Suvardio, 20 mg 28 pcs.

Pharmacotherapeutic group:

Hypolipidemic drug – HMG-CoA reductase inhibitor.

The ATX code: C10AA07.

Pharmacological properties

Pharmacodynamics

. Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A to mevalonate, a cholesterol precursor. Rosuvastatin acts on the liver, where cholesterol (cholesterol) synthesis and catabolism of low-density lipoproteins (LDL) takes place.

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, which increase the capture and catabolism of LDL, and inhibits the liver synthesis of very low density lipoproteins (VLDL), thus reducing LDL and VLDL.
Rosuvastatin reduces the concentration of low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C), and decreases the concentration of apolipoprotein B (ApoB), non-HDL-C, HDL-C, TG-LDL-C and increases the concentration of apolipoprotein A-1 (ApoA-1) (see Table 1), decreases the ratio of LDL-C/HC-LDL, total CH/LC-LDL and non-LC-LDL/CC-LDL and the apoB/apoA-1 ratio.

After the start of therapy with rosuvastatin therapeutic effect appears within one week, after 2 weeks of treatment it reaches 90% of the maximum possible effect. Maximum therapeutic effect is usually reached by 4 weeks and is maintained with regular use of the drug.

Clinical efficacy

Rosuvastatin is effective in adult patients with hypercholesterolemia, with or without hypertriglyceridemia, regardless of their race, sex or age, including patients with diabetes and familial hypercholesterolemia.
In 80% of patients with hypercholesterolemia type IIa and IIb according to Fredrickson classification (mean baseline concentration of LDL-C about 4.8 mmol/l) when using rosuvastatin at a dose of 10 mg, LDL-C concentration reaches values less than 3 mmol/l.
In patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses from 20 to 80 mg according to the scheme of forced dose titration, positive dynamics of lipid profile parameters were observed. After titration of daily dose up to 40 mg per day (12 weeks of therapy) LDL-C concentration decreased by 53%. In 33% of patients a decrease in LDL-C concentration of less than 3 mmol/l was achieved.

In patients with homozygous familial hypercholesterolemia who received rosuvastatin in doses of 20 and 40 mg, the average decrease in LDL-C concentration was 22%.

Additive effect was noted in combination with fenofibrate for TG concentration and with nicotinic acid (more than 1 g per day) for HDL-C concentration.

. Patients with low risk of coronary heart disease (CHD) (Framingham Scale risk less than 10% over 10 years), with a mean LDL-C concentration of 4.0 mmol/L (154.5 mg/dL) and subclinical atherosclerosis, which was assessed by carotid intima-media complex (CTIM) thickness, rosuvastatin at a dose of 40 mg/day significantly slowed the rate of progression of maximum CTIM for 12 carotid segments compared with placebo at a rate of – 0.0145 mm/year (95% confidence interval (CI): -0.0196 to – 0.0093, at p <0.0001). The dose of 40 mg should only be administered to patients with significant hypercholesterolemia and high risk of cardiovascular disease.

Pharmacokinetics

Absorption
Maximum concentration (Cmax) of rosuvastatin in plasma is reached approximately 5 h after oral administration.
Absolute bioavailability is ≈20%.

Distribution
Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and metabolism of LDL-C. The volume of distribution of rosuvastatin is approximately 134 liters. About 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism
A limited amount of rosuvastatin (approximately 10%) undergoes biotransformation.
Metabolism of rosuvastatin is insignificantly associated with isoenzymes of cytochrome P450 system. CYP2C9 is the main isoenzyme involved in metabolism of rosuvastatin, while CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism.

The main identified metabolites of rosuvastatin are N-dismethylrosuvastatin and lactone metabolites.

N-desmethylrosuvastatin is approximately 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of pharmacological activity on inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

Elimation
Approximately 90% of the administered dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin), the remaining part is excreted by the kidneys. About 5% of the administered drug dose is excreted unchanged by the kidneys. The elimination half-life (T1/2) is 19 h, it does not change when increasing the drug dose. Mean geometric plasma clearance is approximately 50 l/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the membrane membrane-bound cholesterol transporter is involved in the “hepatic” uptake of rosuvastatin. This transporter plays a major role in the excretion of rosuvastatin by the liver.

