INSTRUCTION

for medical use of the medicinal product

ROMESTIN 5,

ROMESTIN 10,

ROMESTIN 20

 

Composition:

Active substance: 1 tablet contains rosuvastatin calcium equivalent to rosuvastatin 5 mg, 10 mg, 20 mg;

Inactive substances:

5 mg: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, lactose monohydrate, croscarmellose sodium, crospovidone, talc, acid stearic, Instacoat sol dye (hypromellose, polyethylene glycol, talc, titanium dioxide (E171)), brilliant blue (E 133), erytrozyn (E 127);

10 mg: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, lactose monohydrate, croscarmellose sodium, crospovidone, talc, stearic acid, Instacoat sol dye (hypromellose, polyethylene glycol, talc, titanium dioxide (E171)), quinoline yellow (E 104);

20 mg: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, lactose monohydrate, croscarmellose sodium, crospovidone, talc, acid stearic, Instacoat sol dye (hypromellose, polyethylene glycol, talc, titanium dioxide (E171)), brilliant blue (E 133), tartrazine (E 102).

Pharmaceutical form.  Film-coated tablet.

Basic physical and chemical properties:

5 mg tablets: light purple, round, biconvex, film-coated tablets with a scoring line on one side;

10 mg tablets: light yellow, round, biconvex, film-coated tablets;

20 mg tablets: light green to green, round, biconvex, film-coated tablets.

Pharmaceutical group. Lipid-lowering agents. HMG-CoA reductase inhibitors

ATC code:  С10А А07.

Pharmacological properties.

Pharmacodynamics.

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of rosuvastatin action is the liver, the target organ for cholesterol synthesis and catabolism of low-density lipoproteins (LDL).

Rosuvastatin increases the number of hepatic LDL receptors on the surface of the cell, enhancing uptake and catabolism of LDL, which leads to the inhibition of LDL synthesis, thereby reducing the total number of VLDL and LDL particles.

Romestin reduces increased amounts of LDL-cholesterol, total cholesterol and triglycerides and increases amounts of HDL-cholesterol. It also lowers amounts of ApoB, nonHDL-C, VLDL-C, VLDL-TG and increases the level of  apoliprotein A-I (ApoA-I), lowers the LDL-C/HDL-C ratio, total C/HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios.

A therapeutic effect is obtained within 1 week following the treatment initiation and 90% of maximum response is achieved in 2 weeks. The maximum response is usually achieved in 4 weeks and is maintained after that.

Clinical efficacy

Romestin is effective in adults with hypercholesterolaemia, with or without hypertriglyceridaemia, regardless of race, sex, or age and in special populations such as diabetics, or patients with familial hypercholesterolaemia.

In 80% of the patients with hypercholesterolaemia type IIa and IIb (average baseline LDL-C is about 4.8 mmol / l), LDL-C level is <3 mmol / L in patients treated with the drug in the dose of 10 mg. In patients with heterozygous familial hypercholesterolaemia treated with rosuvastatin in the dose of 20-80 mg, the positive dynamics of lipid profile is observed (study involved 435 patients) is observed. After the titration to a daily dose of 40 mg (12 weeks of therapy) the 53% decrease in LDL-C level is observed. In 33% of  the patients LDL-C level is <3 mmol / L.

In patients with heterozygous familial hypercholesterolaemia, treated with rosuvastatin doses of 20 mg and 40 mg, the average reduction of LDL-C level is 22%.  

There is an additive effect in the combination with fenofibrate regarding triglyceride content and nicotinic acid content regarding HDL-C.

Prevention of cardiovascular events: in the clinical study (JUPITER) the effect of rosuvastatin calcium on the frequency of major events connected with arteriosclerotic cardiovascular diseases was studied in 17,802 men (≥50 years) and women (≥60 years) who had not had a diagnosis of cardiovascular disease. Their LDL-C levels were <3.3 mmol / L (130 mg / dL), and the levels of high-sensitive CRP ≥2 mg / l. The estimated initial risk of ischemic heart disease in the research population was 11.3% during 10 years according to Framingham risk score; a significant part of the population consisted of patients with hypertension (58%), low levels of HDL-C (23%), smokers (16%) or persons with a familial medical history of premature ischemic heart disease (12%). Study participants were randomized in the placebo group (n = 8901) or rosuvastatin group in a dose of 20 mg once a day (n = 8901), and their condition was monitored during approximately 2 years.

