Pharmacological properties
Pharmacodynamics
Mechanism of action: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.
Rosuvastatin increases the number of LDL receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits the hepatic synthesis of VLDL, thus reducing the total number of VLDL and LDL particles.
Pharmacodynamic effects. Rosuvastatin reduces elevated LDL-C, total cholesterol, and triglycerides and increases HDL-C. It also reduces apolipoprotein B (ApoB), non-HDL-C, VLDL-C, VLDL-TG, and increases apolipoprotein A-I (ApoA-I). Rosuvastatin reduces the LDL-C/HDL-C ratio, total cholesterol/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I.
The therapeutic effect is achieved within 1 week after the start of the drug, 90% of the maximum effect - after 2 weeks. The maximum effect is usually achieved after 4 weeks and continues thereafter.
Clinical efficacy and safety. Rosuvastatin is effective in the treatment of adults with hypercholesterolemia - with or without hypertriglyceridemia - regardless of race, sex or age, as well as patients in special groups, such as patients with diabetes mellitus or familial hypercholesterolemia. It has been reported that approximately 80% of patients with hypercholesterolemia type IIa and IIb (mean initial LDL-C level about 4.8 mmol / l) who took rosuvastatin at a dose of 10 mg were able to achieve the regulatory target levels of LDL-C established by the European Atherosclerosis Society (EAS; 1998) (3 mmol / l).
In patients with heterozygous familial hypercholesterolemia, who took rosuvastatin at doses of 20-80 mg according to the scheme of increased dose titration, the drug had a beneficial effect on lipid parameters and achieved target levels at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. In 33% of patients, normative LDL-C levels were achieved by EAS (3 mmol / l).
A study of the response to rosuvastatin 20-40 mg in an up-titration regimen in patients with homozygous familial hypercholesterolemia has been reported. In the general population, LDL-C levels were reduced by an average of 22%.
When rosuvastatin was used in combination with fenofibrate, an additive effect was observed in reducing TG levels. When rosuvastatin was used in combination with niacin (nicotinic acid), an additive effect was observed in increasing HDL-C levels (see Precautions).
In patients aged 45-70 years with a low risk of CHD (defined as a risk according to the Framingham scale of 10% over 10 years), a mean LDL-C value of 4.0 mmol / l (154.5 mg / dl), but with subclinical atherosclerosis (defined by an increase in the thickness of the carotid artery intima-media complex - TCIMSA), who used rosuvastatin at a dose of 40 mg 1 time per day for 2 years, a significant slowdown in the progression of maximum TCIMSA at 12 points of the carotid artery was observed compared with placebo. A direct correlation between a decrease in TCIMSA and a decrease in the risk of cardiovascular disorders was not demonstrated. This study included patients with a low risk of CHD who are not representatives of the target population for the use of rosuvastatin at a dose of 40 mg. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high risk of cardiovascular disorders (see Method of administration).
It was reported that the use of rosuvastatin as a means of primary prevention of major atherosclerotic cardiovascular diseases at a dose of 20 mg once a day for 2 years in men (≥50 years) and women (≥60 years) resulted in a decrease in LDL-C concentrations by almost half compared to placebo.
Children: In patients aged 10-17 years (Tanner stage II-V, girls who started menstruating less than 1 year ago) with heterozygous familial hypercholesterolemia who received rosuvastatin 5, 10, or 20 mg/day for 12 weeks followed by a 40-week open-label dose titration period with rosuvastatin, LDL-C was reduced by 38.3%; 44.6% and 50.0%, respectively, in the rosuvastatin 5, 10, and 20 mg groups compared with 0.7% in the placebo group. At the end of the 40-week open-label dose titration period to achieve the target level (maximum dose was 20 mg once daily), 40.5% of patients achieved the target LDL-C level of 2.8 mmol/L. After 52 weeks of study treatment, no effect on growth, weight, body mass index (BMI), or puberty was observed (see Precautions). Experience in children is limited, and the long-term effects of rosuvastatin (1 year) on puberty are unknown.
Pharmacokinetics
Absorption. C max of rosuvastatin in blood plasma is reached 5 hours after oral administration. Absolute bioavailability is about 20%.
Metabolism. Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a non-proportional substrate for metabolism mediated by cytochrome P450 enzymes. The main isoenzyme involved is CYP 2C9, with 2C19, 3A4 and 2D6 playing a somewhat smaller role. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitory activity.
Excretion. About 90% of the rosuvastatin dose is excreted unchanged in the feces (together with absorbed and unabsorbed active substance), the rest is excreted in the urine. Approximately 5% is excreted in the urine unchanged. T ½ from blood plasma is about 19 hours and does not increase with increasing dose. The geometric mean value of rosuvastatin clearance from blood plasma is about 50 l / h (coefficient of variation - 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs with the participation of the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.
