What are the potential adverse effects of rosuvastatin (Crestor) and how are they managed?

Adverse Effects of Rosuvastatin

Rosuvastatin is generally safe and well-tolerated, with muscle-related symptoms being the most frequent adverse effect (occurring in 5-20% of real-world patients), though serious complications like rhabdomyolysis remain exceedingly rare—and the cardiovascular benefits far outweigh these risks in appropriate patients. 1

Most Common Adverse Effects

Muscle-Related Symptoms

• Myalgia (muscle pain/aches) is the most frequent presentation, typically bilateral, involving proximal muscles, with normal creatine kinase (CK) levels 1, 2
• Symptoms usually begin within weeks to months after starting therapy and resolve after discontinuation 1
• Myositis/myopathy (elevated CK with concerning symptoms or objective weakness) is rare 1
• Rhabdomyolysis (CK >10 times upper limit of normal with renal injury) is exceedingly rare and typically occurs only with multiple predisposing factors 1, 2
• Muscle breakdown can rarely cause kidney damage that can lead to death 2

Other Common Side Effects

• Headache, nausea, muscle aches and pains, weakness, and constipation are the most common side effects 2

Risk Factors for Muscle Symptoms

Your chances of getting muscle problems are higher if you: 2

• Are 65 years of age or older (especially >80 years), with women at higher risk than men 1
• Are of Asian descent (requires dose reduction to 5 mg starting dose) 2
• Have small body frame, frailty, or low body mass index 1
• Have thyroid problems (hypothyroidism) that are not controlled 2
• Have kidney problems or multisystem disease (particularly chronic renal insufficiency from diabetes) 1, 2
• Are taking higher doses of rosuvastatin 1, 2
• Are taking certain other medicines (see Drug Interactions section below) 2

Hepatic (Liver) Effects

• Transaminase elevation (>3 times upper limit of normal) is infrequent (0.5-2.0% of patients), and progression to liver failure is exceedingly rare 1
• Asymptomatic liver enzyme elevations often resolve with dose reduction or rechallenge with alternative statins 1
• Rosuvastatin can be safely used in patients with chronic, stable liver disease (including non-alcoholic fatty liver disease) after obtaining baseline measurements and establishing monitoring schedules 1
• Symptoms of liver problems include: feeling unusually tired or weak, loss of appetite, upper belly pain, dark urine, yellowing of skin or whites of eyes 2

New-Onset Diabetes Mellitus

• Rosuvastatin modestly increases the risk of developing type 2 diabetes in susceptible individuals, but this should NOT be cause for discontinuation as cardiovascular benefits far outweigh this risk 3, 1
• The absolute risk increase is small: 1.2% placebo vs 1.5% rosuvastatin over 5 years 3, 1
• For every 255 patients treated with rosuvastatin for 4 years, one additional case of diabetes occurs while simultaneously preventing 5.4 vascular events 3
• Risk factors include: BMI ≥30, fasting glucose ≥100 mg/dL, metabolic syndrome, or HbA1c ≥6% 1
• Rosuvastatin may cause an increase in blood sugar (glucose) levels 2

Renal (Kidney) Effects

• Proteinuria and blood in the urine may occur with rosuvastatin 2
• This proteinuria appears to be of tubular origin (related to inhibition of low-molecular-weight protein reabsorption by renal tubules), not relating to kidney injury 4
• If protein or blood develops in urine, your healthcare provider may decrease the rosuvastatin dose 2
• Higher doses of rosuvastatin have been associated with cases of renal failure 5

Rare but Serious Adverse Effects

Immune-Mediated Necrotizing Myopathy (IMNM)

• Rare autoimmune myopathy characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation 2
• Positive anti-HMG CoA reductase antibody 2
• May require treatment with immunosuppressive agents 2

Hypersensitivity Reactions

• Rash, pruritus, urticaria, and angioedema have been reported 2

Critical Drug Interactions

Avoid Completely

• Gemfibrozil should be avoided with rosuvastatin due to significantly increased risk of rhabdomyolysis (15 times higher than fenofibrate) 1, 2

Dose Limitations Required

• Cyclosporine: Do not exceed 5 mg once daily 2
• Teriflunomide, enasidenib, capmatinib: Do not exceed 10 mg once daily 2
• Fostamatinib, febuxostat: Do not exceed 20 mg once daily 2
• Antiviral medications (lopinavir/ritonavir, atazanavir/ritonavir, simeprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir): Initiate at 5 mg once daily, do not exceed 10 mg once daily 2
• Darolutamide: Do not exceed 5 mg once daily 2
• Regorafenib: Do not exceed 10 mg once daily 2

Use with Caution

• Colchicine may produce synergistic muscle-related toxicity through both pharmacokinetic and pharmacodynamic mechanisms 3
• Fibrates (fenofibrate is preferred over gemfibrozil if fibrate therapy is needed) 2
• Niacin or nicotinic acid 2

Monitoring Recommendations

What TO DO

• Obtain baseline liver function tests (ALT, AST) before starting rosuvastatin 1
• Evaluate muscle symptoms at baseline, 6-12 weeks after starting therapy, and at each follow-up visit 1
• Measure CK levels ONLY in patients with severe muscle symptoms or objective muscle weakness—NOT routinely 1, 2

What NOT TO DO

• DO NOT routinely measure CK or liver enzymes in asymptomatic patients—this leads to unnecessary discontinuation without improving clinical outcomes 1

Management of Adverse Effects

For Muscle Symptoms

• Tell your healthcare provider right away if you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual 2
• Temporarily discontinue rosuvastatin until symptoms resolve 1
• Evaluate other causes (hypothyroidism, vitamin D deficiency, other medications) 1
• Rechallenge with a reduced dose, alternative statin, or alternative dosing regimen (including alternate-day dosing) 1
• Use a "reassess, rediscuss, and rechallenge" approach—the majority of patients can successfully tolerate at least one statin with this strategy 1

For New-Onset Diabetes

• Continue rosuvastatin therapy if diabetes develops 1
• Emphasize lifestyle modifications: regular moderate-intensity physical activity, healthy dietary pattern, and modest weight loss 1

For Liver Enzyme Elevations

• Asymptomatic elevations often resolve with dose reduction 1
• Discontinue if symptomatic liver problems develop 2

Key Clinical Pitfalls to Avoid

• DO NOT routinely measure CK or liver enzymes in asymptomatic patients—this leads to unnecessary discontinuation 1
• DO NOT discontinue rosuvastatin if diabetes develops—continue with lifestyle modifications 1
• DO NOT attribute all muscle symptoms to rosuvastatin without evaluating other causes (hypothyroidism, vitamin D deficiency, other medications) 1
• DO NOT use coenzyme Q10 for routine prevention or treatment of muscle symptoms—it is not recommended 1
• DO NOT avoid rosuvastatin in patients with stable liver disease—it can be used safely with appropriate monitoring 1
• DO NOT combine rosuvastatin with gemfibrozil—use fenofibrate if fibrate therapy is needed 1

Special Populations

Asian Patients

• Initiate rosuvastatin at 5 mg once daily due to increased rosuvastatin plasma concentrations 2
• Consider the risks and benefits when treating Asian patients not adequately controlled at doses up to 20 mg once daily 2

Severe Renal Impairment

• In patients with severe renal impairment (CrCl <30 mL/min/1.73 m²) not on hemodialysis, the recommended starting dosage is 5 mg once daily and should not exceed 10 mg once daily 2

Elderly Patients

• Advanced age (especially >80 years) increases risk of muscle symptoms 1, 2
• Women are at higher risk than men 1