Rosuvastatin

Description

Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor. The chemical name for rosuvastatin calcium, USP is bis[(E)-7-4-(4-fluorophenyl)-6-isopropyl-2­[methyl(methylsulfonyl)amino]pyrimidin-5-yl4-(4-fluorophenyl)-6-isopropyl-2­[methyl(methylsulfonyl)amino]pyrimidin-5-yl-3,5-dihydroxyhept-6-enoic acid] calcium salt. The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca, and its molecular weight is 1001.14 g/mol. Rosuvastatin calcium, USP appears as a white to almost white amorphous powder. It is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 1.4 at a pH of 7.0. Rosuvastatin tablets, USP for oral use are available in strengths of 5 mg, 10 mg, 20 mg, or 40 mg. Each tablet contains the following inactive ingredients: crospovidone, dibasic calcium phosphate dihydrate, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, red ferric oxide, triacetin, and titanium dioxide.

Uses and Indications

Rosuvastatin tablets are indicated for the reduction of the risk of major adverse cardiovascular (CV) events, including CV death, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization procedures, in adults without established coronary heart disease who are at increased risk of CV disease. This risk is determined by factors such as age, high-sensitivity C-reactive protein (hsCRP) levels of ≥2 mg/L, and the presence of at least one additional CV risk factor.

As an adjunct to diet, rosuvastatin is indicated to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia, to reduce LDL-C and slow the progression of atherosclerosis in adults, and to reduce LDL-C in pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH).

Additionally, rosuvastatin is indicated as an adjunct to other LDL-C-lowering therapies, or as monotherapy if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 7 years and older with homozygous familial hypercholesterolemia (HoFH).

Furthermore, rosuvastatin is indicated as an adjunct to diet for the treatment of adults with primary dysbetalipoproteinemia and hypertriglyceridemia.

No specific teratogenic or nonteratogenic effects have been mentioned.

Dosage and Administration

Rosuvastatin tablets are to be taken orally, with or without food, at any time of day. It is recommended to assess LDL-C levels when clinically appropriate, as early as 4 weeks after initiating therapy, and adjust the dosage if necessary.

For adults, the recommended dosage range is 5 mg to 40 mg once daily.

In pediatric patients with heterozygous familial hypercholesterolemia (HeFH), the recommended dosage is as follows:

• For patients aged 8 to less than 10 years, the dosage range is 5 mg to 10 mg once daily.

• For patients aged 10 years and older, the dosage range is 5 mg to 20 mg once daily.

For pediatric patients with homozygous familial hypercholesterolemia (HoFH), the recommended dosage is 20 mg once daily for patients aged 7 years and older.

Asian patients should initiate treatment at 5 mg once daily. If the condition is not adequately controlled, the risks and benefits of increasing the dosage to a maximum of 20 mg once daily should be considered.

Patients with severe renal impairment who are not on hemodialysis should also initiate treatment at 5 mg once daily, with a maximum dosage not to exceed 10 mg once daily.

Healthcare professionals should refer to the full prescribing information for rosuvastatin tablets for any necessary dosage and administration modifications due to drug interactions.

Contraindications

Use of this product is contraindicated in patients with acute liver failure or decompensated cirrhosis due to the potential for exacerbating liver dysfunction. Additionally, it is contraindicated in individuals with hypersensitivity to rosuvastatin or any excipients present in rosuvastatin tablets, as this may lead to severe allergic reactions.

Warnings and Precautions

Myopathy and Rhabdomyolysis The use of rosuvastatin tablets is associated with an increased risk of myopathy and rhabdomyolysis, particularly in patients aged 65 years or older, those with uncontrolled hypothyroidism, renal impairment, or those receiving concomitant therapy with certain other medications. Higher dosages of rosuvastatin may further elevate this risk. Asian patients may also be at a heightened risk for developing myopathy. It is imperative to discontinue rosuvastatin tablets if markedly elevated creatine kinase (CK) levels are observed or if myopathy is diagnosed or suspected. In cases where patients experience an acute or serious condition that places them at high risk for renal failure secondary to rhabdomyolysis, a temporary discontinuation of rosuvastatin tablets is recommended. Healthcare professionals should inform patients about the potential risks of myopathy and rhabdomyolysis when initiating or increasing the dosage of rosuvastatin tablets. Patients should be instructed to promptly report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

Immune-Mediated Necrotizing Myopathy (IMNM) Rare instances of immune-mediated necrotizing myopathy (IMNM), an autoimmune condition, have been reported in association with statin use, including rosuvastatin. If IMNM is suspected, it is crucial to discontinue rosuvastatin tablets immediately.

