Crevas 40 Mg Tablets

To reduce the risk of cardiovascular events

In adult patients with an increased risk of atherosclerotic cardiovascular disease based on the presence of cardiovascular disease risk markers such as an elevated high-sensitivity C-reactive protein (hsCRP) level, age, hypertension, low HDL-C, smoking or a family history of premature coronary heart disease, CREVAS is indicated to reduce the risk of non-fatal stroke, non-fatal MI, and the need for arterial revascularisation.

In adult patients with hypercholesterolaemia CREVAS is indicated for patients with primary hypercholesterolaemia, mixed dyslipidaemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial and non-familial hypercholesterolaemia) as an adjunct to diet when response to diet and exercise is inadequate.

CREVAS is indicated to treat patients with primary dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinaemia). CREVAS is also indicated to reduce total cholesterol and LDL-C in patients with homozygous familial hypercholesterolaemia, either alone or as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis). CREVAS 40 mg should only be considered in patients with severe hypercholesterolaemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of CREVAS or alternative therapy and in whom routine follow-up will be performed. Specialist supervision is recommended when the 40 mg dose is initiated (see section 4.4).

Children and adolescents 10 to 17 years of age

CREVAS is indicated to reduce the total cholesterol, LDL-C and Apo B in patients with heterozygous familial hypercholesterolaemia (HeFH).

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment.

Posology

The dosage range for CREVAS is 5 - 40 mg orally once a day. The recommended starting dose is 5 mg once a day. The choice of start dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions (see below). A dose adjustment to the next dose level can be made after 4 weeks, if necessary.

In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses (see section 4.8), a final titration to the maximum dose of 40 mg should only be considered in patients with severe hypercholesterolaemia at high cardiovascular risk (in particular those with familial hypercholesterolaemia), who do not achieve their treatment goal on 20 mg, and in whom routine follow-up will be performed (see section 4.4). Specialist supervision is recommended when the 40 mg dose is initiated.

The dose should be individualised according to the goal of therapy and patient response. The majority of patients are controlled at the 10 mg dose. However, if necessary, dose adjustment can be made at 4 week intervals.

Adults: Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), mixed dyslipidaemia, dysbetalipoproteinaemia (Frederickson Type III hyperlipoproteinaemia), and isolated hypertriglyceridaemia

The recommended starting dose is 5 mg once a day. A 5 mg starting dose is recommended for patients of Asian ancestry and for patients requiring a smaller reduction in LDL-C to achieve treatment target. For patients with severe hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), a starting dose of 20 mg may be considered.

Homozygous familial hypercholesterolaemia

For patients with homozygous familial hypercholesterolaemia a starting dose of 20 mg once a day is recommended.

Special populations: Use in the elderly

The usual dose range applies.

Dosage in patients with renal insufficiency

The starting dose applies in patients with mild to moderate renal impairment. The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of CREVAS in patients with severe renal impairment is contraindicated for all doses (see sections 4.3 and 5.2).

Dosage in patients with hepatic insufficiency

The usual starting dose applies in patients with mild to moderate hepatic impairment. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9 (see section 5.2). In these patients an assessment of renal function should be considered (see section 4.4). There is no experience in subjects with Child-Pugh scores above 9. Patients with severe hepatic impairment should start therapy with CREVAS 5 mg. Increased systemic exposure to rosuvastatin has been observed in these patients, therefore the use of doses above 10 mg should be carefully considered (see section 5.2). CREVAS is contraindicated in patients with active liver disease (see section 4.3).

Ethnic differences: A 5 mg starting dose of CREVAS should be considered for Asian patients. Increased plasma concentration of rosuvastatin is seen in Asian subjects (see sections 4.4 and 5.2). The increased systemic exposure should be taken into consideration when treating Asian patients whose hypercholesterolaemia is not adequately controlled at doses up to 20 mg daily. The 40 mg dose is contraindicated in these patients.

Genotypes of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have been shown to be associated with an increase in rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT and ABCG2 c.421CC. For patients known to have the c.521CC or c.421AA genotype, a maximum once daily dose of 20 mg of CREVAS should not be exceeded (see section 4.4, 4.5 and 5.2).

Concomitant therapy

CREVAS has shown to have additive efficacy in lowering triglycerides when used in combination with fenofibrate and in increasing HDL-C levels when used in combination with niacin. CREVAS can also be used in combination with ezetimibe or bile acid sequestrants (see section 4.5).

Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when CREVAS is administered concomitantly with certain medicines that may increase the plasma concentration of rosuvastatin due to interactions with these transporter proteins (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir (see section 4.4 & 4.5). It is recommended that prescribers consult the relevant product information when considering administration of such products together with CREVAS. Whenever possible, alternative medicines should be considered, and if necessary, consider temporarily discontinuing CREVAS therapy. In situations where co-administration of these medicinal products with CREVAS is unavoidable, the risk of concurrent treatment and CREVAS dosing adjustments should be carefully considered (see section 4.4).

Interactions requiring dose adjustments

Ciclosporin

Increased systemic exposure to rosuvastatin has been observed in patients taking concomitant rosuvastatin and ciclosporin. For the CREVAS dose range (10 - 40 mg) this combination is contraindicated (see section 4.3).

Gemfibrozil

Increased systemic exposure to rosuvastatin has been observed in subjects taking concomitant rosuvastatin and gemfibrozil. Patients taking this combination should start with therapy CREVAS 5 mg once daily and should not exceed a dose of CREVAS 20 mg once daily (see section 4.5).

Paediatric population

Children and adolescents 10 - 17 years of age

In children and adolescents with heterozygous familial hypercholesterolaemia the usual dose range is 5 - 20 mg orally once daily. The dose should be approximately titrated to achieve treatment goal. Safety and efficacy of doses greater than 20 mg have not been studied in this population.

In children and adolescents with homozygous familial hypercholesterolaemia experience is limited to a small number of patients (aged 8 years and above).

Method of Administration

For oral administration. CREVAS may be given at any time of day, with or without food.

CREVAS is contraindicated

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• in patients with hypersensitivity to rosuvastatin or to any of the excipients of CREVAS (see section 6.1)
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• in patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN)
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• in patients with severe renal impairment (creatinine clearance < 30 mL/min)
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• in patients receiving concomitant ciclosporin (see section 4.5)
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• during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures (see section 4.6)
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• in patients with myopathy
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• The 40 mg dose is contraindicated in patients with predisposing factors for myopathy/rhabdomyolysis. Such factors include:
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• moderate renal impairment (creatinine clearance < 60 mL/min)
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• hypothyroidism
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• personal or family history of hereditary muscular disorders
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• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
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• alcohol abuse
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• situations where an increase in rosuvastatin-plasma levels may occur
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• Asian patients
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• concomitant use of fibrates (see sections 4.4 and 4.5).
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Renal Effects

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of rosuvastatin, in particular 40 mg. This condition was transient or intermittent in most cases. Proteinuria has not been shown to be a precursor to acute or progressive renal disease (see section 4.8). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function must be considered during routine follow-up of patients treated with a dose of 40 mg.

There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including CREVAS. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with CREVAS, promptly interrupt therapy. If an alternate aetiology is not found, do not restart CREVAS.

Skeletal Muscle Effects

Risk of myasthenia gravis and ocular myasthenia. Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients at all doses, particularly at doses higher than 20 mg. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose. Patients who develop any signs or symptoms suggestive of myopathy should have their Creatine Kinase (CK) levels measured. CREVAS therapy should be discontinued if myopathy is diagnosed or suspected.

An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with ciclosporin, fibric acid derivatives, including gemfibrozil, nicotinic acid, azole antifungals and macrolide antibiotics. CREVAS should be prescribed with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism, or situations where an increase in plasma levels may occur (see section 5.2).

Creatine Kinase Measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of alternative causes of CK increase which may influence the interpretation of the result. If CK levels are significantly elevated at baseline (> 5 x ULN) a confirmatory test should be carried out within 5 - 7 days. If the repeat test confirms a baseline CK > 5 x ULN, treatment must not be started.

Before treatment HMG-CoA reductase inhibitors, such as CREVAS, should be prescribed with caution in patients with predisposing factors for myopathy/rhabdomyolysis. Such factors include:

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• renal impairment
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• hypothyroidism
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• personal or family history of hereditary muscular disorders
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• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
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• alcohol abuse
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• above 70 years of age
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• situations where an increase in plasma levels may occur (see sections 4.2, 4.5 and 5.2)
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• concomitant use of fibrates.
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In this patient group, the risk of treatment should be considered in relation to possible benefit. Clinical monitoring is recommended. If CK levels are significantly elevated at baseline (> 5 x ULN) treatment must not be initiated.

During treatment Patients must be advised to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy must be discontinued if CK levels are markedly elevated (> 5 x ULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are u2264 5 x ULN). If symptoms resolve and CK levels return to normal, then consideration should be given to reintroducing CREVAS or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted.

There have been reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive medicines may be required.