The primary endpoint was a combined one and it covered the time before the first occurrence of any of the following cardiovascular (CV) events: cardiovascular death, non-lethal myocardial infarction, non-lethal stroke, unstable angina or arterial revascularization procedure.

Rosuvastatin significantly reduced the risk of cardiovascular events (252 cases in the placebo group and 142 in the rosuvastatin group) and significantly (p <0,001) reduced the relative risk by 44%. Pronounced effect was observed during the first 6 months of treatment. Risk reduction was comparable in many predetermined subgroups of different age, sex, race, smoking status, a familial medical history of premature ischemic heart disease, body mass index, levels of LDL-C, HDL-C or high-sensitivity C-reactive protein at the time when those subgroups were involved in the research. There was noted that the frequency of combined endpoint of CV death, stroke and myocardial infarction was significantly decreased by 48% (risk ratio (RR): 0.52; 95% CI: 0,40 - 0,68, p <0,001), the frequency of lethal or non-lethal myocardial infarction was decreased by 54% (RR: 0.46, 95% CI: 0,30-0,70) and the frequency of lethal or non-lethal stroke was decreased by 48%. Overall mortality in the rosuvastatin group was reduced by 20% (RR: 0.80, 95% CI: 0,67 - 0,97, p = 0,02). The level of LDL-C in the rosuvastatin group was decreased by 45% (p <0,001) compared with the placebo group. Safety profile of rosuvastatin in the dose of 20 mg was generally similar to placebo. 1.6% participants of the rosuvastatin group and 1.8% participants of the placebo group have left the study because of the development of adverse reactions, regardless of their connectivity with treatment. The frequent adverse reactions that led to treatment discontinuation were: myalgia (0.3% rosuvastatin group, 0.2% placebo group), abdominal pain (0.03% rosuvastatin group, 0.02% placebo group) and rash (0.03% rosuvastatin group and 0.03% placebo group). Adverse reactions, reported in ≥ 2% of patients and with greater than in placebo group, or with similar frequency, were myalgia (7.6% rosuvastatin group, 6.6% - placebo group), constipation (3.3% rosuvastatin group 3.0% - placebo group) and nausea (2.4% rosuvastatin group, 2.3% - placebo group).

Pharmacokinetics

Absorption and Distribution

Maximum rosuvastatin plasma concentrations are achieved approximately in 5 hours after the oral administration. The absolute bioavailability is approximately 20%. Rosuvastatin is accumulated in the liver. 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%). Rosuvastatin is a non-core substrate for cytochrome P450-based metabolism. CYP2C9 is the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone metabolites are is considered pharmacologically inactive.

Excretion

Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (including absorbed and non-absorbed active substance) 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. The average geometric plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the cholesterol transporter, which is important for the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure of rosuvastatin increases proportionally to a dose. There are no changes in pharmacokinetic parameters at the administration of multiple daily doses.

Special populations

Age and sex

There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. 

Race

Comparative studies of rosuvastatin pharmacokinetics in Asian patients showed an approximate 2-fold elevation of AUC (area under the curve "concentration - time") and C_max, compared to Europeans who live in Europe and Asia. The effects of genetic factors and environmental factors on received differences in pharmacokinetic parameters were not found. A population pharmacokinetic analysis revealed no clinically significant differences in pharmacokinetics between European patients and negroid patients.

Renal failure

In patients with mild or moderate renal failure, the concentration of rosuvastatin and N-desmethyl in plasma is not changed significantly. Patients with severe impairment (CrCl <30 ml/min) had a 3-fold increase of rosuvastatin in plasma concentration, and a 9-fold increase in the N-desmethyl metabolite concentration compared to healthy volunteers.  Plasma concentrations of rosuvastatin in patients undergoing haemodialysis were approximately 50% greater compared to healthy volunteers.

Liver failure

In patients with different degrees of liver impairment, there was no increase in rosuvastatin elimination half-life in patients with Child-Pugh scores of 7 or below. However, two subjects with Child-Pugh scores of 8 and 9 showed prolongation of elimination half-life least 2-fold. There is no experience of rosuvastatin administration in subjects with Child-Pugh scores above 9.