Linearity
Systemic exposure to rosuvastatin increases in proportion to the dose. There are no changes in pharmacokinetic parameters after multiple daily doses of the drug.

Genetic polymorphism
HMK-CoA reductase inhibitors, including rosuvastatin, bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in the capture of statins by hepatocytes) and BCRP (efflux transporter). Carriers of SLCO1B1 (OATP1B1) C.521CC and ABCG2 (BCRP) C.421AA genotypes had 1.6 and 2.4-fold increased exposure (AUC – area under the “concentration-time” curve) to rosuvastatin compared with SLCO1B1c.521TT and ABCG2 c.421AA genotypes, respectively.

Special patient populations
Age and sex
Age and sex have no clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Ethnic groups
Pharmacological studies have shown an approximately two-fold increase in median AUC and Cmax of rosuvastatin in patients of the mongoloid race (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared to those of the Caucasian race; median AUC and Cmax increased approximately 1.3-fold in Hindu patients. At the same time the analysis of pharmacokinetic parameters for all studied population showed no clinically significant differences in pharmacokinetics of the drug among representatives of Caucasoid and Negroid races.

Renal failure
In patients with mild to moderate renal failure the plasma concentration of rosuvastatin or N-desmethylrosuvastatin does not change significantly. In patients with severe renal insufficiency (creatinine clearance (CK) less than 30 ml/min) the plasma concentration of rosuvastatin is 3 times higher, and N-desmethylrosuvastatin concentration is 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in patients on hemodialysis are approximately 50% higher than in healthy volunteers.

Hepatic failure
In patients with varying degrees of hepatic failure with a Child-Pugh score of 7 or lower no increase in T1/2 of rosuvastatin was found. However, in 2 patients with Child-Pugh scores 8 and 9 there was observed prolongation of T1/2, approximately 2 times more than in patients with lower Child-Pugh scores. There is no experience with rosuvastatin in patients with a Child-Pugh score above 9.

Indications

– primary hypercholesterolemia according to Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an addition to diet, when diet and other non-medicinal treatments are not sufficient;
– familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (such as LDL-apheresis), or in cases where such therapy is not sufficiently effective;
– Hypertriglyceridemia (type IV according to Fredrickson classification) as a dietary adjunct;
– For deceleration of atherosclerosis progression as a dietary adjunct in patients who are indicated for the reduction of total cholesterol and LDL-C concentration.
– Primary prevention of major cardiovascular complications (stroke, heart attack, unstable angina, arterial revascularization) in adult patients without clinical signs of coronary heart disease (CHD), but with an increased risk of its development (age over 50 years for men, older than 60 years in women, increased concentration of C-reactive protein (≥ 2 mg/L) with at least one additional risk factor, such as arterial hypertension, low concentration of HDL-C, smoking, family history of early onset of CHD).

Active ingredient

Composition

1 tablet 20 mg contains:

the active ingredient:

rozuvastatin calcium in terms of rosuvastatin – 20,000 mg;

excipients:

Lactose anhydrous, 107.380 mg;

Colloidal anhydrous silica – 0.660 mg;

Microcrystalline cellulose,

silicified – 55,000 mg;

dried corn starch – 33,000 mg;

Talc – 2,200 mg;

Sodium stearyl fumarate – 1,760 mg;

pill coating:

Hypromellose-2910, 3.720 mg; mannitol, 0.300 mg; macrogol 6000, 0.180 mg; titanium dioxide, 0.840 mg; Iron (III) oxide, yellow – 0.450 mg; iron (III) oxide, red – 0.150 mg; talcum powder – 0.360 mg; talc (polishing agent)² – 0.113 mg.

How to take, the dosage

Ingestion. Any time of the day, regardless of meals. The tablet should not be chewed or crushed, swallowed whole with water.

People should start a standard hypocholesterolemic diet prior to initiating therapy with the drug Suvardio® and continue it during the whole therapy period.

The dose of Suvardio® is adjusted individually taking into account the target cholesterol concentrations and individual therapeutic response to therapy.

The recommended starting dose of Suvardio® is 5 mg or 10 mg once daily both for patients who have not previously taken statins and for patients switched to this drug after therapy with other HMG-CoA reductase inhibitors.
When choosing the initial dose, cholesterol concentration and possible risk of cardiovascular complications in this patient should be guided by the potential risk of side effects.
If necessary, the drug dose can be adjusted after 4 weeks.