An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appear, CREVAS should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS or DRESS with the use of CREVAS, treatment with CREVAS must not be restarted in this patient at any time.

Effect of co-administered medicines on CREVAS

Transporter protein inhibitors

Rosuvastatin, as contained in CREVAS, is a substrate for certain transporter proteins including the hepatic uptake transporter organic-anion-transporting polypeptide 1B1 (OATP1B1) and efflux transporter breast-cancer-resistance protein (BCRP). Concomitant administration of CREVAS with medicines that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see sections 4.2, 4.4 and 4.5 Table 1).

Ciclosporin

During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). CREVAS is contraindicated in patients receiving concomitant ciclosporin (see section 4.3). Concomitant administration did not affect plasma concentrations of ciclosporin.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects in pharmacokinetic studies receiving rosuvastatin with various protease inhibitors in combination with ritonavir (see Table 1 below). This increase in systemic exposure to rosuvastatin may lead to an increased incidence of adverse events. The concomitant use of CREVAS and some protease inhibitor combinations may be considered after careful consideration of CREVAS dose adjustments based on the expected increase in rosuvastatin exposure (see sections 4.4 and Table 1 below).

Gemfibrozil and other lipid-lowering medicines

Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin C max and AUC (see section 4.4). No pharmacokinetic relevant interaction with fenofibrate has been reported, however, a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (u2265 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors such as rosuvastatin contained in CREVAS, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4). These patients should start with the 5 mg dose.

Ezetimibe

Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1,2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic interaction, in terms of adverse effects, between CREVAS and ezetimibe cannot be ruled out (see section 4.4).

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 CREVAS. The clinical relevance of this interaction has not been studied.

Erythromycin

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

Ticagrelor

Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CPK level and rhabdomyolysis.

Cytochrome P450 enzymes

In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as a substrate, inhibitor or inducer). Therefore, medicine interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustments (see also Table 1 below)

When it is necessary to co-administer CREVAS with other medicines known to increase exposure to rosuvastatin, doses of CREVAS should be adjusted. Start with a 5 mg once daily dose of CREVAS if the expected increase in exposure (AUC) is approximately 2-fold or higher.

The maximum daily dose of CREVAS should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of CREVAS taken without interacting medicines, for example a 20 mg dose of CREVAS with gemfibrozil (1,9-fold increase), and a 10 mg dose of CREVAS with combination ritonavir/atazanavir (3,1-fold increase).

If medicine is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the CREVAS dose above 20 mg.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should use appropriate contraceptive measures.

Pregnancy

CREVAS is contraindicated in pregnancy (see section 4.3).

Breastfeeding

CREVAS is contraindicated in lactation. Rosuvastatin is excreted in the milk of rats. There is no data available with respect to excretion of rosuvastatin in milk in humans (see section 4.3).

Fertility

No data is available on fertility.

Studies to determine the effect of CREVAS on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, CREVAS is unlikely to affect this ability. CREVAS may cause dizziness, therefore patients taking CREVAS should not drive or use machines until their individual susceptibility to dizziness is known.

Summary of the safety profile

The adverse reactions seen with CREVAS are generally mild and transient. The incidence of adverse reactions tends to increase with increasing dose.

Tabulated list of adverse reactions

Frequency will depend on the presence or absence of risk factors (fasting blood glucose u2265 5,6 mmol/L, BMI > 30 kg/m2, raised triglycerides, history of hypertension).

As with other HMG-CoA reductase inhibitors, such as CREVAS, the incidence of adverse reactions tends to be dose dependent. There have been post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Description of selected adverse reactions

Renal effects

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with CREVAS. Shifts in urine protein from none or trace to 100 mg/dL or more were seen in < 1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to 30 mg/dL was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease.

Haematuria has been observed in patients treated with CREVAS and clinical trial data show that the occurrence is low.

Skeletal muscle effects

Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in CREVAS-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 (> 5 x ULN), treatment should be discontinued (see section 4.4).

Liver effects

A dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin as in CREVAS; the majority of cases were mild, asymptomatic and transient. The following adverse events have been reported with some statins:

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• sexual dysfunction
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• exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)
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• the reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.
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Other effects

In a long-term controlled clinical trial rosuvastatin was shown to have no harmful effects on the ocular lens. In rosuvastatin treated patients, there was no impairment of adrenocortical function. The reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose.

Paediatric population

Children and adolescents 10 u2013 17 years of age

Creatine kinase elevations > 10 x ULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults (see section 4.4). In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. An email can be sent directly to the company, [email protected] to ensure safety of the product.

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. Haemodialysis is unlikely to be of benefit.