Clinical particulars.

Indications.

Treatment of hypercholesterolaemia

Adults, adolescents and children aged 10 years or older with primary hypercholesterolaemia (type IIa including heterozygous familial hypercholesterolaemia) or mixed dyslipidaemia (type IIb) as an adjunct to a diet, when response to a diet and to other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

In homozygous familial hypercholesterolaemia as an adjunct to a diet and other lipid lowering treatments (e.g. LDL apheresis) or when such treatments are inappropriate.

Prevention of major cardiovascular events in patients who are estimated to be at high risk for a first cardiovascular event (see section «Pharmacodynamics»), as an adjunct to correction of other risk factors.

Contraindications.

Romestin is contraindicated:

• – in patients with hypersensitivity to rosuvastatin or to any of the excipients;
• – in patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN).
• – in patients with severe renal impairment (creatinine clearance <30 ml/min).
• – in patients with myopathy
• – in patients receiving concomitant ciclosporin;
• – 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 (creatinine clearance < 60 ml/min);
• – hypothyroidism;
• – personal or familial history of hereditary muscular disorders
• – previous history of muscular toxicity with other HMG-CoA reductase inhibitors or fibrates;
• – alcohol abuse;
• – situations where an increase of drug concentration in blood plasma might occur;
• – Asian patients
• – concomitant use of fibrates.

(see sections  «Precautions for use», «Interaction with other medicinal products and other forms of interaction» and «Pharmacodynamics»)

Interaction with other medicinal products and other forms of interaction.

Effect of co-administered medicinal products on rosuvastatin

Transporter protein inhibitors

Rosuvastatin is a substrate for some transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Romestin with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see sections  «Routes of administration and dosage», «Precautions for use», «Interaction with other medicinal products and other forms of interaction», Table 1).

Ciclosporin

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

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 1). For example, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination medicinal product of two protease inhibitors (300 mg atazanavir / 100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and C_max respectively. The concomitant use of Romestin and some protease inhibitor combinations may be considered after careful consideration of Romestin dose adjustments based on the expected increase in rosuvastatin exposure (see sections «Routes of administration and dosage», «Precautions for use», «Interaction with other medicinal products and other forms of interaction», Table 1).

Gemfibrozil and other lipid-lowering products

Concomitant use of Romestin and gemfibrozil results in a 2-fold increase in rosuvastatin C_max and AUC (see section «Precautions for use»).

Based on data from specific interaction studies no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when administered alone. The 40 mg dose is contraindicated during the concomitant use of fibrates (see sections «Precautions for use» and «Contraindications»). These patients should also start with the 5 mg dose.

Ezetimibe

Concomitant use of 10 mg Romestin and 10 mg ezetimibe resulted in a 1.2 fold increase in AUC values of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic interaction, in terms of adverse effects, between Romestin and ezetimibe cannot be ruled out (see sections «Precautions for use»).

Antacids

The concomitant administration of Romestin with antacid suspensions containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentrations by approximately 50%. This effect was mitigated when antacids were administered 2 hours after Romestin. The clinical relevance of this interaction has not been studied.

Erythromycin

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

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. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug 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

When it is necessary to co-administer Romestin with other medicinal products known to increase exposure to rosuvastatin, doses of Romestin should be adjusted. Start with a 5 mg once daily dose of Romestin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of Romestin should be adjusted, so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of Romestin taken without interacting medicinal products, for example a 20 mg dose of Romestin with gemfibrozil (1.9-fold increase), and a 10 mg dose of Romestin with the combination ritonavir/atazanavir (3.1-fold increase). In concomitant use of cyclosporine - 5 mg (7.1-fold increase).

