Rosuvastatin

Uses and Indications

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

As an adjunct to diet, Rosuvastatin is indicated to:

• Reduce LDL-C in adults with primary hyperlipidemia.

• Reduce LDL-C and slow the progression of atherosclerosis in adults.

• Reduce LDL-C in adults and 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 alone 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.

• Hypertriglyceridemia.

No specific teratogenic or nonteratogenic effects are mentioned in the provided information.

Dosage and Administration

Rosuvastatin is administered orally, with or without food, at any time of day. It is essential to assess LDL-C levels when clinically appropriate, as early as 4 weeks after initiating treatment, 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 up to 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 exceeding 10 mg once daily.

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

Contraindications

Use of rosuvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis. Additionally, it is contraindicated in individuals with hypersensitivity to rosuvastatin or any excipients present in rosuvastatin tablets.

Warnings and Precautions

Myopathy and Rhabdomyolysis Risk factors for myopathy and rhabdomyolysis include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher dosages of rosuvastatin tablets. Asian patients may be at an increased risk for myopathy. Rosuvastatin tablets should be discontinued if markedly elevated creatine kinase (CK) levels occur or if myopathy is diagnosed or suspected. It is advised to temporarily discontinue rosuvastatin tablets in patients experiencing an acute or serious condition that places them at high risk of developing renal failure secondary to rhabdomyolysis. Patients should be informed of the risks associated with myopathy and rhabdomyolysis when starting or increasing the dosage of rosuvastatin tablets. They should also be instructed to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

Immune-Mediated Necrotizing Myopathy (IMNM) There have been rare reports of Immune-Mediated Necrotizing Myopathy (IMNM), an autoimmune myopathy, associated with statin use. Rosuvastatin tablets should be discontinued if IMNM is suspected.

Hepatic Dysfunction Increases in serum transaminases have been observed, some of which are persistent. There have been rare reports of both fatal and non-fatal hepatic failure. It is recommended to consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury occurs, characterized by clinical symptoms and/or hyperbilirubinemia or jaundice, rosuvastatin tablets should be promptly discontinued.

Laboratory Tests Liver enzyme testing should be considered before initiating therapy and as clinically indicated thereafter.

Stop Taking and Call Your Doctor Patients should discontinue rosuvastatin tablets if markedly elevated CK levels occur or if myopathy is diagnosed or suspected. Discontinuation is also warranted if IMNM is suspected or if serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs.

Side Effects

Most frequent adverse reactions reported in patients taking rosuvastatin include:

• Headache

• Nausea

• Myalgia

• Asthenia

• Constipation

Serious adverse reactions associated with rosuvastatin include:

Myopathy and Rhabdomyolysis

• Risk factors for myopathy and rhabdomyolysis include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher doses of rosuvastatin.

• Asian patients may be at a higher risk for developing myopathy.

• Rosuvastatin should be discontinued if markedly elevated creatine kinase (CK) levels occur or if myopathy is diagnosed or suspected.

• Temporary discontinuation of rosuvastatin is advised in patients experiencing an acute or serious condition that places them at high risk of developing renal failure secondary to rhabdomyolysis.

• Patients should be informed of the risk of myopathy and rhabdomyolysis when starting or increasing the dosage of rosuvastatin.

• Patients are instructed to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

Immune-Mediated Necrotizing Myopathy (IMNM)

• Rare reports of immune-mediated necrotizing myopathy, an autoimmune condition, have been associated with statin use, including rosuvastatin.

• Discontinuation of rosuvastatin is recommended if IMNM is suspected.

Hepatic Dysfunction

• Increases in serum transaminases have been observed, with some cases being persistent.

• Rare instances of both fatal and non-fatal hepatic failure have been reported.

• Liver enzyme testing should be considered before initiating therapy and as clinically indicated thereafter.

• If serious hepatic injury occurs, characterized by clinical symptoms and/or hyperbilirubinemia or jaundice, rosuvastatin should be promptly discontinued.

Additional Adverse Reactions

• Acute liver failure or decompensated cirrhosis.

• Hypersensitivity reactions to rosuvastatin or any excipients in the formulation.

Drug Interactions

Concomitant use of rosuvastatin tablets with other drugs that increase the risk of myopathy and rhabdomyolysis should be carefully monitored. It is essential to review the details of such interactions to ensure patient safety.

To avoid interaction, rosuvastatin tablets should be administered at least 2 hours before aluminum and magnesium hydroxide combination antacids. This timing helps to minimize the potential for reduced efficacy of rosuvastatin.

Additionally, prior to initiating treatment with rosuvastatin, it is important to obtain an International Normalized Ratio (INR) if the patient is also taking warfarin. INR should be monitored frequently until it stabilizes, particularly during the initiation, dose titration, or discontinuation of rosuvastatin. This monitoring is crucial to prevent any adverse effects related to anticoagulation therapy.

Pediatric Use

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

The safety and effectiveness of rosuvastatin as an adjunct to other LDL-C-lowering therapies have been established in pediatric patients 7 years of age and older with homozygous familial hypercholesterolemia (HoFH), based on a randomized, placebo-controlled, cross-over study involving 14 pediatric patients in this age group.

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 pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH).

Geriatric Use

In clinical studies involving rosuvastatin, 31% of the 10,275 patients were aged 65 years and older, with 6.8% being 75 years and older. No significant differences in safety or effectiveness were observed between geriatric patients and younger subjects. However, advanced age (≥65 years) is identified as a risk factor for myopathy and rhabdomyolysis associated with rosuvastatin.

