Side Effects of Crestor (rosuvastatin)

Crestor (rosuvastatin) is an HMG-CoA reductase inhibitor (a “statin”) used to reduce total blood cholesterol, HDL cholesterol, and triglyceride levels, and to increase HDL cholesterol levels. Crestor also is used to reduce the risk of heart attacks, stroke, and arterial revascularization procedures in patients without clinically evident coronary heart disease but with multiple risk factors for heart disease. Crestor reduces cholesterol levels by inhibiting HMG-CoA reductase, an enzyme that produces cholesterol in the liver. Crestor and other statins lower blood total cholesterol as well as blood LDL cholesterol levels. LDL cholesterol is the "bad" type of cholesterol that increases the risk of coronary artery disease (atherosclerosis) and heart attacks. Lowering LDL cholesterol levels slows the progression of coronary artery disease and may even reverse it. Statins also increase HDL cholesterol, the "good" type of cholesterol, and reduce triglycerides. 

Common side effects of Crestor include

• headache,
• nausea,
• vomiting,
• diarrhea,
• muscle pain, and
• memory problems. 

Serious side effects of Crestor include muscle damage or destruction (rhabdomyolysis) that can lead to acute kidney failure and liver damage.

Drug interactions of Crestor include cyclosporine, because it causes the blood level of Crestor to increase, which may increase the side effects of Crestor. Crestor increases the action of the blood thinner warfarin and could increase the risk of bleeding from warfarin. 

Antacids reduce the absorption of Crestor and should be administered two hours after Crestor. The use of Crestor with nicotinic acid, gemfibrozil, or other drugs that may cause liver or muscle injury may increase the incidence of the muscle injury. 

Statins such as Crestor should not be used by pregnant women because there is a high risk of harm to the fetus. There is no information on whether Crestor passes into breast milk. Consult your doctor before breastfeeding.

The most common side effects of rosuvastatin are:

• headache,
• nausea,
• vomiting,
• diarrhea and
• muscle pain.

Other important side effects include:

• post-marketing reports of memory loss,
• forgetfulness,
• amnesia,
• confusion, and
• memory impairment.

Symptoms may start one day to years after starting treatment and resolve within a median of three weeks after stopping the statin.

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis)
• Liver enzyme abnormalities

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

In the Crestor controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:

• myalgia
• abdominal pain
• nausea

The most commonly reported adverse reactions (incidence ≥2%) in the Crestor controlled clinical trial database of 5394 patients were:

• headache
• myalgia
• abdominal pain
• asthenia
• nausea

Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.

Table 1: Adverse Reactions¹ Reported in ≥2% of Patients Treated with Crestor and > Placebo in Placebo-Controlled Trials (% of Patients)

Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.

In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with Crestor versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea.

Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

Table 2: Adverse Reactions1 Reported in ≥2% of Patients Treated with Crestor and > Placebo in the METEOR Trial (% of Patients)

In the JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.

In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c >6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.

Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 3.

Table 3: Adverse Reactions¹ Reported in ≥2% of Patients Treated with Crestor and > Placebo in the JUPITER Trial (% of Patients)

Pediatric Patients With Heterozygous Familial Hypercholesterolemia

In a 12-week controlled study in boys and postmenarcheal girls 10 to 17 years of age with heterozygous familial hypercholesterolemia with Crestor 5 to 20 mg daily, elevations in serum creatine phosphokinase (CK) >10 x ULN were observed more frequently in rosuvastatin compared with placebo-treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK >10 x ULN, compared to 0 of 46 children on placebo.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Crestor: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy, interstitial lung disease and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Cyclosporine

Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of Crestor should not exceed 5 mg once daily.

Gemfibrozil

Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with Crestor and gemfibrozil should be avoided. If used together, the dose of Crestor should not exceed 10 mg once daily.

Protease Inhibitors

Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure and may increase risk of myopathy. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure. For these protease inhibitors, the dose of Crestor should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors.

Coumarin Anticoagulants

Crestor significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with Crestor. In patients taking coumarin anticoagulants and Crestor concomitantly, INR should be determined before starting Crestor and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Niacin

The risk of skeletal muscle effects may be enhanced when Crestor is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with Crestor.

Fenofibrate

When Crestor was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with Crestor.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing Crestor with colchicine.