Table 1

Effect of co-administered medicinal products on rosuvastatin exposure

(AUC; in order of decreasing value)

Interacting drug dose regimen	Rosuvastatin dose regimen	Change in rosuvastatin AUC*
Ciclosporin 75 mg BID to 200 mg BID, 6 months	10 mg OD, 10 days	↑ 7,1-fold
Atazanavir 300 mg/ritonavir 100 mg OD, 8 days	10 mg, single dose	↑ 3,1-fold
Simeprevir 150 mg OD, 7 days	10 mg, single dose	↑ 2,8-fold
Lopinavir 400 mg/ritonavir 100 mg BID, 17 days	20 mg OD, 7 days	↑ 2,1-fold
Gemfibrozil 600 mg BID, 7 days	80 mg, single dose	↑  1,9-fold
Eltrombopag 75 mg OD, 5 days	10 mg, single dose	↑  1,6-fold
Darunavir 600 mg/ritonavir 100 mg BID, 7 days	10 mg OD, 7 days	↑  1,5-fold
Tipranavir 500 mg/ritonavir 200 mg BID, 11 days	10 mg, single dose	↑ 1,4-fold
Dronedarone 400 mg BID	Unknown	↑  1,4-fold
Itraconazole 200 mg OD, 5 days	10 mg, single dose	↑ 1,4-fold **
Ezetimibe 10 mg OD, 14 days	10 mg, OD, 14 days	↑ 1,2-fold **
Fosamprenavir 700 mg/ritonavir 100 mg BID, 8 days	10 mg, single dose	↔
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	↔
Silymarin 140 mg TID, 5 days	10 mg, single dose	↔
Fenofibrate 67 mg TID, 7 days	10 mg, 7 days	↔
Rifampin 450 mg OD, 7 days	20 mg, single dose	↔
Ketoconazole 200 mg BID, 7 days	80 mg, single dose	↔
Fluconazole 200 mg OD, 11 days	80 mg, single dose	↔
Erythromycin 500 mg QID, 7 days	80 mg, single dose	↓ 20%
Baicalin 50 mg TID, 14 days	20 mg, single dose	↓ 47%

^* Data given as x-fold change represent a simple ratio between co-administrationof the drugs and rosuvastatin alone. Data given as % change represent % difference related to rosuvastatin alone.

Increase is indicated as “↑“, no change as “↔”, decrease as “↓”.

^**Several interaction studies have been performed at different Romestin dosages, the table shows the most significant ratio

OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily

Effect of rosuvastatin on co-administered medicinal products

Vitamin K antagonists

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

Oral contraceptive/hormone replacement therapy (HRT)

Concomitant use of Romestin and oral contraceptives result in an increase in ethinyl estradiol and norgestrel AUC values by 26% and 34%, respectively. These increased blood plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in patients concomitantly administering Romestin and HRT, and therefore, a similar effect cannot be excluded. 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 interaction with digoxin is expected.

Lopinavir / ritonavir

According to study results, the concomitant use of rosuvastatin and combination drug containing two protease inhibitors (400 mg lopinavir / 100 mg ritonavir) was associated with approximately a twofold and fivefold increase of indicators of the balanced AUC _(0-24) and C_max for rosuvastatin respectively. The interaction between rosuvastatin and other protease inhibitors has not been studied.

Children

Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is unknown.

Precautions for use.

Effects on kidneys

Proteinuria, mostly of tubular etiology, has been observed in patients treated with higher doses of Romestin, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease (see section «Adverse reactions»). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. Monitoring of renal function should be regularly carried out during routine follow-up of patients treated with a dose of 40 mg.

Effects on skeletal musulature

Effects on skeletal musculature, e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Romestin-treated patients at all doses and in particular at doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section «Interaction with other medicinal products and other forms of interaction») and caution should be exercised at their combined use.

As with other HMG-CoA reductase inhibitors, the reporting rate of rhabdomyolysis associated with rosuvastatin in post-marketing use is higher at the 40 mg dose. There are reports of rare cases of imunomediated necrotizing myopathy that is clinically showed by a stable proximal muscle weakness and increased serum creatine kinase levels during the treatment or after discontinuation of the treatment with statins, including rosuvastatin. In this case, additional neuromuscular and serological studies and immunosuppressive drugs treatment might be necessary.

Creatine kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative causes of CK increase, which may confound interpretation of the results. If CK levels are significantly elevated at baseline (>5xULN), a confirmatory test should be carried out within 5 – 7 days. If the second test confirms a baseline CK >5xULN, treatment should not be started.

Before treatment

Romestin, just like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

– renal impairment;

– hypothyroidism;

– personal or familial history of hereditary muscular disorders;

– previous history of muscular toxicity with other HMG-CoA reductase inhibitors or fibrates;

– alcohol abuse;

– age >70 years;

– situations where an increase in plasma levels may occur  (see sections «Routes of administration and dosage», «Interaction with other medicinal products and other forms of interaction» and «Pharmacokinetics»);

– concomitant use of fibrates.