Linearity. Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with repeated daily administration.
Special patient groups
Age and gender: There was no clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children with heterozygous familial hypercholesterolemia were similar to those in adult volunteers.
Race. Pharmacokinetic studies have shown that in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) the median AUC and C max are approximately twice as high as in representatives of the Caucasian race; in Indians the median AUC and C max are increased by approximately 1.3 times. Population pharmacokinetic analysis did not reveal clinically significant differences between patients of the Caucasian and Negroid races.
Renal impairment. In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or its N-desmethyl metabolite were observed in subjects with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance 30 ml/min), plasma concentrations of rosuvastatin were 3 times higher, and the levels of the N-desmethyl metabolite were 9 times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.
Hepatic impairment. In a study of patients with varying degrees of hepatic impairment, no evidence of increased exposure to rosuvastatin was observed in patients with Child-Pugh scores of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. There is no experience with rosuvastatin in patients with Child-Pugh scores of more than 9.
Genetic polymorphism. The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, occurs with the participation of transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms of SLCO1B1 (OATP1B1) and / or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. Individual polymorphisms SLCO1B1 c. 521CC and ABCG2 c. 421AA are associated with increased exposure (AUC) of rosuvastatin compared with genotypes SLCO1B1 c. 521TT or ABCG2 c. 421CC. Specific genotyping is not provided in clinical practice, but patients with such polymorphisms are recommended to use a lower dose of rosuvastatin.
Children. Pharmacokinetic parameters in children with heterozygous familial hypercholesterolemia aged 10-17 years have not been fully determined. A small pharmacokinetic study of rosuvastatin (tablet form) in pediatric patients showed that the exposure of the drug in children is similar to that in adult patients. The results also indicate that no significant dose-proportional deviations are expected.
Indication
Treatment of hypercholesterolemia. Adults and children over 10 years of age with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to diet when diet and other non-pharmacological measures (e.g. exercise, weight loss) are inadequate.
In homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or when such treatment is inappropriate.
Prevention of cardiovascular events: Prevention of major cardiovascular events in patients assessed as being at high risk of a first cardiovascular event (see Pharmacological properties), in addition to correction of other risk factors.
Application
Before starting treatment, the patient should be placed on a standard hypocholesterolemic diet, which he should continue to follow during treatment. The dose should be individualized depending on the goal of therapy and the patient's response to treatment, guided by the recommendations of current generally accepted guidelines.
Treatment of hypercholesterolemia. The recommended starting dose is 5 or 10 mg orally once daily for both statin-naive patients and those transferred to rosuvastatin from another HMG-CoA reductase inhibitor. The initial dose should be based on the individual patient's cholesterol levels and the risk of future cardiovascular events, as well as the likelihood of adverse reactions. If necessary, the dose can be increased to the next level after 4 weeks (see Pharmacological properties). Given that adverse reactions are more common with 40 mg than with lower doses (see Adverse reactions), final titration to 40 mg should only be considered in patients with severe hypercholesterolemia and high risk of cardiovascular events (including patients with familial hypercholesterolemia) who have failed to achieve the treatment goal with 20 mg and who will be monitored regularly (see Precautions). At the beginning of taking the drug at a dose of 40 mg, medical supervision is recommended.
Prevention of cardiovascular disorders. In a study to reduce the risk of cardiovascular disorders, rosuvastatin was used at a dose of 20 mg/day (see Pharmacological properties).
Children. The drug should only be used in children by a specialist.
Children aged 10-17 years (boys in Tanner stage II and above and girls who have started menstruating at least a year ago). The initial daily dose for children with heterozygous familial hypercholesterolemia is 5 mg/day. The drug is usually taken orally in doses of 5-20 mg 1 time per day. The dose should be increased according to the child's individual response to treatment and tolerability of the drug, following the recommendations for the treatment of children (see Features of use). Before starting therapy with rosuvastatin, children should be prescribed a standard hypocholesterolemic diet, which patients should adhere to during treatment. The safety and efficacy of rosuvastatin in doses above 20 mg in this population have not been studied.
40 mg tablets are not prescribed to children.
Children under 10 years of age. Experience in children under 10 years of age is limited to the use of rosuvastatin in a small number of patients (aged 8-10 years) with homozygous familial hypercholesterolemia. Therefore, the drug is not recommended for use in children under 10 years of age.
Elderly patients: The recommended starting dose for patients aged 70 years and over is 5 mg (see Precautions). No other dose adjustment is required based on age.