Hepatic Dysfunction Patients may experience increases in serum transaminases, some of which may persist. There have been rare reports of both fatal and non-fatal hepatic failure linked to the use of rosuvastatin tablets. It is advisable to conduct liver enzyme tests prior to initiating therapy and to monitor these levels as clinically indicated thereafter. Should serious hepatic injury manifest with clinical symptoms, hyperbilirubinemia, or jaundice, rosuvastatin tablets should be discontinued without delay.

Side Effects

Patients receiving rosuvastatin tablets may experience a range of adverse reactions. The most frequently reported adverse reactions include headache, nausea, myalgia, asthenia, and constipation.

Serious adverse reactions associated with rosuvastatin include myopathy and rhabdomyolysis. Risk factors for these conditions include age 65 years or older, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other medications, and higher dosages of rosuvastatin tablets. Asian patients may be at an increased risk for myopathy. It is recommended that rosuvastatin tablets be discontinued if markedly elevated creatine kinase (CK) levels occur or if myopathy is diagnosed or suspected. Additionally, in patients experiencing an acute or serious condition that places them at high risk for developing renal failure secondary to rhabdomyolysis, temporary discontinuation of rosuvastatin tablets is advised. Patients should be informed of the risks of myopathy and rhabdomyolysis when initiating or increasing the dosage of rosuvastatin tablets and should be instructed to promptly report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

Another serious adverse reaction, although rare, is immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy that has been reported with statin use. If IMNM is suspected, rosuvastatin tablets should be discontinued.

Hepatic dysfunction is also a concern, with increases in serum transaminases reported, some of which may be persistent. Rare cases of both fatal and non-fatal hepatic failure have been documented. It is advisable to test liver enzymes before initiating therapy and as clinically indicated thereafter. Should serious hepatic injury occur, characterized by clinical symptoms and/or hyperbilirubinemia or jaundice, rosuvastatin tablets should be promptly discontinued.

Additional adverse reactions of note include acute liver failure or decompensated cirrhosis, as well as hypersensitivity reactions to rosuvastatin or any excipients contained in rosuvastatin tablets.

Drug Interactions

Rosuvastatin tablets may interact with certain medications, necessitating specific administration guidelines and monitoring protocols.

Antacids To minimize the risk of interaction, rosuvastatin tablets should be administered at least 2 hours prior to the use of aluminum and magnesium hydroxide combination antacids. This timing helps ensure optimal absorption and efficacy of rosuvastatin.

Anticoagulants Prior to initiating therapy with rosuvastatin tablets, it is essential to obtain a baseline International Normalized Ratio (INR). Continuous monitoring of INR is recommended, particularly during the initiation of treatment, any dose adjustments, or upon discontinuation of rosuvastatin. This practice is crucial to maintain therapeutic effectiveness and safety in patients receiving anticoagulant therapy.

Packaging & NDC

The table below lists all NDC Code configurations of Rosuvastatin, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of rosuvastatin as an adjunct to diet for reducing LDL-C have been established in pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). This indication is supported by a 12-week controlled trial followed by a 40-week open-label extension involving 176 pediatric patients aged 10 years and older with HeFH, as well as a 2-year open-label, uncontrolled trial with 175 pediatric patients aged 8 years and older.

In a 1-year trial with a 12-week controlled phase, no detectable effects of rosuvastatin on growth, weight, body mass index (BMI), or sexual maturation were observed in patients aged 10 to 17 years.

For pediatric patients aged 7 years and older with homozygous familial hypercholesterolemia (HoFH), the safety and effectiveness of rosuvastatin as an adjunct to other LDL-C-lowering therapies have also been established. This indication is based on a randomized, placebo-controlled, cross-over study involving 14 pediatric patients aged 7 years and older with HoFH.

It is important to note that the safety and effectiveness of rosuvastatin have not been established in pediatric patients younger than 8 years of age with HeFH, younger than 7 years of age with HoFH, or in those with other types of hyperlipidemia beyond HeFH or HoFH.

Geriatric Use

In clinical studies involving rosuvastatin, 3,159 out of 10,275 patients (31%) were aged 65 years and older, with 698 patients (6.8%) being 75 years and older. Overall, no significant differences in safety or effectiveness were observed between elderly patients and their younger counterparts.

However, advanced age (≥65 years) is recognized as a risk factor for the development of rosuvastatin-associated myopathy and rhabdomyolysis. Therefore, when prescribing rosuvastatin to geriatric patients, careful consideration of dose selection is essential. It is important to acknowledge the increased likelihood of decreased hepatic, renal, or cardiac function in this population, as well as the potential for concomitant diseases or other drug therapies that may elevate the risk of adverse effects, particularly myopathy.