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

During the treatment

Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if the symptoms are associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are significantly elevated (>5xULN) 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 Romestin or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is unnecessary. There have been very rare 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 blood serum creatine kinase levels, which persist even after discontinuation of treatment with statins.

In clinical trials, there was no evidence of increased skeletal musculature effects in the small number of patients treated with rosuvastatin and concomitant medicinal agents. However, an increase in the incidence of myositis and myopathy has been observed 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. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of Romestin and gemfibrozil is not recommended. The benefit of further changes in lipid levels during the combined use of Romestin with fibrates or niacin should be carefully weighed against the potential risks of such combinations. The 40 mg dose is contraindicated at concomitant use of fibrates (see sections «Interaction with other medicinal products and other forms of interaction» and «Adverse reactions»).

Romestin should not be used in any patient with an acute, serious condition suggestive of myopathy or possible development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

Effects on liver

As with other HMG-CoA reductase inhibitors, Romestin 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 are carried out prior to, and in 3 months following the initiation of treatment. Romestin should be discontinued or the dose should be reduced, if the level of serum transaminases is 3 times greater than the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose.

In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the core disease should first be treated prior to initiating therapy with Romestin.

In post-registration period, lethal or non-lethal cases of liver failure in patients treated with statins, including rosuvastatin, were rarely reported. If during Romestin therapy a severe liver injury with clinical symptoms and / or hyperbilirubinemia or jaundice is developed, the therapy should be discontinued immediately. If no other causes were found, do not renew the treatment with Romestin.

Race

Pharmacokinetic studies show an increase in exposure in Asian subjects compared to Europeans. The Romestin dosage adjustment is necessary for these patients (see sections «Routes of administration and dosage», «Contraindications» and «Pharmacokinetics»). For Asian patients, Romestin starting dose should be 5 mg. Increased rosuvastatin plasma concentration was observed in Asian patients (see sections «Precautions for use» and «Pharmacokinetics»). It is necessary to take into account the increased systemic exposure in Asian patients whose hypercholesterolemia is not adequately controlled by doses under 20 mg.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Romestin in HIV patients receiving protease inhibitors, and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating Romestin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of Romestin is adjusted (see sections «Routes of administration and dosage» and «Interaction with other medicinal products and other forms of interaction»).

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal agent.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section «Adverse reactions»). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If a patient is suspected to have developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus

Some evidence suggests that statins raise blood glucose levels, and in some patients at high risk of future diabetes, it may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping treatment with statins. Patients at risk (fasting glucose 5.6 to 6.0 mmol/l, BMI >30 kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to the national guidelines.

There is evidence that the overall incidence of diabetes in patients treated with rosuvastatin, is slightly increased. As for other inhibitors of HMG-CoA reductase, during the use of rosuvastatin the increase of HbA1c and glucose levels in blood serum is observed. In some cases, these figures can exceed the threshold value for the diagnosis of diabetes, especially in patients at high risk of diabetes development.

Some studies show that rosuvastatin monotherapy does not cause a reduction of the basic plasma cortisol concentrations and no effect on adrenal reserve. The caution is necessary in concomitant use of Romestin and other drugs, which might reduce the levels or endogenous steroid hormones activity, such as ketoconazole, spironolactone and cimetidine.

Children

The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients 10 to 17 years of age taking rosuvastatin is limited to a one-year period. After 52 weeks of treatment, no effect on growth, weight, BMI or sexual maturation was detected (see section «Pharmacodynamics»).

Experience of studies of the drug use in children and adolescents is limited and long term effects of the use of rosuvastatin (> 1 year) on puberty are unknown.

Increase of CC level> 10 times higher than VNM and symptoms of muscles after exercise or increased physical activity were observed more frequently in children and adolescents treated with rosuvastatin for 52 weeks in comparison with adults (see section «Adverse reactions»).

Use during pregnancy and Lactation.

Romestin is contraindicated in pregnancy and lactation.

Women of childbearing age should use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the fetus, the potential risk from inhibition of HMG-CoA reductase outweighs the possible advantage of treatment during pregnancy. If a patient becomes pregnant during the use of this product, treatment should be discontinued immediately.

