What are the common side effects of low dose Rosuvastatin (rosuvastatin calcium)?

Side Effects of Low Dose Rosuvastatin

Low-dose rosuvastatin (5-10 mg) is generally safe and well-tolerated, with muscle-related symptoms being the most common side effect, occurring in 5-20% of patients in real-world practice, though serious complications remain exceedingly rare. 1

Most Common Side 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, 2
• Myositis/myopathy (elevated CK with concerning symptoms or objective weakness) is rare 1, 2
• Rhabdomyolysis (CK >10 times upper limit of normal with renal injury) is exceedingly rare and typically occurs only with multiple predisposing factors 1, 2

Other Common Side Effects

• Headache, nausea, muscle aches and pains, weakness, and constipation are the most commonly reported side effects 3
• These side effects are mostly transient and mild 4

Risk Factors for Muscle Symptoms

Patient-Specific Risk Factors

• Advanced age (especially >80 years), with women at higher risk than men 1, 2
• Small body frame, frailty, and low body mass index 1, 2
• Asian ancestry (requires dose reduction) 1, 3
• Multisystem disease, particularly chronic renal insufficiency from diabetes 1, 2
• Uncontrolled thyroid problems (hypothyroidism) 3

Drug Interactions That Increase Risk

• CYP3A4 inhibitors, OATP1B1 inhibitors, cyclosporine, gemfibrozil, macrolide antibiotics, antifungal agents 1, 2
• Gemfibrozil should be avoided with rosuvastatin due to significantly increased risk of rhabdomyolysis (15 times higher than fenofibrate) 1
• HIV or hepatitis C virus drugs (lopinavir, ritonavir, fosamprenavir, tipranavir, atazanavir, simeprevir combinations) 3

Hepatic Side 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
• Statins 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, 2
• Warning signs of liver problems include: feeling unusually tired or weak, loss of appetite, upper belly pain, dark urine, or yellowing of skin or whites of eyes 3

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 1, 2
• Risk factors include: BMI ≥30, fasting glucose ≥100 mg/dL, metabolic syndrome, or HbA1c ≥6% 1
• The absolute risk increase is small (1.2% placebo vs 1.5% rosuvastatin over 5 years), and cardiovascular event rate reduction outweighs diabetes risk 1
• Data from JUPITER demonstrated that rosuvastatin-treated patients attaining LDL-C < 30 mg/dL had increased risk for developing new-onset diabetes compared to those with LDL-C ≥30 mg/dL 5
• Rosuvastatin tablets may cause an increase in blood sugar (glucose) levels 3

Renal Effects

• Protein and blood in the urine may occur with rosuvastatin 3
• If protein or blood develops in urine, the healthcare provider may decrease the dose of rosuvastatin 3
• The incidence of proteinuria or microscopic hematuria with rosuvastatin 10 or 20 mg/day was <1%; these events were mostly transient and not associated with acute or progressive deterioration in renal function at recommended dosages 4

Ocular Effects

• In the HOPE-3 trial, individuals in the 10-mg rosuvastatin per day group had a statistically significant greater number of cataract surgeries than in the placebo group 5
• However, other sub-studies in patients with very low LDL-C did not find any significant correlation between very low LDL-C and cataract development 5

Monitoring Recommendations

What TO DO:

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

What NOT TO DO:

• Routine monitoring of CK and liver enzymes in asymptomatic patients is NOT recommended as it leads to unnecessary discontinuation without improving clinical outcomes 1, 2

Management of Side Effects

Stepwise Approach:

• Use a "reassess, rediscuss, and rechallenge" approach—the majority of patients can successfully tolerate at least one statin with this strategy 1, 2
• Temporarily discontinue rosuvastatin until symptoms resolve 1
• Rechallenge with a reduced dose, alternative statin, or alternative dosing regimen (including alternate-day dosing) 1, 2
• Consider combination therapy with ezetimibe and low-dose statin for patients who cannot tolerate standard doses 2

Critical Clinical Pitfalls to Avoid

• DO NOT routinely measure CK or liver enzymes in asymptomatic patients—this leads to unnecessary discontinuation 1, 2
• DO NOT discontinue rosuvastatin if diabetes develops—continue with lifestyle modifications 1, 2
• DO NOT attribute all muscle symptoms to rosuvastatin without evaluating other causes (hypothyroidism, vitamin D deficiency, other medications) 1, 2
• DO NOT use coenzyme Q10 for routine prevention or treatment of muscle symptoms—it is not recommended 1, 2
• DO NOT avoid rosuvastatin in patients with stable liver disease—it can be used safely with appropriate monitoring 1, 2
• DO NOT combine rosuvastatin with gemfibrozil—use fenofibrate if fibrate therapy is needed 1

Safety Profile Compared to Other Statins

• Very few patients experienced elevations in serum CPK levels of over 10-fold the upper limit of normal (0.2-0.4% of patients) or treatment-related myopathy (≤0.1%) at dosages of 5-40 mg/day 4
• In clinical trials of more than 10,000 patients (exceeding the number evaluated before the launch of any other statin), rosuvastatin demonstrates a safety profile similar to that of other marketed statins with regard to muscle, renal, and hepatic toxicity 6
• Both rosuvastatin 10 mg and atorvastatin 20 mg were well tolerated, with a similar incidence of adverse events (rosuvastatin 10 mg, 27.5%; atorvastatin 20 mg, 26.1%) 7
• No cases of rhabdomyolysis, liver, or renal insufficiency were recorded in the PULSAR trial comparing rosuvastatin 10 mg to atorvastatin 20 mg 7

Special Considerations for Low Doses

• At low doses (5-10 mg), rosuvastatin produces mean reductions in plasma LDL cholesterol of 39-45% 5
• The safety profile at these lower doses is particularly favorable, with the risk of serious adverse events being extremely low 4, 6
• Rosuvastatin has a low potential for cytochrome P450 drug interactions due to minimal metabolism by CYP3A4 4, 8