Healthcare providers should closely monitor elderly patients receiving rosuvastatin for signs of myopathy, given their heightened susceptibility. This vigilance is crucial to ensure patient safety and to mitigate the risk of serious complications associated with the medication.

Pregnancy

Discontinuation of rosuvastatin is recommended upon recognition of pregnancy, although consideration may be given to the ongoing therapeutic needs of the individual patient. Rosuvastatin functions by decreasing the synthesis of cholesterol and potentially other biologically active substances derived from cholesterol, which may pose a risk of fetal harm when administered to pregnant patients due to its mechanism of action.

Generally, treatment of hyperlipidemia is not deemed necessary during pregnancy, as atherosclerosis is a chronic process. The discontinuation of lipid-lowering drugs during pregnancy is unlikely to adversely affect the long-term outcomes of primary hyperlipidemia for most patients.

Available data from case series and observational cohort studies over decades of statin use in pregnant women have not identified a significant drug-associated risk of major congenital malformations. However, published data specifically regarding rosuvastatin use in pregnant women are insufficient to ascertain a drug-associated risk of miscarriage. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively.

In a Medicaid cohort linkage study involving 1,152 statin-exposed pregnant women compared to 886,996 controls, no significant teratogenic effects were observed from maternal statin use during the first trimester. The relative risk of congenital malformations in the statin-exposed group compared to the non-exposed group was calculated to be 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounding factors.

Animal reproduction studies have shown no adverse developmental effects in pregnant rats or rabbits administered rosuvastatin during the organogenesis period at doses resulting in systemic exposures equivalent to the maximum recommended human dose (MRHD) of 40 mg/day. However, in female rats, doses of 50 mg/kg/day prior to mating and through gestation day 7 resulted in decreased fetal body weight and delayed ossification. Additionally, in pregnant rats given 50 mg/kg/day from gestation day 7 through lactation day 21, decreased pup survival was noted. Pregnant rabbits receiving 3 mg/kg/day from gestation day 6 to day 18 exhibited decreased fetal viability and maternal mortality. Rosuvastatin is known to cross the placenta in both rats and rabbits, with fetal tissue and amniotic fluid concentrations reaching 3% and 20%, respectively, of maternal plasma concentration following a single oral dose.

Given these findings, healthcare professionals should weigh the potential risks and benefits of continuing rosuvastatin therapy in pregnant patients and consider alternative management strategies for hyperlipidemia during pregnancy.

Lactation

Limited data from case reports in published literature indicate that rosuvastatin is present in human milk. There is no available information on the effects of rosuvastatin on the breastfed infant or its impact on milk production. Statins, including rosuvastatin, decrease cholesterol synthesis and may also affect the synthesis of other biologically active substances derived from cholesterol, which could potentially harm the breastfed infant.

Due to the potential for serious adverse reactions in a breastfed infant, it is advised that lactating mothers refrain from breastfeeding during treatment with rosuvastatin.

Renal Impairment

Patients with renal impairment are at an increased risk for myopathy and rhabdomyolysis. It is recommended to temporarily discontinue rosuvastatin tablets in patients who are experiencing an acute or serious condition that places them at high risk of developing renal failure secondary to rhabdomyolysis. Careful monitoring and consideration of renal function are essential in this patient population to mitigate potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment may experience increases in serum transaminases, some of which may persist. There have been rare reports of both fatal and non-fatal hepatic failure associated with the use of rosuvastatin tablets.

It is recommended that liver enzyme testing be conducted prior to the initiation of therapy and as clinically indicated thereafter to monitor liver function. In the event of serious hepatic injury characterized by clinical symptoms, hyperbilirubinemia, or jaundice, rosuvastatin tablets should be promptly discontinued to mitigate potential risks associated with compromised liver function.

Overdosage

In cases of rosuvastatin overdosage, it is important to note that there are no specific antidotes available. Healthcare professionals should be aware that hemodialysis does not significantly enhance the clearance of rosuvastatin from the body.

In the event of an overdose, it is advisable to contact the Poison Help Line at 1-800-222-1222 or consult a medical toxicologist for further guidance on management strategies. Prompt communication with poison control or a toxicology expert can provide valuable recommendations tailored to the specific circumstances of the overdose.

Nonclinical Toxicology

In rat fertility studies involving oral gavage doses of 5 mg/kg/day, 15 mg/kg/day, and 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating, while females received treatment 2 weeks prior to mating and continued until gestation day 7. No adverse effects on fertility were observed at the highest dose of 50 mg/kg/day, which corresponds to systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC.