Since another drug of this class gets into human breast milk, and considering that inhibitors of HMG-CoA reductase can cause severe adverse reactions in infants, women who require treatment with Romestin, should stop the breastfeeding. There are no data on penetration into human breast milk (see section «Contraindications»).

 

Effects on reaction rates while driving vehicles and other machines.

Studies to determine the effect of Romestin on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, Romestin is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during the treatment.

 

Routes of administration and dosage.

Before treatment initiation, the patient should be placed on a standard cholesterol-lowering diet that should continue during the treatment. The dose should be individualized according to the goal of therapy and patient’s response, using current commonly adopted guidelines.

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

Treatment of hypercholesterolaemia

The recommended initiation dose is 5 or 10 mg orally once a day in both statin naïve and patients switched from another HMG CoA reductase inhibitor. The choice of the initiation dose should be made according to 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 (see section «Pharmacodynamics»). Due to the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses (see section «Adverse reactions»), 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 at 20 mg doses, and in whom routine follow-up will be performed (see section «Precautions for use»). Specialist supervision is recommended when the 40 mg dose is initiated.

Prevention of cardiovascular system events

In the cardiovascular events risk reduction study, the used dose was 20 mg daily (see section «Pharmacodynamics»).

Use in the elderly patients

A start dose of 5 mg is recommended in patients >70 years (see section «Precautions for use»). No other dose adjustment is necessary in relation to age.

Patients with renal failure

No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min). The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of Romestin in patients with severe renal impairment is contraindicated at all doses (see sections «Contraindications» and «Pharmacokinetics»).

Patients with liver failure

There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposur of rosuvastatin e has been observed in subjects with Child-Pugh scores of 8 and 9 (see section «Pharmacokinetics»). In these patients, an assessment of renal function should be considered (see section «Precautions for use»). There is no experience in subjects with Child-Pugh scores above 9. Romestin is contraindicated in patients with active liver disease (see section «Contraindications»).

Race

Increased systemic exposure has been seen in Asian subjects (see sections «Contraindications», «Precautions for use» and «Pharmacokinetics»). The recommended start dose is 5 mg for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.

Genetic polymorphisms

Specific types of genetic polymorphisms can lead to increased rosuvastatin exposure (see section «Pharmacokinetics»). For patients who are known to have such specific types of polymorphisms, a lower daily dose of Romestin is recommended.

Patients with pre-disposing factors to myopathy

The recommended start dose is 5 mg in patients with predisposing factors to myopathy (see section «Precautions for use»).

The 40 mg dose is contraindicated in some of these patients. (see section «Contraindications»).

Concomitant therapy

Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when Romestin is administered concomitantly with certain medicinal agents that may increase the plasma concentrations 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 sections “Precautions for use” and “Interaction with other medicinal products and other forms of interaction”). Whenever possible, use of alternative medications should be considered, and, if necessary, consider temporary termination of Romestin therapy. In situations where co-administration of these medicinal products with Romestin is unavoidable, the benefit and the risk of concurrent treatment should be carefully considered and doses of Romestin should be adjusted (see section «Interaction with other medicinal products and other forms of interaction»).

Children.

Use in children should only be carried out by specialists.

Children and adolescents 10 to 17 years of age (Boys on II Tanner Stage and above and girls whose menstruation began at least one year before).

In children and adolescents with heterozygous familial hypercholesterolaemia the usual start dose is 5 mg daily. The drug is usually taken orally in doses of 5 mg to 20 mg once a day. Increase of the dose should be individualized according to the child's response to treatment and tolerability to the drug, following recommendations for the treatment of children (see section «Precautions for use»). Before the initiation of rosuvastatin therapy, a standard hypocholesterolemic diet should be prescribed for children and adolescents which should be followed during the treatment as well. The safety and efficacy of the preparation in doses over 20 mg in this population have not been studied.

Tablets 40 mg are not used for children.

Children under 10 years

Experience of treatment of children under 10 years is limited by use of the drug in a small number of patients (aged 8 to 10 years) with homozygous familial hypercholesterolemia. So, Romestin is not recommended to use in children under 10 years.

Overdose.