Patients with renal impairment. No dose adjustment is required for patients with mild or moderate renal impairment. The recommended starting dose for patients with moderate renal impairment (creatinine clearance 60 ml/min) is 5 mg. The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of rosuvastatin in patients with severe renal impairment is contraindicated at any dose (see Adverse Reactions and Excipients).
Patients with hepatic impairment. In patients with hepatic impairment, who were assessed as 7 or less points on the Child-Pugh scale, an increase in systemic exposure to rosuvastatin was not observed. However, in patients with impairments of 8 and 9 points on the Child-Pugh scale, systemic exposure increased (see Pharmacological properties). In such patients, assessment of renal function is advisable (see Features of use). There is no experience with the use of rosuvastatin in patients who scored more than 9 points on the Child-Pugh scale. Rosuvastatin is contraindicated in patients with liver disease in the active phase (see Side effects).
Race: Increased systemic exposure to rosuvastatin has been observed in patients of Asian origin (see Adverse Reactions, Precautions and Excipients). The recommended starting dose for patients of Asian origin is 5 mg; the 40 mg dose is contraindicated in such patients.
Genetic polymorphisms: Certain types of genetic polymorphisms may lead to increased exposure to rosuvastatin (see Pharmacological properties). Patients with known presence of such types of polymorphisms are recommended to use a lower dose of rosuvastatin.
Patients with a predisposition to myopathy. The recommended starting dose for patients with risk factors for myopathy is 5 mg (see Precautions). The 40 mg dose is contraindicated in some of these patients (see Adverse Reactions).
Children. The drug is not prescribed to children under 10 years of age (see Side effects, use).
Contraindication
Hypersensitivity to rosuvastatin or any other component of the drug. liver disease in the active phase, including a persistent increase in plasma transaminases of unknown etiology and any increase in plasma transaminases 3 times the upper limit of normal (ULN). severe renal impairment (creatinine clearance 30 ml / min). myopathy. simultaneous use of cyclosporine. pregnancy or breastfeeding. the drug is contraindicated in women of reproductive age who do not use adequate contraception, and in children under 10 years of age. The 40 mg dose is contraindicated in patients with a predisposition to myopathy / rhabdomyolysis. such risk factors include:
moderate renal impairment (creatinine clearance 60 ml/min); hypothyroidism; personal or family history of hereditary muscle diseases; history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates; alcohol abuse; situations that may lead to an increase in the concentration of rosuvastatin in the blood plasma; belonging to the Mongoloid race;
simultaneous use of fibrates (see Features of use, Interactions and Pharmacological properties).
Side effects
Adverse reactions are classified by frequency as follows: common (≥1/100 and 1/10), uncommon (≥1/1000 and 1/100), rare (≥1/10,000 and 1/1000), very rare (1/10,000), unknown (cannot be estimated from the available data).
From the nervous system: often - headache, dizziness; very rarely - polyneuropathy, memory loss; frequency unknown - peripheral neuropathy, sleep disorders (including insomnia and nightmares).
On the part of the psyche: frequency unknown - depression.
From the digestive system: often - constipation, nausea, abdominal pain; rarely - pancreatitis; frequency unknown - diarrhea.
From the hepatobiliary system: rarely - increased levels of hepatic transaminases; very rarely - jaundice, hepatitis.
On the part of the endocrine system: often - diabetes mellitus (the frequency depends on the presence or absence of risk factors (fasting glucose level ≥5.6 mmol / l, BMI 30 kg / m 2, elevated TG levels, history of hypertension)).
From the respiratory system: frequency unknown - cough, shortness of breath.
On the part of the blood: rarely - thrombocytopenia.
On the part of the immune system: rarely - hypersensitivity reactions, including angioedema.
Skin and subcutaneous tissue disorders: infrequently - itching, rash, urticaria; frequency unknown - Stevens-Johnson syndrome.
From the musculoskeletal system: often - muscle pain; rarely - myopathy (including myositis), rhabdomyolysis; very rarely - arthralgia; frequency unknown - tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy.
From the urinary system: very rarely - hematuria.
From the reproductive system: very rarely - gynecomastia.
General disorders: often - asthenia; frequency unknown - edema.
As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions is most often dose-dependent.
Renal Effects. Proteinuria, detected by dipstick analysis, predominantly of tubular origin, has been reported in patients taking rosuvastatin. Changes in urinary protein from 0 or trace to ++ or greater were observed in 1% of patients at some time points with the 10 and 20 mg doses and in approximately 3% with the 40 mg dose. A slight increase in the frequency of changes in urinary protein from 0 or trace to + was observed with the 20 mg dose of rosuvastatin. In most cases, proteinuria decreased or disappeared spontaneously with continued therapy. To date, no causal relationship between proteinuria and acute or progressive renal disease has been established from clinical trials and post-marketing experience.