In dogs treated with rosuvastatin at a dose of 30 mg/kg/day for one month, spermatidic giant cells were noted in the testicles. Similarly, in monkeys subjected to a 6-month treatment at the same dose, spermatidic giant cells were also observed, along with vacuolation of the seminiferous tubular epithelium. The systemic exposures in dogs were 20 times and in monkeys 10 times the human exposure at 40 mg/day based on body surface area. These findings are consistent with observations made with other drugs in this class.

In a 104-week carcinogenicity study conducted in rats, doses of 2 mg/kg/day, 20 mg/kg/day, 60 mg/kg/day, or 80 mg/kg/day were administered via oral gavage. A significant increase in the incidence of uterine stromal polyps was observed in females at the highest dose of 80 mg/kg/day, which resulted in systemic exposure 20 times that of the human exposure at 40 mg/day based on AUC. No increased incidence of polyps was noted at lower doses.

A separate 107-week carcinogenicity study in mice, which received doses of 10 mg/kg/day, 60 mg/kg/day, or 200 mg/kg/day by oral gavage, revealed an increased incidence of hepatocellular adenoma/carcinoma at the highest dose of 200 mg/kg/day, corresponding to systemic exposures 20 times the human exposure at 40 mg/day based on AUC. No increased incidence of hepatocellular tumors was observed at lower doses.

Rosuvastatin was evaluated for mutagenicity and clastogenicity and was found to be non-mutagenic and non-clastogenic, both with and without metabolic activation, in the Ames test using Salmonella typhimurium and Escherichia coli, as well as in the mouse lymphoma assay and the chromosomal aberration assay in Chinese hamster lung cells. Additionally, rosuvastatin was negative in the in vivo mouse micronucleus test.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

Muscle-related issues, including myopathy characterized by muscle pain, tenderness, and weakness, have been noted. In some cases, these muscle problems can lead to serious complications, such as muscle breakdown and potential kidney damage, which may be fatal. Patients are advised to inform their healthcare provider immediately if they experience unexplained muscle pain, tenderness, or weakness, particularly if accompanied by fever or unusual fatigue. Persistent muscle issues despite discontinuation of rosuvastatin tablets may necessitate further diagnostic testing by healthcare providers.

The likelihood of developing muscle problems may be increased in individuals who are concurrently taking certain medications, are aged 65 years or older, are of Asian descent, have uncontrolled hypothyroidism, have kidney issues, or are on higher doses of rosuvastatin tablets.

Liver-related adverse events have also been reported. Healthcare providers may conduct blood tests to monitor liver function prior to initiating treatment with rosuvastatin tablets and if symptoms indicative of liver problems arise during treatment. Patients should seek immediate medical attention if they experience symptoms such as unusual fatigue, loss of appetite, upper abdominal pain, dark urine, or yellowing of the skin or eyes.

Additionally, the presence of protein and blood in urine has been associated with the use of rosuvastatin tablets. In such cases, healthcare providers may consider adjusting the dosage.

An increase in blood glucose levels has been observed in some patients taking rosuvastatin tablets.

Common side effects reported include headache, nausea, muscle aches and pains, weakness, and constipation. Patients are encouraged to communicate any bothersome or persistent side effects to their healthcare provider. For further medical advice regarding side effects, patients may contact their healthcare provider or report adverse events to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. It is important to inform patients that rosuvastatin may cause myopathy and rhabdomyolysis. They should be made aware that the risk of these conditions can increase when taking certain types of medications. Patients are encouraged to discuss all medications, including both prescription and over-the-counter drugs, with their healthcare provider. They should be instructed to promptly report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

Patients should also be informed that rosuvastatin may lead to liver enzyme elevations and potentially liver failure. They should be advised to report any symptoms such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice without delay.

Additionally, patients should be made aware that increases in HbA1c and fasting serum glucose levels may occur with the use of rosuvastatin. They are encouraged to optimize their lifestyle measures, which include regular exercise, maintaining a healthy body weight, and making healthy food choices.

For pregnant patients and those who may become pregnant, it is crucial to discuss the potential risks to a fetus. Patients should be advised to inform their healthcare provider of any known or suspected pregnancy to determine whether rosuvastatin should be discontinued.

Breastfeeding during treatment with rosuvastatin is not recommended, and patients should be informed of this.

When taking rosuvastatin in conjunction with an aluminum and magnesium hydroxide combination antacid, patients should be instructed to administer rosuvastatin tablets at least 2 hours before taking the antacid.

In the event that a dose is missed, patients should be advised not to take an extra dose but to simply resume their usual dosing schedule.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 20ºC to 25ºC (68ºF to 77ºF). Temporary excursions are permissible between 15ºC and 30ºC (59°F and 86°F). It is essential to protect the product from moisture to maintain its integrity and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Rosuvastatin as submitted by REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)