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 if required. Liver function and CK levels should be monitored. Haemodialysis is unlikely to be effective.

Adverse reactions.

The adverse reactions observed with Romestin are generally mild and transient. In controlled clinical trials, less than 4% of Romestin-treated patients were withdrawn due to the development of adverse reactions.

Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for rosuvastatin. Adverse reactions listed below are classified according to the frequency and system organ class (SOC).

The frequency of adverse reactions is ranked as follows: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000); Of unknown frequency (cannot be estimated from the available data).

Table  2

Adverse reactions

System organ class	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders			Thrombocytopenia
Immune system disorders			Hypersensitivity reactions including angioedema
Endocrine disorders	Diabetes mellitus1
Psychiatric disorders					Depression
Nervous system disorders	Headache Dizziness			Polyneuropathy Memory loss	Peripheral neuropathy Sleep disturbances (including insomnia and nightmares)
Respiratory, thoracic and mediastinal disorders					Cough Dyspnoea
Gastro-intestinal disorders	Constipation Nausea Abdominal pain		Pancreatitis		Diarrhoea
Hepatobiliary disorders			Increased hepatic transaminases	Jaundice Hepatitis
Skin and subcutaneous tissue disorders		Pruritis Rash Urticaria			Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders	Myalgia		Myopathy (including myositis) Rhabdomyolysis	Arthralgia	Tendon disorders, sometimes complicated by ruptures Immune-mediated necrotising myopathy
Renal and urinary disorders				Haematuria
Reproductive system and breast disorders				Gynaecomastia
General disorders and administration site conditions	Asthenia				Oedema

¹ Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI >30 kg/m², raised triglycerides, history of hypertension).

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

Effects on kidneys

Proteinuria, mostly of tubular etiology, has been observed in patients treated with rosuvastatin. Changes in urine proteins from none or trace to ++ or more were observed in <1% of patients at some points during the treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or traces to + was observed with the 20 mg dose. In most cases, proteinuria decreased or disappeared spontaneously on continued therapy. Current review of data from clinical trials and post-marketing experience has not identified a causal association between proteinuria and acute or progressive renal disease.

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

Effects on skeletal musculature

Effects on skeletal musculature, e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in Romestin-treated patients at 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 (>5xULN), treatment should be discontinued (see section «Precautions for use»).

Effects on liver

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. At the administration of rosuvastatin, increased levels of HbA1c were also observed.

The following adverse events have been reported with some statins:

Sexual dysfunction.

Exceptional cases of interstitial lung disease, especially with long-term therapy (see section «Precautions for use»).

The reporting rate for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

During post-registration use of rosuvastatin drugs, such adverse reactions as lethal and non-lethal liver failure were identified. Since this reaction was spontaneously reported from the population of uncertain quantity, the frequency or the existence of a causal effect with the use of the drug cannot be estimated reliably.

Disturbance of cognitive functions (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of statins was rarely reported in post-registration period. Such cognitive problems were reported in connection with all statins. The phenomena referred to in the reports, usually have a mild effect and disappear after discontinuation of treatment with statins, as well as they have different time to onset of symptoms (from 1 day to years) and the disappearance of symptoms (median - 3 weeks).

Children

 Creatine kinase elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently in clinical trial of children and adolescents compared to adults (see section «Precautions for use»). In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Storage life. 2 years.

Storage conditions. Store in the original package at temperature not exceeding 30 °С. Keep out of reach of children.

Package.

10 tablets in a blister; 3 blisters in a carton box.

Terms of dispensing. On prescription.

Manufacturer.

Marksans Pharma Ltd.

Manufacturer’s registered address.  

Legal address: Lotus Business Park, Off New Link Road, Andheri (West), Mumbai – 400053, India.

Production site address: Plot № L-82, L-83 , Verna Industrial Estate, Verna Goa, IN-403 722, India.

Or

Manufacturer.

Kopran Limited.

Manufacturer’s registered address.

Village Savroli, Khalapur, Raigad, Maharashtra, IN - 410202, India.

Or

Manufacturer.

Artura Pharmaceuticals Pvt. Ltd.

Manufacturer’s registered address.

1505 Portia Road, Sri City SEZ, Satyavedu Mandal,  Chittoor District – 517 588, Andhra Pradesh, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.  

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of last review. 31.10.14