Cases of hematuria have been reported with rosuvastatin; according to clinical studies, their frequency is insignificant.
Musculoskeletal effects: Skeletal muscle disorders, such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure, have been reported with all doses of rosuvastatin, especially 20 mg.
Dose-dependent increases in CPK levels have been observed in patients taking rosuvastatin; in most cases, the phenomenon was mild, asymptomatic and transient. If CPK levels are elevated (5 × ULN), treatment should be discontinued (see Precautions).
Hepatic Effects: As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin experienced dose-related increases in transaminases; in most cases, the phenomenon was mild, asymptomatic, and transient.
Rarely, in the post-marketing period, there have been reports of cognitive impairment (e.g., memory impairment, forgetfulness, amnesia, confusion) associated with the use of statins. Such cognitive problems have been reported with all statins. The events reported are usually mild and resolve after discontinuation of statins, and the time to onset of symptoms (from 1 day to several years) and resolution of symptoms (median 3 weeks) vary.
During post-marketing use of rosuvastatin, an adverse reaction of fatal and non-fatal hepatic failure has been identified. Because this reaction was reported spontaneously from a population of uncertain size, it is not possible to reliably estimate its frequency or establish a causal relationship to rosuvastatin use.
The frequency of reports of rhabdomyolysis, serious renal and hepatic disorders (mainly increased activity of hepatic transaminases) is higher when using rosuvastatin at a dose of 40 mg.
An increase in glycosylated hemoglobin (HbA1c) levels was also observed with rosuvastatin.
Children: Elevations of CPK >10 × ULN and muscle symptoms following exercise or strenuous activity were more common in a 52-week clinical trial in children compared to adults (see Precautions). However, the safety profile of rosuvastatin in children was similar to that in adults.
Special instructions
Renal effects. Proteinuria, detected by dipstick analysis and predominantly of tubular origin, has been observed in patients treated with high doses of rosuvastatin, particularly 40 mg, and in most cases was transient or intermittent. Proteinuria was a precursor of acute or progressive renal disease (see Adverse Reactions). The frequency of reports of serious renal events in post-marketing studies of rosuvastatin is higher with the 40 mg dose. Patients taking the drug at a dose of 40 mg should have their renal function checked regularly.
Musculoskeletal effects: Musculoskeletal disorders, such as myalgia, myopathy and rarely rhabdomyolysis, have been reported in patients taking rosuvastatin at all doses, especially 20 mg. Isolated cases of rhabdomyolysis have been reported when ezetimibe was used in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded (see Interactions with other medicinal products), and therefore such a combination should be used with caution.
As with other HMG-CoA reductase inhibitors, the frequency of reports of rhabdomyolysis associated with the use of rosuvastatin in the post-marketing period is higher when using a dose of 40 mg.
CPK level. CPK level should not be measured after significant exercise or in the presence of possible alternative causes of CPK elevation that may complicate interpretation of results. If baseline CPK levels are significantly elevated (5 times the upper limit of normal), a repeat test should be performed within 5-7 days to confirm the results. If the results of the repeat test confirm that the baseline CPK value is more than 5 times the ULN, the drug should not be started.
Before starting treatment. Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution to patients with a predisposition to myopathy/rhabdomyolysis. Risk factors for this include:
renal impairment; hypothyroidism; personal or family history of hereditary muscle diseases; history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates; alcohol abuse; age 70 years; situations that may lead to increased plasma levels of rosuvastatin (see USAGE, Interactions and Pharmacological properties); concomitant use of fibrates.
In such patients, the risk of treatment should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline CPK levels are significantly elevated (5 × ULN), treatment should not be initiated.
In patients taking rosuvastatin and concomitant medications, there was no evidence of increased effects on the musculoskeletal system. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with some HMG-CoA reductase inhibitors. Therefore, the use of rosuvastatin in combination with gemfibrozil is not recommended. The benefits of further lipid changes when using rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risks associated with the use of such combinations. The 40 mg dose is contraindicated with concomitant use of fibrates (see Interactions with other drugs and Adverse reactions).
The use of rosuvastatin in combination with fusidic acid is not recommended. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination (see Interactions with other medicinal products).
Rosuvastatin should not be used in patients with acute, serious conditions that suggest myopathy or the possibility of developing renal failure as a result of rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders or uncontrolled seizures).