When prescribing rosuvastatin to elderly patients, dose selection should be approached with caution. This is due to the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, which may elevate the risk of myopathy.

Healthcare professionals are advised to closely monitor geriatric patients receiving rosuvastatin for any signs of myopathy, ensuring timely intervention if necessary.

Pregnancy

Discontinuation of rosuvastatin is recommended when pregnancy is recognized, although the ongoing therapeutic needs of the individual patient may be considered. 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.

Treatment of hyperlipidemia is generally not necessary during pregnancy, as atherosclerosis is a chronic process. The discontinuation of lipid-lowering drugs during pregnancy is unlikely to significantly impact 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 drug-associated risk of major congenital malformations. However, published data regarding rosuvastatin use in pregnant women are insufficient to determine a drug-associated risk of miscarriage.

In animal reproduction studies, no adverse developmental effects were observed 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. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2% to 4% and 15% to 20%, respectively, although the specific background risk for the indicated population remains unknown.

A Medicaid cohort linkage study involving 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal statin use during the first trimester. The relative risk of congenital malformations between the statin-exposed group and the non-exposed group in the first trimester was calculated to be 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounding factors.

In most cases, statin treatment is initiated prior to pregnancy and is typically discontinued during the first trimester upon recognition of pregnancy. Animal studies have shown that in female rats given doses of 5 mg/kg/day, 15 mg/kg/day, and 50 mg/kg/day before mating and continuing through gestation day 7, there were observed decreases in fetal body weight (female pups) and delayed ossification at the highest dose. Additionally, in pregnant rats given doses of 2 mg/kg/day, 10 mg/kg/day, and 50 mg/kg/day from gestation day 7 through lactation day 21, decreased pup survival was noted at the highest dose. In pregnant rabbits administered doses of 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day from gestation day 6 to day 18, decreased fetal viability and maternal mortality were observed at the highest dose.

Rosuvastatin is known to cross the placenta in both rats and rabbits, with concentrations found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats.

Lactation

Limited data from case reports indicate that rosuvastatin is present in human milk. However, there is no available information regarding the effects of rosuvastatin on breastfed infants or its impact on milk production. Statins, including rosuvastatin, inhibit cholesterol synthesis and may also affect the production of other biologically active substances derived from cholesterol, potentially causing harm to breastfed infants.

Due to the risk of serious adverse reactions in breastfed infants, 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 when treated with rosuvastatin. It is essential to monitor these patients closely, particularly when initiating or adjusting the dosage of rosuvastatin.

In cases where patients experience an acute or serious condition that may elevate the risk of renal failure secondary to rhabdomyolysis, it is recommended to temporarily discontinue the use of rosuvastatin tablets. Healthcare providers should inform patients about the potential risks associated with myopathy and rhabdomyolysis, ensuring they are aware of the signs and symptoms to report.

Regular assessment of renal function is advised to guide appropriate dosing and to mitigate the risk of adverse effects in this patient population.

Hepatic Impairment

In patients with hepatic impairment, increases in serum transaminases have been observed, with some cases being persistent. There have been rare reports of both fatal and non-fatal hepatic failure associated with the use of rosuvastatin.

It is recommended to test liver enzymes prior to initiating therapy and to continue monitoring them as clinically indicated thereafter. If serious hepatic injury is suspected, characterized by clinical symptoms and/or the presence of hyperbilirubinemia or jaundice, rosuvastatin should be promptly discontinued.

Overdosage

In cases of rosuvastatin overdose, it is important to note that no specific antidotes are available. Hemodialysis does not significantly enhance the clearance of rosuvastatin from the body.

In the event of an overdose, it is recommended to contact the Poison Help Line at 1-800-222-1222 or consult a medical toxicologist for further management recommendations. Monitoring of the patient may be necessary to assess for any potential symptoms or complications arising from the overdose.

Nonclinical Toxicology

Teratogenic Effects

No information regarding teratogenic effects has been provided.

Non-Teratogenic Effects

In rat fertility studies utilizing 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 were treated for 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effects on fertility were observed at the 50 mg/kg/day dose, 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 observed along with vacuolation of the seminiferous tubular epithelium. The exposures in dogs were approximately 20 times, and in monkeys, 10 times the human exposure at 40 mg/day based on body surface area. Comparable findings have been reported with other drugs in this class.

Carcinogenesis

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 80 mg/kg/day dose, which corresponds to 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.

In a separate 107-week carcinogenicity study in mice, doses of 10 mg/kg/day, 60 mg/kg/day, or 200 mg/kg/day were given by oral gavage. An increased incidence of hepatocellular adenoma/carcinoma was observed at the 200 mg/kg/day dose, with systemic exposures also 20 times the human exposure at 40 mg/day based on AUC. No increased incidence of hepatocellular tumors was detected at lower doses.

Mutagenesis

Rosuvastatin was evaluated for mutagenic and clastogenic potential and was found to be negative in several assays, including the Ames test with Salmonella typhimurium and Escherichia coli, 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.

Impairment of Fertility

No adverse effects on fertility were observed in the rat studies at the highest tested dose of 50 mg/kg/day. However, the presence of spermatidic giant cells in the testicles of dogs and monkeys suggests potential reproductive effects that warrant further investigation.

Storage and Handling

Rosuvastatin is supplied in the form of film-coated tablets.

The product should be stored at a controlled room temperature of 20ºC to 25ºC (68ºF to 77ºF). Temporary excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF). It is essential to protect the product from moisture to maintain its integrity and effectiveness.