. Because of the possible development of side effects at a dose of 40 mg compared to lower doses of the drug, final titration to the maximum dose of 40 mg should only be performed in patients with severe hypercholesterolemia and high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia), in whom the target cholesterol concentration was not achieved at the 20 mg dose, and who will be under medical supervision. If a dose of 40 mg is prescribed, close observation by a physician is recommended.

Prescribing the 40 mg dose to patients who have not previously seen a physician is not recommended.

Elderly patients
For patients over 65 years of age, the recommended starting dose of Suvardio® is 5 mg. In other cases no dose adjustment due to age is required.

Patients with renal impairment
In patients with mild to moderate renal impairment a dose adjustment of Suvardio® is not required. The recommended starting dose of the drug is 5 mg for patients with moderate renal failure (CKR less than 60 ml/min). The use of the drug Suvardio® in any dose is contraindicated in patients with severe renal insufficiency (CKR less than 30 ml/min) (see section “Contraindications”).

Patients with moderate renal insufficiency are contraindicated in a dose of 40 mg (see section “Contraindications”).

Patients with hepatic impairment
No increase in systemic rosuvastatin concentration was detected in patients with a Child-Pugh score of 7 or lower. However, increased systemic concentrations of rosuvastatin have been observed in patients with Child-Pugh scores of 8 and 9. Liver function during rosuvastatin therapy should be monitored in these patients. There are no data on administration of rosuvastatin in patients with a Child-Pugh score above 9. Rosuvastatin is contraindicated in patients with active liver disease (see section “Contraindications”).

Special populations
Ethnic groups
. Mongoloid patients may have increased systemic plasma concentrations of rosuvastatin. The recommended starting dose of Suvardio® in patients of mongoloid race is 5 mg. The use of the drug in a dose of 40 mg is contraindicated in these patients (see section “Contraindications”).

Patients with predisposition to myopathy
The recommended starting dose of Suvardio® for patients with predisposition to myopathy is 5 mg. The use of the drug in dose of 40 mg is contraindicated in such patients (see section “Contraindications”).

Genetic polymorphism
Carriers of SLCO1B1 (OATP1B1) C.521CC and ABCG2 (BCRP) C.421AA had 1.6 and 2.4-fold increased exposure (AUC) to rosuvastatin, respectively, compared with SLCO1B1c.521TT and ABCG2 c.421AA genotype carriers.

For carriers of c.521CC or c.421AA genotypes, the recommended maximum dose of Suvardio® is 20 mg once daily (see Section “Pharmacokinetics”).

Companion therapy
Rosuvastatin binds to various transport proteins (in particular to OATP1B1 and BCRP). When concomitant use of Suvardio® with drugs (such as cyclosporine, some human immunodeficiency virus (HIV) protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin due to interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase (see section “Interactions with transport proteins”). see section “Interactions with other medicinal products”; read the instructions for use for these drugs before prescribing Suvardio®).

In these cases, alternative therapy or temporary discontinuation of Suvardio® should be evaluated. If it is necessary to use the above drugs, the benefit-risk ratio of concomitant therapy with Suvardio® should be evaluated and the possibility of reducing its dose should be considered.

Interaction

In concomitant use of rosuvastatin and cyclosporine the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers. Concomitant use of these drugs leads to an 11-fold increase in plasma concentrations of rosuvastatin, while the plasma concentration of cyclosporine does not change (see section “Contraindications”).

In the use of other statins there have been reports of cases of rhabdomyolysis with concomitant use of rosuvastatin and fusidic acid, monitoring of patients is required, if necessary, temporary discontinuation of rosuvastatin is possible.

As with other HMG-CoA reductase inhibitors, starting therapy with rosuvastatin or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (such as warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (MHO). Cancellation or reduction of the dose of rosuvastatin may cause a decrease in MHO. In such cases, MHO should be monitored.

Concomitant use of rosuvastatin and gemfibrozil and other lipid-lowering agents leads to a 2-fold increase in Cmax and AUC of rosuvastatin.