Hepatic Effects: As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.
It is recommended to check biochemical indicators of liver function before starting treatment and 3 months after it. Rosuvastatin should be discontinued or the dose reduced if the level of transaminases in the blood plasma is more than 3 times the upper limit of normal. The frequency of reports of serious liver events (mainly increased levels of hepatic transaminases) in the post-marketing period is higher with a dose of 40 mg.
In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying disease should be treated first before initiating therapy with rosuvastatin.
In the post-marketing period of rosuvastatin use, there have been rare reports of fatal or non-fatal cases of hepatic failure in patients taking statins, including rosuvastatin. If serious liver damage develops during treatment with rosuvastatin with clinical symptoms and / or hyperbilirubinemia or jaundice, rosuvastatin should be discontinued immediately. Unless other causes are established, treatment with rosuvastatin should not be resumed.
Race: Increased exposure is observed in patients of Mongoloid race compared to Caucasians. For such patients, dose adjustment of rosuvastatin is required (see USAGE, Contraindications, Excipients).
Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects taking rosuvastatin in combination with various protease inhibitors in combination with ritonavir. The benefit of lipid-lowering effects of rosuvastatin in HIV patients receiving protease inhibitors should be weighed against the potential for increased plasma concentrations of rosuvastatin at the start of therapy and with an increase in the dose of rosuvastatin in this group of patients. Concomitant use of rosuvastatin with protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted (see Dosage and Administration and Interactions).
Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Interstitial lung disease: Exceptional cases of interstitial lung disease have been reported with some statins, particularly with long-term treatment (see Adverse Reactions). Symptoms may include shortness of breath, non-productive cough, and general malaise (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statins should be discontinued.
Diabetes mellitus. Some evidence suggests that statins increase blood glucose levels and, in some patients at high risk of future diabetes, may cause hyperglycemia to a level requiring appropriate diabetes management. This risk, however, is outweighed by the reduced risk of vascular events with statins and should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6-6.9 mmol/L, BMI 30 kg/m2, elevated TG, hypertension) should be monitored both clinically and biochemically.
Children: Assessment of linear growth, body weight, BMI and secondary Tanner puberty characteristics in 10-17 year olds taking rosuvastatin is limited to a 1 year period. No effect on growth, body weight, BMI or puberty was reported after 52 weeks of study treatment (see Pharmacological properties). In children taking rosuvastatin for 52 weeks, an increase in CPK levels of 10 × ULN and muscle symptoms after exercise or increased physical activity were observed more often compared with those in adults (see Adverse Reactions).
Use during pregnancy or breastfeeding. Rosuvastatin is contraindicated during pregnancy or breastfeeding. Women of childbearing potential should use appropriate contraception.
Since cholesterol and other cholesterol biosynthesis products play an essential role in fetal development, the potential risk of inhibition of HMG-CoA reductase outweighs the benefits of using the drug during pregnancy. Animal data on reproductive toxicity are limited. If the patient becomes pregnant while taking this drug, treatment should be discontinued immediately.
Because another drug of this class is excreted in human milk and because HMG-CoA reductase inhibitors can cause serious adverse reactions in nursing infants, women receiving rosuvastatin should be advised not to breastfeed. Rosuvastatin is excreted in animal milk. There are no data on the excretion of rosuvastatin in human milk (see Adverse Reactions).
Ability to influence the reaction rate when driving vehicles or other mechanisms. Studies of the effect of rosuvastatin on the ability to drive a car and work with mechanisms have not been conducted. However, given the pharmacodynamic properties of rosuvastatin, it is unlikely that the drug will affect such ability. When driving vehicles or working with other mechanisms, one should take into account possible dizziness during treatment.
Interactions
Effect of concomitant medications on rosuvastatin
Transporter protein inhibitors: Rosuvastatin is a substrate for several transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with drugs that inhibit these transporters may result in increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see USAGE, Precautions, Interactions, table below).
Cyclosporine. During co-administration of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table). Rosuvastatin is contraindicated in patients receiving concomitant cyclosporine (see Adverse Reactions). Concomitant use affected the plasma concentration of cyclosporine.
Protease inhibitors. Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase exposure to rosuvastatin (see Table). For example, in a pharmacokinetic study, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an increase in AUC and C max of rosuvastatin approximately 3- and 7-fold, respectively. In a pharmacology study, co-administration of rosuvastatin and a combination product containing two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers was associated with an increase in AUC (0-24) and C max of rosuvastatin approximately 2- and 5-fold, respectively. Interactions between rosuvastatin and other protease inhibitors have not been studied. Concomitant use of rosuvastatin
