuvastatine 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).
• As with other HMG-CoA reductase inhibitors, rosuvastatin 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.
•  Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal.
•  In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin .
• Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians. 

Effects on ability to drive and use machines:

When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

Drug Interactions

Cyclosporin: During concomitant treatment with rosuvastatin and cyclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers. Concomitant administration did not affect plasma concentrations of cyclosporin.

Vitamin K antagonists:    As with other HMG-CoA reductase inhibitors the initiation of treatment or dosage up-titration of rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Gemfibrozil and other lipid-lowering products:   Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin C _max and AUC.

Gemfibrozil, fenofibrate , other fibrates and lipid lowering dose ( > or equal to 1g / day  of niacin ) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors , probably because they can produce myopathy when given alone .  The 40 mg dose is contraindicated with concomitant use of a fibrate .

Antacid: The simultaneous dosing of rosuvastatin 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 rosuvastatin.

Erythromycin:    Concomitant use of rosuvastatin and erythromycin resulted in a 20 % decrease in AUC and 30 % decrease in C_max of rosuvastatin . This interaction may be caused by the increase in gut motility caused by erythromycin.

Oral contraceptive / hormone replacement therapy (HRT) :

Concomitant use of rosuvastatin and an oral contraceptive resulted in an increase in ethinyl osetradiol and norgestrel AUC of 26 % and 34% respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant rosuvastatin and HRT. However, the combination has been extensively used in women in clinical trials and was well tolerated.

Other medicinal products: Based on data from specific interaction studies no clinically relevant interactions with digoxin are expected.

Cytochrome p 450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome p 450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole

or ketoconazole. Concomitant administration of itraconazole and rosuvasatin resulted in a 28% increase in AUC of rosuvastatin . This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome p450-mediated metabolism are not expected.

Overdosage

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be of benefit.

Dosage and Administration

• Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualized according to the goal of therapy and response. 
• The recommended start dose is 10 mg orally once daily and the majority of patients are controlled at this dose.
•  Patients who are switched over from another HMG-CoA reductase inhibitor should also start with the 10 mg dose.  A dose adjustment to 20 mg can be made after 4 weeks, if necessary.
• In light of the increased reported rate of adverse reactions with the 40 mg dose compared to lower doses, a doubling of the dose to 40 mg after an additional 4 weeks should only be considered in patients with severe hypercholesterolemia at high cardiovascular risk ( in particular those with familial hypercholesterolemia ), who do not achieve their treatment goal on 20 mg , and in whom routine follow-up will be performed .
• Specialist supervision is recommended when the 40 mg dose is initiated.

 

 

 

• Crestomed may be given at any time of day, with or without food.

Paediatric  use

Safety and efficacy have not been established in children, therefore Crestomed is not recommended for paediatric use at this time.

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. The use of Crestomed in patients with severe renal impairment is contraindicated for all doses. The 40 mg dose is also contraindicated in patients with moderate renal impairment (Cr CL < 60 mL/min).

Dosage in patients with hepatic impairment

For patients with hepatic impairment, Crestomed should be taken with caution under specialist supervision and an assessment of liver function should be considered.

Crestomed is contraindicated in patients with active liver disease.

Race

Increased systemic exposures have been seen in Asian subjects this should be considered when making dose decisions for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.

Presentation:

Box of 15 or 20 or 30 coated tablets rosuvastatin (as rosuvastatin calcium)  5 mg

Box of 15 or 20 or 30 coated tablets rosuvastatin (as rosuvastatin calcium)  10 mg

Box of 15 or 20 or 30 coated tablets  rosuvastatin (as rosuvastatin calcium)  20 mg

Box of 15 or 20 or 30 coated tablets rosuvastatin (as rosuvastatin calcium)  40mg