Special Instructions

Proteinuria (determined using test strips), predominantly of tubular origin, has been observed in patients taking high doses of rosuvastatin, especially 40 mg, but in most cases was intermittent or transient. It has been shown that such proteinuria does not indicate the occurrence of acute or progression of existing renal disease. The incidence of severe renal function impairment is increased when taking 40 mg of rosuvastatin. It is recommended to monitor renal function parameters during rosuvastatin therapy.

Myalgia, myopathy and, in rare cases, rhabdomyolysis have been reported with all doses of Suvardio® and particularly with doses greater than 20 mg. Rhabdomyolysis was very rare when concomitant administration of ezetimibe and HMG-CoA reductase inhibitors.

In this case pharmacological interaction of the drugs cannot be excluded, therefore Suvardio® and ezetimibe should be used together with caution.

The incidence of rhabdomyolysis increases with the use of 40 mg of Suvardio®.

The determination of CPK activity should not be performed after vigorous physical activity or in the presence of other possible causes of increased CPK activity, which may lead to misinterpretation of the results. If CPK activity is significantly elevated (5-fold higher than VGN) before the start of therapy, a repeat measurement should be performed in 5-7 days. The therapy by Suvardio® should not be started if the repeated test confirms the initial CPK activity (more than 5 times higher than the ULN).

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be administered with extreme caution in patients with existing risk factors for myopathy/rhabdomyolysis. These factors include:

– renal insufficiency;
– hypothyroidism (for 40 mg dose);
– history of myopathy (including. hereditary) (for 40 mg dose);
– history of myotoxicity against other HMG-CoA reductase inhibitors or fibrates (for 40 mg dose);
– alcohol abuse (for 40 mg dose);
– age over 65 years;
– conditions accompanied by increased plasma concentration of rosuvastatin (for 40 mg dose);
– concomitant use of fibrates (for 40 mg dose).

In such patients the risk/benefit ratio of therapy should be assessed and clinical monitoring should be performed throughout the course of therapy.

Patients are advised to inform their physician immediately if they experience sudden onset of muscle pain, muscle weakness, or cramping, especially if combined with malaise or fever!

In these patients, CPK activity should always be monitored. Treatment should be discontinued if CPK activity is more than 5 times VGN or if muscle symptoms are severe and cause daily discomfort throughout the day (even if CPK activity is 5 times less than VGN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing the drug or prescribing an alternative HMG-CoA reductase inhibitor at a lower dose with close monitoring of the patient. Regular monitoring of CPK activity in patients without symptoms of rhabdomyolysis is not advisable.

There are no indications of increased skeletal muscle adverse events with Suvardio® and concomitant therapy. However, increased incidence of myositis and myopathy has been found in patients taking other HMG-CoA reductase inhibitors together with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g/day), azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with some HMG-CoA reductase inhibitors. Therefore, concomitant administration of rosuvastatin and gemfibrozil is not recommended. It is necessary to carefully assess the risk/benefit ratio when co-administering rosuvastatin with fibrates or nicotinic acid at lipid-lowering doses (more than 1 g/day). Concomitant administration of 40 mg rosuvastatin and fibrates is contraindicated.
Suvardio® should not be administered to patients with acute, severe diseases, with suspected myopathy or with possible development of secondary renal failure (e.g., sepsis, arterial hypertension, surgery, trauma, metabolic syndrome, diabetes, seizures, endocrine disorders, water and electrolyte disorders).

In 2-4 weeks after the beginning of the treatment and / or if the dose of the drug increases it is necessary to control the parameters of lipid metabolism (if necessary the dose adjustment is required).

Like other HMG-CoA reductase inhibitors, rosuvastatin should be administered with special caution to patients who abuse alcohol or have a history of liver disease.

It is recommended that liver function parameters be determined before and 3 months after the start of treatment. If the activity of “hepatic” transaminases in blood serum exceeds 3 times the upper limit of normal, the drug should be discontinued or the dose taken should be reduced. The incidence of marked liver function abnormalities (associated mainly with an increase in “hepatic” transaminases activity) is increased when taking 40 mg of the drug. In patients with secondary hypercholesterolemia due to hypothyroidism, nephrotic syndrome therapy of the underlying disease should be conducted prior to treatment with rosuvastatin.
In the course of pharmacokinetic studies an increase in systemic concentration of rosuvastatin was found in patients of mongoloid race in comparison with data obtained in representatives of Caucasoid race.

The concomitant administration of rosuvastatin with HIV protease inhibitors is not recommended.

In the use of some statins, especially over a long period of time, sporadic cases of interstitial lung disease have been reported. Manifestations of the disease may include dyspnea, non-productive cough, and deterioration in general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, therapy with the drug has been associated with an increased risk of developing type 2 diabetes.

Special precautions for disposal of unused medication

There is no need for special precautions for disposal of unused Suvardio®.

Impact on driving, operating machinery

Perhaps caution should be exercised when driving motor vehicles, engaging in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions (risk of dizziness).

Contraindications

– hypersensitivity to rosuvastatin or any of the drug components;
– liver disease in the active phase, including persistent increase in “hepatic” transaminase activity, as well as any increase in “hepatic” transaminase activity in serum more than 3 times the upper limit of normal (ULN);
– severe renal function impairment (CKR less than 30 ml/min);
– myopathy;
– concomitant use of cyclosporine;
– pregnancy, breastfeeding;
– use in patients predisposed to the development of myotoxic complications;
– lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome (the drug contains lactose);
– age under 18 years (effectiveness and safety are not established).

With caution

For daily doses of 5 mg, 10 mg and 20 mg: presence of risk of myopathy/rhabdomyolysis – renal failure, hypothyroidism; personal or family history of hereditary muscle disease and prior history of muscle toxicity with other HMG-CoA reductase inhibitors (statins) or fibrates; excessive alcohol intake; conditions in which increased plasma concentrations of rosuvastatin have been noted; age over 65 years; high risk of diabetes mellitus; history of liver disease; sepsis; arterial hypotension; major surgical interventions; trauma; severe metabolic, endocrine or water-electrolyte disorders; uncontrolled epilepsy; race (mongoloid race); concomitant use of fibrates.

Side effects

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: Very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000) and very rare (< 1/10000); frequency unknown – the incidence could not be determined from available data.

Disorders of the blood and lymphatic system
frequency unknown: thrombocytopenia.

Immune system disorders
rare: hypersensitivity reactions, including angioedema.

Endocrine system disorders
often: type 2 diabetes.

Central nervous system disorders
often: headache, dizziness;
very rarely: polyneuropathy, memory loss.

Respiratory system disorders
frequency unknown: cough, shortness of breath.

Digestive system disorders
often: constipation, nausea, abdominal pain;
rare: pancreatitis; frequency unknown: diarrhea.

Skin disorders
infrequent: skin itching, rash, urticaria;
frequency unknown: Stevens-Johnson syndrome.

Laboratory parameters
Increase in creatine phosphokinase (CPK) activity, concentration of glucose, glycosylated hemoglobin, bilirubin in plasma, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid function disorders.

Other
often: asthenic syndrome, gynecomastia, peripheral edema.

Urinary system disorders
very rarely: hematuria.

Proteinuria may be observed when taking rosuvastatin. Changes in urine protein content (from absence to trace amounts to ++ and above) are observed in less than 1% of patients taking rosuvastatin in doses of 10 mg and 20 mg and about 3% of patients taking the drug in dose of 40 mg.

Significant changes in the amount of protein in the urine, expressed as a change from zero or trace levels to + levels, were observed when taking the drug at a dose of 20 mg. In most cases, proteinuria decreased and passed on its own during treatment. When analyzing data from clinical trials, no causal relationship between proteinuria and acute or progressive kidney disease was found.

Musculoskeletal and connective tissue disorders
often: myalgia;
rarely: Myopathy (including myositis), rhabdomyolysis;
very rare: arthralgia;
frequency unknown: immune-mediated necrotizing myopathy.

Liver and biliary tract disorders
rare: increased activity of “hepatic” transaminases;
very rare: jaundice, hepatitis.

With the use of some statins side effects have been reported such as: depression, sleep disorders, including insomnia and nightmares, sexual dysfunction.

Overdose

There is no specific treatment for rosuvastatin overdose.

In case of overdose it is recommended to perform symptomatic treatment and measures aimed at maintaining the function of vital organs and systems.

Liver function and CPK activity should be monitored. Hemodialysis is unlikely to be effective.

Similarities